Targeting subchondral bone mesenchymal stem cell activities for intrinsic joint repair in osteoarthritis

Osteoarthritis (OA) is a common age-related disease with complex pathophysiology. It is characterized by wide-ranging tissue damage and ultimate biomechanical failure of the whole joint. However, signs of tissue adaptation and attempted repair responses are evident in OA-affected osteochondral tissues. Highlighted in this review article is the role of bone-resident mesenchymal stem cells (MSCs) in these bone remodeling responses, and a proposal that targeting MSC activities in OA subchondral bone could represent a novel approach for intrinsic joint regeneration in OA. The development of these therapies will require better understanding of MSC proliferation, migration and differentiation patterns in relation to OA tissue damage and further clarification of the molecular signaling events in these MSCs during disease progression

Editorial: Extracellular vesicles as modulators of cancer cell adaptive responses linked to therapy resistance

No abstract availabl

INFN What Next: Ultra-relativistic Heavy-Ion Collisions

This document was prepared by the community that is active in Italy, within INFN (Istituto Nazionale di Fisica Nucleare), in the field of ultra-relativistic heavy-ion collisions. The experimental study of the phase diagram of strongly-interacting matter and of the Quark-Gluon Plasma (QGP) deconfined state will proceed, in the next 10-15 years, along two directions: the high-energy regime at RHIC and at the LHC, and the low-energy regime at FAIR, NICA, SPS and RHIC. The Italian community is strongly involved in the present and future programme of the ALICE experiment, the upgrade of which will open, in the 2020s, a new phase of high-precision characterisation of the QGP properties at the LHC. As a complement of this main activity, there is a growing interest in a possible future experiment at the SPS, which would target the search for the onset of deconfinement using dimuon measurements. On a longer timescale, the community looks with interest at the ongoing studies and discussions on a possible fixed-target programme using the LHC ion beams and on the Future Circular Collider.Comment: 99 pages, 56 figure

Phosphorylated c-Src in the nucleus is associated with improved patient outcome in ER-positive breast cancer

Elevated c-Src protein expression has been shown in breast cancer and <i>in vitro</i> evidence suggests a role in endocrine resistance. To investigate whether c-Src is involved in endocrine resistance, we examined the expression of both total and activated c-Src in human breast cancer specimens from a cohort of oestrogen receptor (ER)-positive tamoxifen-treated breast cancer patients. Tissue microarray technology was employed to analyse 262 tumour specimens taken before tamoxifen treatment. Immunohistochemistry using total c-Src and activated c-Src antibodies was performed. Kaplan–Meier survival curves were constructed and log-rank test were performed. High level of nuclear activated Src was significantly associated with improved overall survival (<i>P</i>=0.047) and lower recurrence rates on tamoxifen (<i>P</i>=0.02). Improved patient outcome was only seen with activated Src in the nucleus. Nuclear activated Src expression was significantly associated with node-negative disease and a lower NPI (<i>P</i><0.05). On subgroup analysis, only ER-positive/progesterone receptor (PgR)-positive tumours were associated with improved survival (<i>P</i>=0.004). This shows that c-Src activity is increased in breast cancer and that activated Src within the nucleus of ER-positive tumours predicts an improved outcome. In ER/PgR-positive disease, activated Src kinase does not appear to be involved in <i>de novo</i> endocrine resistance. Further study is required in ER-negative breast cancer as this may represent a cohort in which it is associated with poor outcome

Lipocalin 2 Influences Bone and Muscle Phenotype in the MDX Mouse Model of Duchenne Muscular Dystrophy

Lipocalin 2 (Lcn2) is an adipokine involved in bone and energy metabolism. Its serum levels correlate with bone mechanical unloading and inflammation, two conditions representing hallmarks of Duchenne Muscular Dystrophy (DMD). Therefore, we investigated the role of Lcn2 in bone loss induced by muscle failure in the MDX mouse model of DMD. We found increased Lcn2 serum levels in MDX mice at 1, 3, 6, and 12 months of age. Consistently, Lcn2 mRNA was higher in MDX versus WT muscles. Immunohistochemistry showed Lcn2 expression in mononuclear cells between muscle fibres and in muscle fibres, thus confirming the gene expression results. We then ablated Lcn2 in MDX mice, breeding them with Lcn2−/− mice (MDXxLcn2−/− ), resulting in a higher percentage of trabecular volume/total tissue volume compared to MDX mice, likely due to reduced bone resorption. Moreover, MDXxLcn2−/− mice presented with higher grip strength, increased intact muscle fibres, and reduced serum creatine kinase levels compared to MDX. Consistently, blocking Lcn2 by treating 2-month-old MDX mice with an anti-Lcn2 monoclonal antibody (Lcn2Ab) increased trabecular volume, while reducing osteoclast surface/bone surface compared to MDX mice treated with irrelevant IgG. Grip force was also increased, and diaphragm fibrosis was reduced by the Lcn2Ab. These results suggest that Lcn2 could be a possible therapeutic target to treat DMD-induced bone loss

Individualized Whole-Body Vibration: Neuromuscular, Biochemical, Muscle Damage and Inflammatory Acute Responses

Objective. We aimed to investigate the acute residual hormonal, biochemical, and neuromuscular responses to a single session of individualized whole-body vibration (WBV) while maintaining a half-squat position. Methods. Twenty male sport science students voluntarily participated in the present study and were randomly assigned to an individualized WBV group (with the acceleration load determined for each participant) or an isometric group (ISOM). A double-blind, controlled parallel study design with repeated measures was employed. Results. Testosterone and growth hormone increased significantly over time in the WBV group (P <.05 and P <.01, respectively; effect size [ES] ranged from 1.00 to 1.23), whereas cortisol increased over time in both groups (P <.01; ES ranged from 1.04 and 1.36). Interleukin-6 and creatine kinase increased significantly over time only in the WBV group (P <.05; ES = 1.07). The maximal voluntary contraction decreased significantly over time in the ISOM group (P =.019; ES = 0.42), whereas in the WBV group, the decrease did not reach a significant level (P =.05). The ratio of electromyographic activity and power decreased significantly over time in the WBV group (P <.01; ES ranged from 0.57 to 0.72). Conclusion. Individualized WBV increased serum hormonal concentrations, muscle damage, and inflammation to levels similar to those induced by resistance training and hypertrophy exercises

Prioritization Patterns of Nurses in the Management of a Patient With Delirium: Results of a Q-Methodology Study

Nurses are required to decide on priorities; however, how they prioritize the interventions toward patients with delirium is still unclear. Therefore, expanding the knowledge on (a) how nurses prioritize interventions to manage episodes of delirium and (b) the underlying prioritization patterns were the aims of this study. The Q-methodology was applied in 2021. A systematic review to identify the recommended interventions for patients with delirium was performed, and a nominal group technique was used to select those interventions that are applicable in daily practice (35 out of 96 identified). Then, using a specific scenario, 56 clinical nurses working in hospital medical (n = 31), geriatric (n = 15), and postacute (n = 10) units were asked to order the 35 interventions (from -4 the lowest to +4 the highest priority) using a Q-sort table. Averages (confidence interval at 95%) were calculated at the group level, and a by-person factor analysis was applied to discover underlying patterns of prioritization at the overall and at the individual levels. At the group level, "Ensuring a safe environment (e.g., reducing bed height)" was ranked as the highest priority (2.29 out of four); at the individual level, three prioritization patterns accounting for a total variance of 50.21% have emerged: "Individual needs-oriented" (33.82% variance explained; 41 nurses); "Prevention-oriented" (8.47%; five nurses); and "Cognitive-oriented" (7.92%; six nurses). At the group level, nurses prioritize safety while caring for patients with delirium; however, at the individual level, they follow three different patterns of prioritization oriented toward diverse aspects, suggesting uncertainty in the actions to be taken-with potential implications for patients

Notch2 pathway mediates breast cancer cellular dormancy and mobilisation in bone and contributes to haematopoietic stem cell mimicry

BACKGROUND: Recurrence after >5-year disease-free survival affects one-fifth of breast cancer patients and is the clinical manifestation of cancer cell reactivation after persistent dormancy.METHODS: We investigated cellular dormancy in vitro and in vivo using breast cancer cell lines and cell and molecular biology techniques.RESULTS: We demonstrated cellular dormancy in breast cancer bone metastasis, associated with haematopoietic stem cell (HSC) mimicry, in vivo competition for HSC engraftment and non-random distribution of dormant cells at the endosteal niche.Notch2 signal implication was demonstrated by immunophenotyping the endosteal niche-associated cancer cells and upon co-culture with sorted endosteal niche cells, which inhibited breast cancer cell proliferation in a Notch2-dependent manner. Blocking this signal by in vivo acute administration of the gamma-secretase inhibitor, dibenzazepine, induced dormant cell mobilisation from the endosteal niche and colonisation of visceral organs. Sorted Notch2(HIGH) breast cancer cells exhibited a unique stem phenotype similar to HSCs and in vitro tumour-initiating ability in mammosphere assay. Human samples confirmed the existence of a small Notch2(HIGH) cell population in primary and bone metastatic breast cancers, with a survival advantage for Notch2(HIGH) vs Notch2(LOW) patients.CONCLUSIONS: Notch2 represents a key determinant of breast cancer cellular dormancy and mobilisation in the bone microenvironment