Cell deformation behavior in mechanically loaded rabbit articular cartilage 4 weeks after anterior cruciate ligament transection

SummaryObjectiveChondrocyte stresses and strains in articular cartilage are known to modulate tissue mechanobiology. Cell deformation behavior in cartilage under mechanical loading is not known at the earliest stages of osteoarthritis. Thus, the aim of this study was to investigate the effect of mechanical loading on volume and morphology of chondrocytes in the superficial tissue of osteoarthritic cartilage obtained from anterior cruciate ligament transected (ACLT) rabbit knee joints, 4 weeks after intervention.MethodsA unique custom-made microscopy indentation system with dual-photon microscope was used to apply controlled 2 MPa force-relaxation loading on patellar cartilage surfaces. Volume and morphology of chondrocytes were analyzed before and after loading. Also global and local tissue strains were calculated. Collagen content, collagen orientation and proteoglycan content were quantified with Fourier transform infrared microspectroscopy, polarized light microscopy and digital densitometry, respectively.ResultsFollowing the mechanical loading, the volume of chondrocytes in the superficial tissue increased significantly in ACLT cartilage by 24% (95% confidence interval (CI) 17.2–31.5, P < 0.001), while it reduced significantly in contralateral group tissue by −5.3% (95% CI −8.1 to −2.5, P = 0.003). Collagen content in ACLT and contralateral cartilage were similar. PG content was reduced and collagen orientation angle was increased in the superficial tissue of ACLT cartilage compared to the contralateral cartilage.ConclusionsWe found the novel result that chondrocyte deformation behavior in the superficial tissue of rabbit articular cartilage is altered already at 4 weeks after ACLT, likely because of changes in collagen fibril orientation and a reduction in PG content

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Drug sensitivity profiling of 3D tumor tissue cultures in the pediatric precision oncology program INFORM

The international precision oncology program INFORM enrolls relapsed/refractory pediatric cancer patients for comprehensive molecular analysis. We report a two-year pilot study implementing ex vivo drug sensitivity profiling (DSP) using a library of 75–78 clinically relevant drugs. We included 132 viable tumor samples from 35 pediatric oncology centers in seven countries. DSP was conducted on multicellular fresh tumor tissue spheroid cultures in 384-well plates with an overall mean processing time of three weeks. In 89 cases (67%), sufficient viable tissue was received; 69 (78%) passed internal quality controls. The DSP results matched the identified molecular targets, including BRAF, ALK, MET, and TP53 status. Drug vulnerabilities were identified in 80% of cases lacking actionable (very) high-evidence molecular events, adding value to the molecular data. Striking parallels between clinical courses and the DSP results were observed in selected patients. Overall, DSP in clinical real-time is feasible in international multicenter precision oncology programs. © 2022, The Author(s)