Nitrogen Containing Bisphosphonates Impair the Release of Bone Homeostasis Mediators and Matrix Production by Human Primary Pre-Osteoblasts

Bisphosphonates (BPs) represent the first-line treatment for a wide array of bone disorders. Despite their well-known action on osteoclasts, the effects they induce on osteoblasts are still unclear. In order to shed light on this aspect we evaluated the impact of two nitrogen containing bisphosphonates, Alendronate (ALN) and Zoledronate (ZOL), on human primary pre-osteoblasts. At first, we showed an inhibitory effect on cell viability and alkaline phosphatase activity starting from \u3bcM concentrations of both drugs. In addition, an inhibitory trend on mineralized nodules deposition was observed. Then low doses of both ALN and ZOL rapidly increased the release of the pro-inflammatory mediators TNF\u3b1 and IL-1\u3b2, while increased DKK-1 and Sclerostin, both inhibitors of osteoblastogenesis. Finally, ALN and 10-7M ZOL decreased the expression of type I Collagen and Osteopontin, while both drugs slightly stimulated SPARC production. With these results, we would like to suggest a direct inhibitory action on bone-forming cells by nitrogen containing bisphosphonates

Star clusters near and far; tracing star formation across cosmic time

© 2020 Springer-Verlag. The final publication is available at Springer via https://doi.org/10.1007/s11214-020-00690-x.Star clusters are fundamental units of stellar feedback and unique tracers of their host galactic properties. In this review, we will first focus on their constituents, i.e.\ detailed insight into their stellar populations and their surrounding ionised, warm, neutral, and molecular gas. We, then, move beyond the Local Group to review star cluster populations at various evolutionary stages, and in diverse galactic environmental conditions accessible in the local Universe. At high redshift, where conditions for cluster formation and evolution are more extreme, we are only able to observe the integrated light of a handful of objects that we believe will become globular clusters. We therefore discuss how numerical and analytical methods, informed by the observed properties of cluster populations in the local Universe, are used to develop sophisticated simulations potentially capable of disentangling the genetic map of galaxy formation and assembly that is carried by globular cluster populations.Peer reviewedFinal Accepted Versio

THE RATE OF BINARY BLACK HOLE MERGERS INFERRED FROM ADVANCED LIGO OBSERVATIONS SURROUNDING GW150914

A transient gravitational-wave signal, GW150914, was identi fi ed in the twin Advanced LIGO detectors on 2015 September 2015 at 09:50:45 UTC. To asse ss the implications of this discovery, the detectors remained in operation with unchanged con fi gurations over a period of 39 days around the time of t he signal. At the detection statistic threshold corresponding to that observed for GW150914, our search of the 16 days of simultaneous two-detector observational data is estimated to have a false-alarm rate ( FAR ) of < ́ -- 4.9 10 yr 61 , yielding a p -value for GW150914 of < ́ - 210 7 . Parameter estimation follo w-up on this trigger identi fi es its source as a binary black hole ( BBH ) merger with component masses ( )( ) = - + - + mm M ,36,29 12 4 5 4 4 at redshift = - + z 0.09 0.04 0.03 ( median and 90% credible range ) . Here, we report on the constraints these observations place on the rate of BBH coalescences. Considering only GW150914, assuming that all BBHs in the universe have the same masses and spins as this event, imposing a search FAR threshold of 1 per 100 years, and assuming that the BBH merger rate is constant in the comoving frame, we infer a 90% credible range of merger rates between – -- 2 53 Gpc yr 31 ( comoving frame ) . Incorporating all search triggers that pass a much lower threshold while accounting for the uncerta inty in the astrophysical origin of each trigger, we estimate a higher rate, ranging from – -- 13 600 Gpc yr 31 depending on assumptions about the BBH mass distribution. All together, our various rate estimat es fall in the conservative range – -- 2 600 Gpc yr 31

Human Adipose-derived Stromal Cell secretome beneficial potential in contrasting osteoarthritis

OBJECTIVE: Adipose-derived Stromal Cells (ASCs) possess a strong anti-inflammatory potential, which is mediated by a wide array of released bioactive factors. The use of conditioned medium (CM) instead of cells presents substantial advantages especially in terms of handling and safety. The purpose of this study is to investigate the potential of hASC secretome in contrasting osteoarthritis (OA), an inflammatory disease characterized by hypertrophic differentiation of chondrocytes (CHs) and extracellular-matrix-degrading proteases production. MATERIALS AND METHODS: CM was collected from hASCs derived from subcutaneous adipose tissue, cultured for 72 hours in starving conditions. The CM was then concentrated trough Amicon Ultra-15 Centrifugal Filter Unit (Merck-Millipore) of about 46\ub110-folds (n=26). Hypertrophy was induced in vitro in human primary articular chondrocytes with 10ng/ml TNF\u3b1. CM (ratio 5:1, hASCs:hCHs) effect on cell proliferation (up to 9 days) was assessed by AlamarBlue. Gene and protein expression of MMPs and other hypertrophic markers were evaluated (24 and 72 hours) by RT-PCR, Western blot and multiplex immunoassay. RESULTS: hCH proliferation was prompted (+40%) by a 9-day-treatment with 10 ng/ml TNF\u3b1, suggesting the induction of a hypertrophic growth status. Despite the lack of CM effect on CH proliferation, the conditioned medium treatment reverted the TNF\u3b1\u2013induced significant increase in MMP3 and MMP13 expression (-50% and -30%, respectively), after 24 hours. The reduction in MMP13 protein expression was also evident after both 24 and 72 hours. Moreover, hASC conditioned medium inhibited TNF\u3b1-mediated osteocalcin release. The effect of CM on other OA and hypertrophic markers, in TNF\u3b1-inflamed CHs, is currently under investigation. CONCLUSION: Our data reinforce the idea that ASC secretome might be considered a promising source of factors for future therapeutic applications in the OA treatment. The analysis of CM sub-components (EVs and soluble factors) and the comparison of ASC secretome with CM from cells lacking this therapeutic potential, might allow us to reveal the factors responsible for secretome beneficial action

Effect of granulocytic chalone on the growth rate of continuous cell lines propagated in vitro : a new assay system

The progress of research on granulocytic chalone has been hampered by a lack of reliable assay systems. This paper reports the use of continuous cell lines growing in liquid suspension culture as a new method for assessing the effect of granulocytic chalone on cell proliferation. Partially purified granulocytic chalone (PPGC) was added to cultures of a rat myeloid cell line (W25), a human myeloid cell line (HL60), a human B lymphocytic cell line (8392), and a human T lymphocytic cell line (8402). The growth rate of the target cell populations was directly assessed by serial cell counts. PPGC pretreatment resulted in a significant inhibition of cell proliferation of the 2 myeloid permanent cell lines, while the growth rate of the lymphocytic cell lines was not affected. Moreover, inhibition of cell proliferation was spontaneously reversed when PPGC treatment was discontinued. Since PPGC from ox leucocytes displayed an inhibitory effect on cell proliferation which was specific to the myeloid cells, spontaneously reversible and not species-specific, it appears to have all the essential properties of a granulocytic chalone

Nitrogen Containing Bisphosphonates Impair the Release of Bone Homeostasis Mediators and Matrix Production by Human Primary Pre-Osteoblasts

Bisphosphonates (BPs) represent the first-line treatment for a wide array of bone disorders. Despite their well-known action on osteoclasts, the effects they induce on osteoblasts are still unclear. In order to shed light on this aspect we evaluated the impact of two nitrogen containing bisphosphonates, Alendronate (ALN) and Zoledronate (ZOL), on human primary pre-osteoblasts. At first, we showed an inhibitory effect on cell viability and alkaline phosphatase activity starting from mu M concentrations of both drugs. In addition, an inhibitory trend on mineralized nodules deposition was observed. Then low doses of both ALN and ZOL rapidly increased the release of the pro-inflammatory mediators TNF alpha and IL-1 beta, while increased DKK-1 and Sclerostin, both inhibitors of osteoblastogenesis. Finally, ALN and 10(-7)M ZOL decreased the expression of type I Collagen and Osteopontin, while both drugs slightly stimulated SPARC production. With these results, we would like to suggest a direct inhibitory action on bone-forming cells by nitrogen containing bisphosphonates

Heterogeneous pattern of chromosomal breakpoints involving the MYC locus in multiple myeloma

Chromosomal rearrangements of the MYC locus, which often involve the IG loci, are recurrent events in multiple myeloma (MM) and plasma cell leukemia (PCL). We used dual-color fluorescence in situ hybridization (FISH) to characterize the breakpoint locations of chromosomal translocations/rearrangements involving the MYC locus at 8q24 found in a panel of 14 MM cell lines and 70 primary tumors (66 MM and 4 PCL). MYC locus alterations were observed in 21 cases: MYCIIG (mainly IGH@) fusions in II cell lines and three patients (2 MM and 1 PCL), and extra signals and/or abnormal MYC localizations in seven patients (5 MM and 2 PCL). Fourteen of these cases were investigated by FISH analyses by use of a panel of BAC clones covering about 6 Mb encompassing the MYC locus. The breakpoints were localized in a region 100-250 kb centromeric to MYC in four cases, a region 500-800 kb telomeric to the gene in four cases, and regions 652 Mb centromeric or telomeric to MYC in five cases. Two different breakpoints were detected in the KMS-18 cell line, whereas the insertion of a MYC allele was found in a complex t(16;22) chromosomal translocation in the RPM18226 cell line. Our data document a relatively high dispersion of 8q24 breakpoints in MM