A multi-model approach identifies ALW-II-41-27 as a promising therapy for osteoarthritis-associated inflammation and endochondral ossification.

Low-grade inflammation and pathological endochondral ossification are key processes underlying the progression of osteoarthritis, the most prevalent joint disease worldwide. In this study, we employed a multi-faceted approach, integrating publicly available datasets, analyses, experiments and models to identify new therapeutic candidates targeting these processes. Data mining of transcriptomic datasets identified EPHA2, a receptor tyrosine kinase associated with cancer, as being linked to both inflammation and endochondral ossification in osteoarthritis.

Mapping the use of computational modelling and simulation in clinics: A survey.

medicine describes the application of computational modelling and simulation (CM&S) to the study, diagnosis, treatment or prevention of a disease. Tremendous research advances have been achieved to facilitate the use of CM&S in clinical applications. Nevertheless, the uptake of CM&S in clinical practice is not always timely and accurately reflected in the literature.

An integrated in silico-in vitro approach for identifying therapeutic targets against osteoarthritis.

Background: Without the availability of disease-modifying drugs, there is an unmet therapeutic need for osteoarthritic patients. During osteoarthritis, the homeostasis of articular chondrocytes is dysregulated and a phenotypical transition called hypertrophy occurs, leading to cartilage degeneration. Targeting this phenotypic transition has emerged as a potential therapeutic strategy.

Human pluripotent stem cell-derived cartilaginous organoids promote scaffold-free healing of critical size long bone defects.

Background: Bones have a remarkable capacity to heal upon fracture. Yet, in large defects or compromised conditions healing processes become impaired, resulting in delayed or non-union. Current therapeutic approaches often utilize autologous or allogeneic bone grafts for bone augmentation.

Scientific and regulatory evaluation of mechanistic in silico drug and disease models in drug development: Building model credibility.

The value of in silico methods in drug development and evaluation has been demonstrated repeatedly and convincingly. While their benefits are now unanimously recognized, international standards for their evaluation, accepted by all stakeholders involved, are still to be established. In this white paper, we propose a risk-informed evaluation framework for mechanistic model credibility evaluation.

Dissecting the effects of preconditioning with inflammatory cytokines and hypoxia on the angiogenic potential of mesenchymal stromal cell (MSC)-derived soluble proteins and extracellular vesicles (EVs).

Mesenchymal stromal cells (MSCs) are characterized by a regulatory phenotype and respond promptly to the environmental signals modulating their secretory activity. An appropriate preconditioning may induce MSCs to release secretomes with an enhanced regenerative potential. However, it fails to take into account that secretomes are composed by both soluble factors and extracellular vesicles (EVs), whose functions could be altered differently by the preconditioning approach.

Turning Nature's own processes into design strategies for living bone implant biomanufacturing: a decade of Developmental Engineering.

A decade after the term developmental engineering (DE) was coined to indicate the use of developmental processes as blueprints for the design and development of engineered living implants, a myriad of proof-of-concept studies demonstrate the potential of this approach in small animal models. This review provides an overview of DE work, focusing on applications in bone regeneration. Enabling technologies allow to quantify the distance between in vitro processes and their developmental counterpart, as well as to design strategies to reduce that distance.

Computational Modeling and Reverse Engineering to Reveal Dominant Regulatory Interactions Controlling Osteochondral Differentiation: Potential for Regenerative Medicine.

The specialization of cartilage cells, or chondrogenic differentiation, is an intricate and meticulously regulated process that plays a vital role in both bone formation and cartilage regeneration. Understanding the molecular regulation of this process might help to identify key regulatory factors that can serve as potential therapeutic targets, or that might improve the development of qualitative and robust skeletal tissue engineering approaches. However, each gene involved in this process is influenced by a myriad of feedback mechanisms that keep its expression in a desirable range, making the prediction of what will happen if one of these genes defaults or is targeted with drugs, challenging.

Discrete adipose-derived stem cell subpopulations may display differential functionality after in vitro expansion despite convergence to a common phenotype distribution.

Background: Complex immunophenotypic repertoires defining discrete adipose-derived stem cell (ASC) subpopulations may hold a key toward identifying predictors of clinical utility. To this end, we sorted out of the freshly established ASCs four subpopulations (SPs) according to a specific pattern of co-expression of six surface markers, the CD34, CD73, CD90, CD105, CD146, and CD271, using polychromatic flow cytometry.

Method: Using flow cytometry-associated cell sorting and analysis, gating parameters were set to select for a CD73CD90CD105 phenotype plus one of the four following combinations, CD34CD146CD271 (SP1), CD34CD146CD271 (SP2), CD34CD146CD271 (SP3), and CD34CD146CD271 (SP4).

Physical characterization of heparin by light scattering.

Dynamic and electrophoretic light scattering were used to measure the size and charge heterogeneity of a commercial preparation of heparin. For this preparation of porcine mucosal heparin (M(r) = 10-20 kDa), the diffusion coefficient was 1.2 +/- 0.

Surgical reconstruction of the internal carotid artery with contralateral occlusion without use of shunt.

Between 1979 and 1989, 133 carotid artery reconstructions were performed in 130 patients with contralateral internal carotid artery occlusion. These 133 reconstructions represent 7.3% of 1815 revascularizations of the internal carotid artery for atheromatous lesions performed during the same period.

Aerobic performance in brothers, dizygotic and monozygotic twins.

Forty-two brothers, 66 dizygotic twins of both sexes and 106 monozygotic twins of both sexes, 16 to 34 yr of age, took part in this study that was designed to investigate the effect of heredity in aerobic performance. Maximal oxygen uptake (VO2 max), maximal heart rate (HR max), maximal ventilation, and maximal oxygen pulse were obtained from a progressive ergocycle test to exhaustion. Total work output in a 90-min maximal ergocycle test was also determined in the twins.

Familial resemblance in maximal heart rate, blood lactate and aerobic power.

There are considerable interindividual differences in maximal oxygen uptake per kilogram of body weight (VO2 max/kg), maximal heart rate (max HR) and maximal blood lactate (max blood La) measured during a progressive exercise test. The aim of the study was to quantify the familial relationships for these variables. Parents and children of 38 families of French-Canadian descent were submitted to a modified Balke treadmill test.

Gastro-cutaneous syndrome: peptic ulcer/hiatal hernia, multiple lentigines/café-au-lait spots, hypertelorism, and myopia.

We report the familial occurrence in a French Canadian family of peptic ulcer/hiatal hernia, multiple lentigines/café-au-lait spots, apparent hypertelorism, and myopia caused by a pleiotropic autosomal dominant gene with high penetrance and variable expressivity. Other probable but rarer components of the syndrome include ischemic heart disease, congenital heart disease, and maturity onset diabetes. Symptoms of peptic ulcer/hiatal hernia usually started in the second or third decade and were associated, as least in some examined individuals, with relatively increased acid secretion and abnormal dermatoglyphics.

Brief clinical report: renal hypodysplasia and unilateral ovarian agenesis in the penta-X syndrome.

We report the case of a 3-year-old penta-X female with two previously undescribed anomalies: hypoplastic kidney and absent ipsilateral ovary. The gross and histologic structure of the contralateral ovary was normal, suggesting that adults with this syndrome may be fertile.

[Immunoelectrophoresis used for identification of blood stains in forensic medicine].

Conclusive evidence was obtained in this study that immunoelectrophoresis could be used in the identification of blood-stains in two particular cases: for diagnosis or approach to diagnosis of the age of a blood-stain, and for diagnosis of the human origin of a blood-stain that had been treated with petroleum products. Although many aspects should be investigated in more detail, it is certain that this method can be employed in combination with other methods.