Search Results (3)

MDM2 and MDM4 are major negative regulators of tumor suppressor p53. Beyond regulating p53, MDM2 possesses p53-independent activity in promoting cell cycle progression and tumorigenesis via its RING domain ubiquitin E3 ligase activity. MDM2 and MDM4 form heterodimer polyubiquitin E3 ligases via their RING domain interaction. Inhibitors disrupting p53 interaction with MDM2/MDM4 are in clinical trials in patients bearing wild-type p53 cancers. However, these inhibitors are not designed to work for p53-null/mutant cancer cells. Owing to the importance of the E3 ligase of MDM2 in its p53-independent oncogenic activity, inhibitors targeting the E3 ligase activity of MDM2-MDM4 are desirable for p53-mutant cancer cells. Here, we report the development of such inhibitors with pro-apoptotic activity in p53-null leukemic cells. Among analogues of MDM2-MDM4 E3 ligase inhibitors, we initially identified MMRi36 as a potent pro-apoptotic compound in p53-null leukemic cells with acquired drug resistance. MMRi36 acts as an activator of MDM2-MDM4 E3 ligase by stabilizing MDM2-MDM4 heterodimers and promotes MDM2/MDM4 degradation in cells. Interestingly, replacement of the sulfur in 1,3,4-thiadiazole MMRi36 with a carbon led to identification of pyrazole MMRi36C that dissociates the MDM2-MDM4 RING heterodimers, inhibits the E3 ligase activity of the complex, and induces p53 protein accumulation, but retains the p53-independent pro-apoptotic activity. A brief SAR study identified a fluorine derivative of MMRi36C with improved pro-apoptotic activity. This study discovered a novel class of compound that targets MDM2-MDM4 ubiquitin E3 ligase activity for apoptosis induction in p53-mutant cancer cells. Full article

Objective: This study aimed to assess the relevance of using multi-positional MRI (mMRI) to identify cranio-vertebral junction (CVJ) instability in pediatric patients with CVJ anomalies while determining objective mMRI criteria to detect this condition. Material and Methods: Data from children with CVJ anomalies who underwent a mMRI between 2017 and 2021 were retrospectively reviewed. Mobility assessment using mMRI involved: (1) morphometric analysis using hierarchical clustering on principal component analysis (HCPCA) to identify clusters of patients by considering their mobility similarities, assessed through delta $(\mathsf{\Delta }$) values of occipito-cervical parameters measured on mMRI; and (2) morphological analysis based on dynamic geometric CVJ models and analysis of displacement vectors between flexion and extension. Receiver operating characteristics (ROC) curves were generated for occipito-cervical parameters to establish instability cut-off values. (3) Additionally, an anatomical qualitative analysis of the CVJ was performed to identify morphological criteria of instability. Results: Forty-seven patients with CVJ anomalies were included (26 females, 21 males; mean age: 10.2 years [3–18]). HCPCA identified 2 clusters: cluster №1 (stable patients, n = 39) and cluster №2 (unstable patients, n = 8). $\mathsf{\Delta }$pB-C2 (pB-C2 line delta) at $\ge$2.5 mm (AUC 0.98) and $\mathsf{\Delta }$BAI (Basion-axis Interval delta) $\ge$ 3 mm (AUC 0.97) predicted instability with 88% sensibility and 95% specificity and 88% sensitivity and 85% specificity, respectively. Geometric CVJ shape analysis differentiated patients along a continuum, from a low to a high CVJ motion that was characterized by a subluxation of C1 in the anterior direction. Qualitative analysis found correlations between instability and C2 anomalies, including fusions with C3 (body p = 0.032; posterior arch p = 0.045; inferior articular facets p = 0.012; lateral mass p = 0.029). Conclusions: We identified a cluster of pediatric patients with CVJ instability among a cohort of CVJ anomalies that were characterized by morphometric parameters with corresponding cut-off values that could serve as objective mMRI criteria. These findings warrant further validation through prospective case–control studies. Full article

Multiple myeloma (MM) is a common plasma cell malignancy, which is responsible for significant mortality, often related to severe renal impairment (RI). Kidney injury can limit therapeutic choices and may often translate into poor outcomes, but it remains potentially reversible in a proportion of patients. The most accessible, conventional markers of RI are subject to several shortfalls, among which are the delayed onset following kidney insult, multiple interfering factors, and lesser sensitivity to mild changes in glomerular filtration. Neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C have accumulated large interest in MM-RI due to being very sensitive markers of renal injury, as well as indicators of tubular-glomerular axis impairment. Of interest, recent data suggest that prediction of acute kidney injury may be aided by urinary tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7), which both act to induce G1 cell cycle arrest, reflective of a state of pre-injury, and thus may be superior to other measures of kidney insult (NGAL, kidney injury molecule ((KIM-1)). Moreover, TIMP-2 seems to be a biomarker dedicated to distal tubular cells, whereas insulin-like growth factor-binding protein 7 (IGFBP7) secretion has been found in proximal tubule cells. IGFBP7 can also identify a subsection of the normal proximal nephron, even, maybe the one that is responding to insult. They may be adopted into a conceptual screening panel for MM-RI. Unfortunately, no biomarker is ideal (influence of non-renal, biologic factors), and novel measures are limited by economic constraints, availability, lack of standardization. With the emergence of more advanced diagnostic and prognostic MM models, markers reflective of disease processes (including RI) are of high interest. Candidate molecules also include peptidome markers. Full article