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Runt-related (RUNX) gene family is composed of three members, RUNX1/AML1 , RUNX2 and RUNX3 , and encodes the DNA-binding ( α ) subunits of the Runt domain transcription factor polyomavirus enhancer-binding protein 2 (PEBP2)/core-binding factor (CBF), which is a heterodimeric transcription factor. RUNX1 is most frequently involved in human acute leukemia. RUNX2 shows oncogenic potential in mouse experimental system. RUNX3 is a strong candidate as a gastric cancer tumor suppressor. The β subunit gene of PEBP2/CBF is also frequently involved in chromosome rearrangements associated with human leukemia. In this Overview, I will summarize how this growing field has been formed and what are the challenging new frontiers for better understanding of the oncogenic potential of this gene family.

Infection with high-risk human papillomavirus (HPV) has been linked to several human cancers, the most prominent of which is cervical cancer. The integration of the viral genome into the host genome is one of the manners in which the viral oncogenes E6 and E7 achieve persistent expression. The most well-studied cellular targets of the viral oncogenes E6 and E7 are p53 and pRb, respectively. However, recent research has demonstrated the ability of these two viral factors to target many more cellular factors, including proteins which regulate epigenetic marks and splicing changes in the cell. These have the ability to exert a global change, which eventually culminates to uncontrolled proliferation and carcinogenesis.

The WW domain-containing protein 2 ( Wwp2 ) gene, the host gene of miR-140, codes for the Wwp2 protein, which is an HECT-type E3 ubiquitin ligases abundantly expressed in articular cartilage. However, its function remains unclear. Here, we show that mice lacking Wwp2 and mice in which the Wwp2 E3 enzyme is inactivated (Wwp2-C838A) exhibit aggravated spontaneous and surgically induced osteoarthritis (OA). Consistent with this phenotype, WWP2 expression level is downregulated in human OA cartilage. We also identify Runx2 as a Wwp2 substrate and Adamts5 as a target gene, as similar as miR-140. Analysis of Wwp2-C838A mice shows that loss of Wwp2 E3 ligase activity results in upregulation of Runx2-Adamts5 signaling in articular cartilage. Furthermore, in vitro transcribed Wwp2 mRNA injection into mouse joints reduces the severity of experimental OA. We propose that Wwp2 has a role in protecting cartilage from OA by suppressing Runx2-induced Adamts5 via Runx2 poly-ubiquitination and degradation. Wwp2 is an HECT-type E3 ubiquitin ligase abundantly expressed in articular cartilage. Here, the authors show that in mice, loss of Wwp2 leads to upregulated Runx2-Adamts5 signaling in articular cartilage and development of osteoarthritis, and that disease severity is reduced by injection of Wwp2 mRNA

Osteoarthritis (OA), the most common aging-related joint disease, is caused by an imbalance between extracellular matrix synthesis and degradation. Here, we discover that both strands of microRNA-455 (miR-455), -5p and -3p, are up-regulated by Sox9, an essential transcription factor for cartilage differentiation and function. Both miR-455-5p and -3p are highly expressed in human chondrocytes from normal articular cartilage and in mouse primary chondrocytes. We generate miR-455 knockout mice, and find that cartilage degeneration mimicking OA and elevated expression of cartilage degeneration-related genes are observed at 6-months-old. Using a cell-based miRNA target screening system, we identify hypoxia-inducible factor-2α (HIF-2α), a catabolic factor for cartilage homeostasis, as a direct target of both miR-455-5p and -3p. In addition, overexpression of both miR-455-5p and -3p protect cartilage degeneration in a mouse OA model, demonstrating their potential therapeutic value. Furthermore, knockdown of HIF-2α in 6-month-old miR-455 knockout cartilage rescues the elevated expression of cartilage degeneration-related genes. These data demonstrate that both strands of a miRNA target the same gene to regulate articular cartilage homeostasis. Osteoarthritis is caused by an imbalance between extracellular matrix synthesis and degradation. Here, the authors show that both strands of microRNA-455, -5p and -3p, target HIF2α and regulate cartilage homeostasis, and show that overexpression of these miRNAs is protective against osteoarthritis in mice.

The cellular decision regarding whether to undergo proliferation or death is made at the restriction (R)-point, which is disrupted in nearly all tumors. The identity of the molecular mechanisms that govern the R-point decision is one of the fundamental issues in cell biology. We found that early after mitogenic stimulation, RUNX3 binds to its target loci, where it opens chromatin structure by sequential recruitment of Trithorax group proteins and cell-cycle regulators to drive cells to the R-point. Soon after, RUNX3 closes these loci by recruiting Polycomb repressor complexes, causing the cell to pass through the R-point toward S phase. If the RAS signal is constitutively activated, RUNX3 inhibits cell cycle progression by maintaining R-point-associated genes in an open structure. Our results identify RUNX3 as a pioneer factor for the R-point and reveal the molecular mechanisms by which appropriate chromatin modifiers are selectively recruited to target loci for appropriate R-point decisions. The transcription factor RUNX3 plays a key role in the restriction point of cell cycle. Here the authors showed that RUNX3 binds and opens chromatin structure of restriction point associated genes, by sequential recruitment of chromatin remodeling complex, transcription complex and cell cycle regulators.

Background During hemodialysis, the formation of thrombi inside the venous air trap chamber is associated with high venous pressure. Direct observation inside the venous air trap chamber involves invasive procedures and risks affecting the closed-circuit system. Methods for non-invasive observation inside venous air trap chambers have not yet been generalized. Case presentation A thrombus was identified in the filter inside a venous air trap chamber during emergency hemodialysis performed on a man in his 60s with acute renal dysfunction. During subsequent hemodialysis sessions, we regularly monitored the venous air trap chamber using ultrasound imaging and employed colour Doppler to identify the thrombus. Images were also captured that revealed signs of anomalies. Conclusions Ultrasound imaging allows non-invasive observation of the interior of a venous air trap chamber. Employing this non-invasive method poses less risk to patients and can potentially be applicable to continuous renal replacement therapy in circuit configurations that use chambers.

Background This study verified whether the dynamic changes in finger plethysmograms (FPGs) can be trained into a machine learning model to discriminate status changes associated with dialysis therapy. Methods FPGs were recorded in 18 participants undergoing dialysis therapy at the start of dialysis and during dialysis for 3 min. The FPGs were converted to acceleration pulse waves, the indices obtained from the acceleration pulse waves were trained as features into an elastic net model (a type of explainable machine learning), and the performance of classification for distinguishing between the state change at the start of and during dialysis was verified. Results Throughout the dialysis therapy, significant changes were observed in d/a (an index of peripheral vascular resistance), PR, low frequency, low frequency/high frequency, Lyapunov index, entropy, systolic, and diastolic blood pressures. The classification performance of the elastic net model was as follows: precision, 88%; recall, 64%; F1 score, 74%; accuracy, 77%; and area under curve, 83%. Conclusions These results suggest that machine learning models trained on FPG-derived features offer a promising new technique for noninvasive and objective observation of hemodynamic changes during dialysis. However, given the small sample size ( n  = 18) and participant variability, these preliminary findings require validation in larger studies to establish their generalizability.

Patients who undergo cardiac surgery have a high risk of significant blood loss and anemia. While allogeneic red blood cell (RBC) transfusions are effective, they are associated with increased morbidity and mortality. Intraoperative cell salvage may reduce reliance on allogeneic transfusions. Although intraoperative RBC salvage is recommended for cardiovascular surgery under cardiopulmonary bypass, there are concerns about increased bleeding due to coagulopathy in patients with a high bleeding risk, and its clinical impact remains unclear. This study aims to evaluate whether salvaged RBC transfusion is noninferior to allogeneic transfusion in terms of postoperative blood loss in patients with a high bleeding risk. This single-center, randomized, two-arm, parallel group, interventional clinical trial will include 142 participants aged ≥ 40 years with a high bleeding risk who undergo elective cardiovascular surgery with cardiopulmonary bypass. Participants will be randomly assigned to receive either salvaged RBC or allogeneic RBC transfusions intraoperatively. The primary outcome is postoperative chest tube blood loss within 12 hours from the end of surgery. Noninferiority will be demonstrated if the upper limit of the 95% confidence interval for the mean difference in blood loss between the salvaged and allogeneic groups is < 200 mL. Secondary outcomes comprise the RBC transfusion volume intraoperatively and for 12 hours from the end of surgery, prevalence of re-thoracotomy within 48 hours from the end of surgery, and prevalence of ≥ 1000 mL postoperative chest tube blood loss within 12 hours from the end of surgery. These outcomes will be analyzed using the modified intention-to-treat set and repeated, for sensitivity reasons, for the per-protocol set. Our trial aims to determine the noninferiority of intraoperative RBC salvage compared with allogeneic blood transfusions regarding postoperative blood loss and to promote its use in surgical procedures with a high bleeding risk. The trial was registered with the Japan Registry of Clinical Trials (jRCT1052240102) on July 30, 2024.

The Hippo–YAP signaling pathway serves roles in cell proliferation, stem cell renewal/maintenance, differentiation and apoptosis. Many of its functions are central to early development, adult tissue repair/regeneration and not surprisingly, tumorigenesis and metastasis. The Hippo pathway represses the activity of YAP and paralog TAZ by modulating cell proliferation and promoting differentiation to maintain tissue homeostasis and proper organ size. Similarly, master regulators of development RUNX transcription factors have been shown to play critical roles in proliferation, differentiation, apoptosis and cell fate determination. In this review, we discuss the multiple interactions of RUNX with the Hippo–YAP pathway, their shared collaborators in Wnt, TGFβ, MYC and RB pathways, and their overlapping functions in development and tumorigenesis.

Cell-based or pharmacological approaches for promoting tendon repair are currently not available because the molecular mechanisms of tendon development and healing are not well understood. Although analysis of knockout mice provides many critical insights, small animals such as mice have some limitations. In particular, precise physiological examination for mechanical load and the ability to obtain a sufficient number of primary tendon cells for molecular biology studies are challenging using mice. Here, we generated Mohawk (Mkx)−/− rats by using CRISPR/Cas9, which showed not only systemic hypoplasia of tendons similar to Mkx −/− mice, but also earlier heterotopic ossification of the Achilles tendon compared with Mkx −/− mice. Analysis of tendon-derived cells (TDCs) revealed that Mkx deficiency accelerated chondrogenic and osteogenic differentiation, whereas Mkx overexpression suppressed chondrogenic, osteogenic, and adipogenic differentiation. Furthermore, mechanical stretch stimulation of Mkx −/− TDCs led to chondrogenic differentiation, whereas the same stimulation in Mkx +/+ TDCs led to formation of tenocytes. ChIP-seq of Mkx overexpressing TDCs revealed significant peaks in tenogenic-related genes, such as collagen type (Col)1a1 and Col3a1, and chondrogenic differentiation-related genes, such as SRY-box (Sox)5, Sox6, and Sox9. Our results demonstrate that Mkx has a dual role, including accelerating tendon differentiation and preventing chondrogenic/osteogenic differentiation. This molecular network of Mkx provides a basis for tendon physiology and tissue engineering.