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Osteosarcoma(OS) is a highly aggressive bone cancer for which treatment has remained essentially unchanged for decades. Although OS is characterized by extensive genomic heterogeneity and instability, RB1 and TP53 have been shown to be the most commonly inactivated tumor suppressors in OS. We previously generated a mouse model with a double knockout (DKO) of Rb1 and Trp53 within cells of the osteoblastic lineage, which largely recapitulates human OS with nearly complete penetrance. SKP2 is a repression target of pRb and serves as a substrate recruiting subunit of the SCFSKP2 complex. In addition, SKP2 plays a central role in regulating the cell cycle by ubiquitinating and promoting the degradation of p27. We previously reported the DKOAA transgenic model, which harbored a knock-in mutation in p27 that impaired its binding to SKP2. Here, we generated a novel p53-Rb1-SKP2 triple-knockout model (TKO) to examine SKP2 function and its potential as a therapeutic target in OS. First, we observed that OS tumorigenesis was significantly delayed in TKO mice and their overall survival was markedly improved. In addition, the loss of SKP2 also promoted an apoptotic microenvironment and reduced the stemness of DKO tumors. Furthermore, we found that small-molecule inhibitors of SKP2 exhibited anti-tumor activities in vivo and in OS organoids as well as synergistic effects when combined with a standard chemotherapeutic agent. Taken together, our results suggest that SKP2 inhibitors may reduce the stemness plasticity of OS and should be leveraged as next-generation adjuvants in this cancer.

Osteosarcoma is a highly aggressive malignancy for which treatment has remained essentially unchanged for years. Our previous studies found that the F-box protein SKP2 is overexpressed in osteosarcoma, acting as a proto-oncogene; p27Kip1 (p27) is an inhibitor of cyclin-dependent kinases and a downstream substrate of SKP2-mediated ubiquitination. Overexpression of SKP2 and underexpression of p27 are common characteristics of cancer cells. The SCFSKP2 E3 ligase ubiquitinates Thr187-phosphorylated p27 for proteasome degradation, which can be abolished by a Thr187Ala knock-in (p27T187A KI) mutation. RB1 and TP53 are two major tumor suppressors commonly coinactivated in osteosarcoma. We generated a mouse model with a double knockout (DKO) of Rb1 and Trp53 within cells of the osteoblastic lineage, which developed osteosarcoma with full penetrance. When p27T187A KI mice were crossed on to the DKO background, p27T187A protein was found to accumulate in osteosarcoma tumor tissues. Furthermore, p27T187A promoted apoptosis in DKO tumors, slowed disease progression, and significantly prolonged overall survival. RNA sequencing analysis also linked the SCFSKP2 -p27T187A axis to potentially reduced cancer stemness. Given that RB1 and TP53 loss or coinactivation is common in human osteosarcoma, our study suggests that inhibiting the SKP2-p27 axis may represent a desirable therapeutic strategy for this cancer.

Synovial sarcoma (SS) is an aggressive soft-tissue cancer with a poor prognosis and a propensity for local recurrence and distant metastasis. In this study, we investigated whether S phase kinase-associated protein (Skp2) plays an oncogenic role in tumor initiation, progression, and metastasis of SS. Our study revealed that Skp2 is frequently overexpressed in SS specimens and SS18-SSX transgenic mouse tumors, as well as correlated with clinical stages. Next, we identified that genetic depletion of Skp2 reduced mesenchymal and stemness markers, and inhibited the invasive and proliferative capacities of SS cell lines. Furthermore, Skp2 depletion markedly suppressed the growth of SS xenografts tumors. Treatment of SS cell lines with the skp2 inhibitor flavokawain A (FKA) reduced Skp2 expression in a dose-dependent manner and resulted in cell cycle arrest and apoptosis. FKA also suppressed the invasion and tumor-initiating properties in SS, similar to the effects of Skp2 knockdown. In addition, a combination of FKA and conventional chemotherapy showed a synergistic therapeutic efficacy. Taken together, our results suggest that Skp2 plays an essential role in the biology of SS by promoting the mesenchymal state and cancer stemness. Given that chemotherapy resistance is often associated with cancer stemness, strategies of combining Skp2 inhibitors with conventional chemotherapy in SS may be desirable.

Objective: Nutrition and physical activity are key components of daily diabetes care in young children with type I diabetes (T1D). Normative developmental behavioral challenges related to nutrition and physical activity complicate management of T1D. The current pilot study evaluated the feasibility, acceptability, and indications of behavior change of an intervention aimed at improving nutrition and physical activity in young children with T1D. Method: Thirty-6 parents of young children (ages 2-5 years, M - 4.2) with T1D from 2 clinics in the Washington, DC area were randomized to receive the type One Training (TOTs) program or Usual Care (UC). Assessments included recruitment and completion rates, participant acceptability, and outcomes including glycemic variability via continuous glucose monitoring, nutritional intake via remote food photography, physical activity via accelerometers, and parental report on behavior and psychosocial functioning. Results: Despite recruitment challenges, the TOTs program was feasible to administer, with high program and assessment completion rates. Acceptability ratings were very high but differed by recruitment site. Participants randomized to TOTs had an increase in percent of time in target glycemic range and reduction in behavioral feeding problems between baseline and follow-up while those randomized to UC did not. Participants in UC demonstrated a decrease in in moderate to vigorous physical activity at follow-up. Conclusions: The TOTs program demonstrated preliminary feasibility and acceptability. Future research will examine components of treatment for evidence of efficacy and target the intervention to those most likely to benefit. Keywords: type 1 diabetes, young children, parents, eating, Type I diabetes (T1D) occurs in 1 in 500-600 children and incidence is increasing annually, with higher growth in young children ages 0-9 years (Dabelea et al., 2014; Mayer-Davis et [...]

Osteosarcoma (OS), the most common primary cancer of bone, exhibits a high propensity for local invasion and distant metastasis. This study sought to elucidate the role of S phase kinase-associated protein (Skp2) in osteosarcoma invasion and metastasis and to explore flavokawain A (FKA), a natural chalcone from kava extract, as a potential Skp2 targeting agent for preventing osteosarcoma progression. Skp2 was found to be overexpressed in multiple osteosarcoma cell lines, including 5 standard and 8 primary patient-derived cell lines. Patients whose tumors expressed high levels of Skp2 sustained a significantly worse metastasis-free (p = 0.0095) and overall survival (p = 0.0013) than those with low Skp2. Skp2 knockdown markedly reduced in vitro cellular invasion and in vivo lung metastasis in an orthotopic mouse model of osteosarcoma. Similar to Skp2 knockdown, treatment with FKA also reduced Skp2 expression in osteosarcoma cell lines and blocked the invasion of osteosarcoma cells in vitro and lung metastasis in vivo. Together, our findings suggest that Skp2 is a promising therapeutic target in osteosarcoma, and that FKA may be an effective Skp2-targeted therapy to reduce osteosarcoma metastasis.

Synovial sarcoma (SS) is an aggressive soft tissue sarcoma with poor prognosis due to late recurrence and metastasis. Metastasis is an important prognostic factor of SS. This study aimed to identify the core genes and mechanisms associated with SS metastasis. Microarray data for GSE40021 and GSE40018 were obtained from the Gene Expression Omnibus database. 186 differentially expressed genes (DEGs) were identified. The biological functions and signalling pathways closely associated with SS metastasis included extracellular matrix (ECM) organization and ECM‐receptor interaction. Gene set enrichment analysis showed that the terms cell cycle, DNA replication, homologous recombination and mismatch repair were significantly enriched in the metastasis group. Weighted gene co‐expression network analysis identified the most relevant module and 133 hub genes, and 31 crossover genes were identified by combining DEGs. Subsequently, four characteristic genes, EXO1, NCAPG, POLQ and UHRF1, were identified as potential biomarkers associated with SS metastasis using the least absolute shrinkage and selection operator algorithm and validation dataset verification analysis. Immunohistochemistry results from our cohort of 49 patients revealed visible differences in the expression of characteristic genes between the non‐metastatic and metastatic groups. Survival analysis indicated that high expression of characteristic genes predicted poor prognosis. Our data revealed that primary SS samples from patients who developed metastasis showed activated homologous recombination and mismatch repair compared to samples from patients without metastasis. Furthermore, EXO1, NCAPG, POLQ and UHRF1 were identified as potential candidate metastasis‐associated genes. This study provides further research insights and helps explore the mechanisms of SS metastasis. [ABSTRACT FROM AUTHOR]

Background Accurately diagnosing urinary tract infections (UTI) in children with neuropathic bladders can be difficult given the lack of specificity of both clinical symptoms and routine screening tests. We aimed to identify a priori unknown classes/groups of children with neuropathic bladder with respect to symptoms and UA results and examine their relationships with odds of UTI. Methods We used latent class analysis (LCA) to identify unobserved classes/groups of children with neuropathic bladder based on symptoms and urinalysis (UA) results, respectively. Demographic and clinical data were gathered by retrospective chart review of a cohort with neuropathic bladder. Symptoms and UA results were obtained by chart review of visits where urine culture was ordered. Results Around 193 patients were included in UA results analysis and 179 in symptom-based analysis. Two latent classes of patients were identified with respect to symptoms, labeled 'pyelonephritis class' and 'cystitis class,' and two, with respect to UA results, were labeled 'positive UA class' and 'negative UA class.' The pyelonephritis class had significantly higher odds of UTI compared to the asymptomatic class. While odds of UTI in cystitis class were higher than the asymptomatic class, this difference was not statistically significant. Positive UA class had significantly higher odds of UTI compared to negative UA class. Conclusion Two unobserved classes/groups exist in children with neuropathic bladder with respect to symptoms, corresponding to cystitis and pyelonephritis, and two classes of UA results that correspond with either a positive or negative UA. Our results suggest a differential approach to treatments may be considered., Author(s): Catherine S. Forster [sup.1] , Jichuan Wang [sup.2] [sup.3] Author Affiliations: (1) grid.239560.b, 0000 0004 0482 1586, Department of Pediatrics, Children's National Health System, , 111 Michigan Ave NW, [...]

In order to study the effects of different irrigation amounts on the root characteristics and yield of cotton without film mulching (abbreviated as filmless cotton) under drip irrigation in Southern Xinjiang, five irrigation amounts of filmless cotton (300, 375, 450, 525 and 600 mm, represented by W1, W2, W3, W4 and W5) and one irrigation amount of cotton with film mulching (abbreviated as filmed cotton) (450 mm, represented by WCK) were set. The effects of irrigation amount on root length density (RLD), root surface area (RSA), root average diameter (RAD), root volume (RV), root weight density (RED) and yield of filmless cotton were analyzed. The results of the two-year experiment showed the following: (1) The indexes of cotton root growth reached the maximum at the flowering and bolling stage, and the growth of soil root in the periphery (30 cm from the main root) and the lower layer (40–60 cm soil layer) reached the peak at the flowering and bolling stages, respectively; (2) The average value of root growth index of film-free cotton in each treatment was W2 > W3 > W4 > W5 and W1. The RLD of W2 and W3 increased by 19.41–106.67% and 13.66–84.22% in the peripheral and lower soil layer, and the proportion of RSA in the peripheral and middle soil layer (20–40 cm soil layer) increased by 1.64–3.41% and 0.49–4.09% compared with other treatments. The RAD, RV and RWD after W2 treatment were relatively large at various distribution points in the soil, followed by W3 treatment; (3) The average root indexes of WCK were not significantly different from those of W3, but the indexes of the lower soil layer were the smallest, at only 29.18–66.84% of the average value of the non-film mulching treatment, while the root indexes of the surface layer (0–20 cm soil layer) and the surrounding soil were larger, with an increase of 11.43–102.17% and 29.60–111.57%, respectively, compared with the non-film mulching treatment; (4) The seed cotton yield of W3 was the highest in the non-film mulching treatment, reaching 4833.25 kg·hm−2, but was still lower than that of WCK by 27.79%. Conclusion: An appropriate water deficit is conducive to root growth and increases the uniformity of its distribution in the soil layer. The irrigation amount of 375–450 mm for filmless cotton in Southern Xinjiang can promote root growth, prevent senescence and increase yield, which can be used as a reference in production. [ABSTRACT FROM AUTHOR]