Atmospheric (in vitro) oxygen pressure is around 150 mm Hg (20% O 2 ), whereas physiologic (in vivo) oxygen pressure ranges between 5 and 50 mm Hg (0.7-7% O 2 ). The normoxic environment in cell culture does not refer to a physiological stem cell niche. The aim of this study is to investigate the effect of oxygen concentration on cell properties of human mesenchymal stem cells (MSCs). We analyzed cell proliferation rate, senescence, immunophenotype, stemness gene expression and differentiation potency with human urine stem cells (USCs), dental pulp stem cells (DPSCs), amniotic fluid stem cells (AFSCs), and bone marrow stromal cells (BMSCs). USCs, DPSCs, AFSCs and BMSCs were cultured under either 5% O 2 hypoxic or 20% O 2 normoxic conditions for 5 days. MSCs cultured under hypoxia showed significantly increased proliferation rate and high percentage of S-phase cells, compared to normoxic condition. In real-time PCR assay, the cells cultured under hypoxia expressed higher level of Oct4, C-Myc, Nanog, Nestin and HIF-1a. In immunophenotype analysis, MSCs cultured under hypoxia maintained higher level of the MSC surface markers, and lower hematopoietic markers. Senescence was inhibited under hypoxia. Hypoxia enhances osteogenic differentiation efficiency compared to normoxia. Hypoxia showed enhanced cell proliferation rate, retention of stem cell properties, inhibition of senescence, and increased differentiation ability compared to normoxia.
DNA methylation patterns are associated with the development and prognosis of cancer. The aim of this study was to identify novel methylation markers for the prediction of patient outcomes using microarray analysis of DNA methylation and RNA expression patterns in samples from long-term follow-up patients with nonmuscle invasive bladder cancer (NMIBC). A total of 187 human bladder specimens were used for microarray array or pyrosequencing (PSQ) analyses: 6 normal controls (NC) and 181 NMIBC. Tumor-specific hypermethylated genes were selected from a data set comprising 24 matched microarray-based DNA methylation and gene expression profiles (6 controls and 18 NMIBC), and their clinical relevance was verified by quantitative PSQ analysis. The methylation status of Homeobox A9 (HOXA9), ISL LIM homeobox 1 (ISL1) and Aldehyde dehydrogenase 1 family, member A3 (ALDH1A3) was significantly associated with decreased gene expression levels and aggressive clinicopathological characteristics. Multivariate regression analyses showed that hypermethylation of these genes was an independent predictor of disease recurrence (HOXA9, ISL1 and ALDH1A3, either alone or in combination) and progression (ISL1 and ALDH1A3, either alone or in combination) (each p < 0.05). The results of this study suggest that these novel methylation markers are independent prognostic indicators in NMIBC patients, which may facilitate the assessment of disease recurrence and progression in NMIBC patients and inform clinical decision making regarding treatment.
Background:Androgen ablation is the first-line therapy for patients with metastatic prostate cancer (CaP). However, castration resistance will eventually emerge. In the present study, we have investigated the role of bone morphogenetic protein-6 (BMP-6) in the development of castration-resistant prostate cancer (CRPC) in the context of bone metastases.Methods:We initially investigated the clinical course of 158 men with advanced CaP who were treated with primary androgen deprivation therapy. To elucidate the underlying mechanism of CRPC in the context of bone metastases, we examined the impact of bone stromal cells on CaP in the absence of androgens using a co-culture model.Results:In the 158 patients, we found that the median time to prostate-specific antigen progression was significantly shorter when bone metastases were present (14 months (95% CI, 10.2–17.8 months) vs 57 months (95% CI, 19.4–94.6 months)). These results suggest that bone–tumour interactions may accelerate castration resistance. Consistent with this hypothesis, in vitro co-cultures demonstrated that CaP cells proliferated under an androgen-depleted condition when incubated with bone stromal cells. Mechanistically, gene expression analysis using quantitative polymerase chain reaction arrays showed a dramatic induction of BMP-6 by CaP cell lines in the presence of bone stromal cells. Further studies revealed that WNT5A derived from bone stromal cells induced the expression of BMP-6 by CaP cells; BMP-6 in turn stimulated cellular proliferation of CaP cells in an androgen-deprived media via a physical interaction between Smad5 and β-catenin. Intracellularly, WNT5A increased BMP-6 expression via protein kinase C/NF-κB pathway in CaP cell lines.Conclusions:These observations suggest that bone–CaP interaction leads to castration resistance via WNT5A/BMP-6 loop.
PurposeThe aim of this study was to evaluate the outcome of ureter stones with expectant management and the clinical factors associated with stone passage in Koreans.Materials and MethodsWe reviewed the charts of patients who visited the emergency room or urological office of our institution with acute renal colic between 2001 and 2008. A total of 656 ureter stone formers were enrolled in this study who had decided to be treated by expectant management. Clinical data such as gender, age, size and location of the stone, body mass index, and previous stone history were analyzed to find the factors related to spontaneous passage of ureter stones.ResultsOf the 656 ureter stones, 566 stones (86.3%) were spontaneously expelled. Mean duration of follow-up was 17.5 days (range, 1 to 100 days). Mean time to stone passage was 6.8 days for stones less than 2 mm in size, 12.6 days for stones 2 to 4 mm, 14.8 days for stones 4 to 6 mm, and 21.8 days for stones 6 to 8 mm (p<0.001). The cumulative spontaneous passage rate was 55.3% in 7 days, 73.7% in 14 days, 88.5% in 28 days, and 97.7% in 60 days after the first attack. A total of 90 patients (13.7%) required interventions because of symptom relapse or renal deterioration that was related to the location and size of the stone (each, p<0.001). The more proximal the location and the larger the stone was than 6 mm, the less the chance of spontaneous passage (each, p<0.001).ConclusionsSize and location of ureter stones are the most important factors for predicting the spontaneous passage of the stone. If a patient has a distal ureter stone of less than 6 mm in size, it is acceptable for the urologist to observe for spontaneous passage for 2 months.
Younger age (<70 years), higher preoperative SHIM score, clinical T(1) stage, lower BMI, and smaller prostate volume (<40 cc) independently predicted recovery of continence within 3 months after RARP.
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