The differential effects of bisphosphonates, SERMS (selective estrogen receptor modulators), and parathyroid hormone on bone remodeling in osteoporosis

Osteoporosis is a skeletal metabolic disease characterized by a compromised bone fragility, leading to an increased risk of developing spontaneous and traumatic fractures. Osteoporosis is considered a multifactorial disease and fractures are the results of several different risk factors both extra- and intraskeletal. Thus bone fragility can be the end point of several different causes: a) failure to reach an optimal peak bone mass during growth; b) excessive bone resorption resulting in decreased bone mass and microarchitectural deterioration; c) inadequate formation upon an increased resorption during the process of bone remodeling. The pharmacological therapeutical options, available to date, are directed on prevention of fractures. The aim of this paper is to describe the activities and the mechanisms of action, as known at present, of the most used therapies for osteoporosis and their clinical implications. Improvement of knowledge in this field will allow us to further improve therapeutical choices and pharmacological interventions

Management of glucocorticoids-induced osteoporosis: role of teriparatide

Glucocorticoids (GC)-induced osteoporosis (GIOP) is the most common cause of secondary osteoporosis, which leads to an increased fracture risk in patients. The normal bone turnover depends on a balance between osteoblasts and osteoclasts activity and GC can cause a rapid bone loss, decreasing bone formation and increasing bone resorption. The decreased bone formation is mainly due to the GC-induced apoptosis of both osteoblasts and osteocytes, while the increased bone resorption is due to the increased life-span of pre-existing osteoclasts. Bisphosphonates are clearly effective in preventing and treating GIOP but anabolic therapeutic strategies are the new promising therapeutic alternative. Experimental and clinical studies indicate that teriparatide, the active (1–34) parathyroid hormone (PTH) molecule, is efficacious for the treatment of GIOP, being able to induce an increase in bone mass in these patients. Intermittent administration of human PTH (1–34) stimulates bone formation by increasing osteoblast number. Additionally, human PTH (1–34) modulates the level and/or activity of locally produced growth factors and cytokines. Teriparatide has been demonstrated in several clinical studies to significantly decrease the incidence of fractures in patients affected by GIOP. It has recently received an indication for GIOP and its label indication has also been expanded

Cosmic chronometers to calibrate the ladders and measure the curvature of the Universe. A model-independent study

We use the state-of-the-art data on cosmic chronometers (CCH) and the Pantheon+ compilation of supernovae of Type Ia (SNIa) to test the constancy of the SNIa absolute magnitude, $M$, and the robustness of the cosmological principle (CP) at $z\lesssim 2$ with a model-agnostic approach. We do so by reconstructing $M(z)$ and the curvature parameter $\Omega_{k}(z)$ using Gaussian Processes. Moreover, we use CCH in combination with radial and angular data on baryon acoustic oscillations (BAO) from various galaxy surveys (6dFGS, BOSS, eBOSS, WiggleZ, DES Y3) to measure the sound horizon at the baryon-drag epoch, $r_d$, from each BAO data point and check their consistency. Given the precision allowed by the CCH data, we find that $M(z)$, $\Omega_k(z)$ and $r_d(z)$ are fully compatible (at $<68\%$ C.L.) with constant values. This justifies our final analyses, in which we put constraints on these constant parameters under the validity of the CP, the metric description of gravity and standard physics in the vicinity of the stellar objects, but otherwise in a model-independent way. If we exclude the SNIa contained in the host galaxies employed by SH0ES, our results read $M=(-19.314^{+0.086}_{-0.108})$ mag, $r_d=(142.3\pm 5.3)$ Mpc and $\Omega_k=-0.07^{+0.12}_{-0.15}$ ($68\%$ C.L.). These values have been obtained without using any information from the main data sets involved in the $H_0$ tension, namely, the cosmic microwave background and the first two rungs of the cosmic distance ladder. If, instead, we also consider the SNIa in the host galaxies, calibrated with Cepheids, we measure $M=(-19.252^{+0.024}_{-0.036})$ mag, $r_d=(141.9^{+5.6}_{-4.9})$ Mpc and $\Omega_k=-0.10^{+0.12}_{-0.15}$.Comment: 17 pages, 10 figures, 5 table

Late-time phenomenology required to solve the H0H_0 tension in view of the cosmic ladders and the anisotropic and angular BAO data sets

The $\sim 5\sigma$ mismatch between the value of the Hubble parameter measured by SH0ES and the one inferred from the inverse distance ladder (IDL) constitutes the biggest tension afflicting the standard model of cosmology, which could be pointing to the need of physics beyond $\Lambda$CDM. In this paper we study the background history required to solve the $H_0$ tension if we consider standard prerecombination physics, paying special attention to the role played by the data on baryon acoustic oscillations (BAO) employed to build the IDL. We show that the anisotropic BAO data favor an ultra-late-time (phantom-like) enhancement of $H(z)$ at $z\lesssim 0.2$ to solve the tension, accompanied by a transition in the absolute magnitude of supernovae of Type Ia $M(z)$ in the same redshift range. The effective dark energy (DE) density must be smaller than in the standard model at higher redshifts. Instead, when angular BAO data (claimed to be less subject to model dependencies) is employed in the analysis, we find that the increase of $H(z)$ starts at much higher redshifts, typically in the range $z\sim 0.6-0.9$. In this case, $M(z)$ could experience also a transition (although much smoother) and the effective DE density becomes negative at $z\gtrsim 2$. Both scenarios require a violation of the weak energy condition (WEC), but leave an imprint on completely different redshift ranges and might also have a different impact on the perturbed observables. They allow for the effective crossing of the phantom divide. Finally, we employ two alternative methods to show that current data from cosmic chronometers do not exclude the violation of the WEC, but do not add any strong evidence in its favor neither. Our work puts the accent on the utmost importance of the choice of the BAO data set in the study of the possible solutions to the $H_0$ tension.Comment: 20 pages, 13 figures, 3 table

DEMNUni: cross-correlating the nonlinear ISWRS effect with CMB-lensing and galaxies in the presence of massive neutrinos

We present a novel analytical approach to study the cross-correlations between the Integrated Sachs Wolfe--Rees Sciama (ISWRS) effects and large-scale structure tracers in the presence of massive neutrinos. Our method has been validated against large N-body simulations with a massive neutrino particle component, namely the DEMNUni suite. We investigate the impact of different neutrino masses on the cross-correlations between ISWRS and both Cosmic Microwave Background (CMB) lensing and galaxies. We show that the position of the sign inversion due to nonlinear effects is strongly related to the neutrino mass. While such nonlinear cross-correlation signals may not be able alone to constrain the neutrino mass, our approach paves the way for future studies to detect the amplitude of these cross-spectra on small scales, and to explore the combined impact of dark energy and neutrino mass from future galaxy surveys and CMB experiments.Comment: 31 pages , 15 fig

Updated constraints on amplitude and tilt of the tensor primordial spectrum

We have taken a comprehensive approach to update the limits on the tensor-to-scalar ratio ($r$) and the tensor spectral index ($n_t$), using 10 datasets from the BICEP/Keck Array 2015 and 2018, Planck releases 3 and 4, and LIGO-Virgo-KAGRA Collaboration. By fitting the complete $\Lambda$CDM+$r$+$n_t$ model with two different approaches for the tensor sector, we have not only established which method is the most reliable, but have also achieved the strongest constraint on the tensor-to-scalar ratio in current literature: $r<0.028$ and $-1.37 < n_t < 0.42$ at 95% confidence level. Furthermore, our examination of the common signal detected by the NANOGrav Collaboration further confirms that a simple power-law cannot reconcile the constraints from different datasets if the NANOGrav detection is due to a primordial inflationary gravitational wave background, as previously shown in the literature.Comment: Version coherent with published one. Added new analysis in section 2.4. Added new section 5.1. Added appendix B. Conclusions unchange

Androgen-stimulated DNA synthesis and cytoskeletal changes in fibroblasts by a nontranscriptional receptor action

In NIH3T3 cells, 0.001 nM of the synthetic androgen R1881 induces and stimulates association of androgen receptor (AR) with Src and phosphatidylinositol 3-kinase (Pl3-kinase), respectively, thereby triggering S-phase entry. 10 nM R1881 stimulates Rac activity and membrane ruffling in the absence of the receptor–Src–PI3-kinase complex assembly. The antiandrogen Casodex and specific inhibitors of Src and PI3-kinase prevent both hormonal effects, DNA synthesis and cytoskeletal changes. Neither low nor high R1881 concentration allows receptor nuclear translocation and receptor-dependent transcriptional activity in fibroblasts, although they harbor the classical murine AR. The very low amount of AR in NIH3T3 cells (7% of that present in LNCaP cells) activates the signaling pathways, but apparently is not sufficient to stimulate gene transcription. This view is supported by the appearance of receptor nuclear translocation as well as receptor-mediated transcriptional activity after overexpression of AR in fibroblasts. In addition, AR-negative Cos cells transiently transfected with a very low amount of hAR cDNA respond to low and high R1881 concentrations with signaling activation. Interestingly, they do not show significant transcriptional activation under the same experimental conditions. Fibroblasts are the first example of cells that respond to steroid hormones with activation of signaling pathways in the absence of endogenous receptor transcriptional activity. The data reported also show that hormone concentration can be crucial in determining the type of cell responsiveness

Using CMB data to constrain non-isotropic Planck-scale modifications to Electrodynamics

We develop a method to constrain non-isotropic features of Cosmic Microwave Background (CMB) polarization, of a type expected to arise in some models describing quantum gravity effects on light propagation. We describe the expected signatures of this kind of anomalous light propagation on CMB photons, showing that it will produce a non-isotropic birefringence effect, i.e. a rotation of the CMB polarization direction whose observed amount depends in a peculiar way on the observation direction. We also show that the sensitivity levels expected for CMB polarization studies by the \emph{Planck} satellite are sufficient for testing these effects if, as assumed in the quantum-gravity literature, their magnitude is set by the minute Planck length.Comment: 18 pages, 4 figures, 2 table

Glucose Metabolic Reprogramming of ER Breast Cancer in Acquired Resistance to the CDK4/6 Inhibitor Palbociclib

The majority of breast cancers express the estrogen receptor (ER) and are dependent on estrogen for their growth and survival. Endocrine therapy (ET) is the standard of care for these tumors. However, a superior outcome is achieved in a subset of ER positive (ER+)/human epidermal growth factor receptor 2 negative (HER2&minus;) metastatic breast cancer patients when ET is administrated in combination with a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor, such as palbociclib. Moreover, CDK4/6 inhibitors are currently being tested in ER+/HER2+ breast cancer and reported encouraging results. Despite the clinical advances of a combinatorial therapy using ET plus CDK4/6 inhibitors, potential limitations (i.e., resistance) could emerge and the metabolic adaptations underlying such resistance warrant further elucidation. Here we investigate the glucose-dependent catabolism in a series of isogenic ER+ breast cancer cell lines sensitive to palbociclib and in their derivatives with acquired resistance to the drug. Importantly, ER+/HER2&minus; and ER+/HER2+ cell lines show a different degree of glucose dependency. While ER+/HER2&minus; breast cancer cells are characterized by enhanced aerobic glycolysis at the time of palbociclib sensitivity, ER+/HER2+ cells enhance their glycolytic catabolism at resistance. This metabolic phenotype was shown to have prognostic value and was targeted with multiple approaches offering a series of potential scenarios that could be of clinical relevance