Transitional cell carcinoma (TCC) is the most common type of bladder cancer. Here we sequenced the exomes of nine individuals with TCC and screened all the somatically mutated genes in a prevalence set of 88 additional individuals with TCC with different tumor stages and grades. In our study, we discovered a variety of genes previously unknown to be mutated in TCC. Notably, we identified genetic aberrations of the chromatin remodeling genes (UTX, MLL-MLL3, CREBBP-EP300, NCOR1, ARID1A and CHD6) in 59% of our 97 subjects with TCC. Of these genes, we showed UTX to be altered substantially more frequently in tumors of low stages and grades, highlighting its potential role in the classification and diagnosis of bladder cancer. Our results provide an overview of the genetic basis of TCC and suggest that aberration of chromatin regulation might be a hallmark of bladder cancer.
We sequenced whole exomes of ten clear cell renal cell carcinomas (ccRCCs) and performed a screen of ∼1,100 genes in 88 additional ccRCCs, from which we discovered 12 previously unidentified genes mutated at elevated frequencies in ccRCC. Notably, we detected frequent mutations in the ubiquitin-mediated proteolysis pathway (UMPP), and alterations in the UMPP were significantly associated with overexpression of HIF1α and HIF2α in the tumors (P = 0.01 and 0.04, respectively). Our findings highlight the potential contribution of UMPP to ccRCC tumorigenesis through the activation of the hypoxia regulatory network.
Cuticular waxes play an important part in protecting plant aerial organs from biotic and abiotic stresses. In previous studies, the biosynthetic pathway of cuticular waxes and relative functional genes has been researched and understood; however, little is known in cucumber (Cucumis sativus L.). In this study, we cloned and characterized an AtWAX2 homolog, CsWAX2, in cucumber and found that it is highly expressed in the epidermis, where waxes are synthesized, while subcellular localization showed that CsWAX2 protein is localized to the endoplasmic reticulum (ER). The transcriptional expression of CsWAX2 was found to be induced by low temperature, drought, salt stress and ABA, while the ectopic expression of CsWAX2 in an Arabidopsis wax2 mutant could partially complement the glossy stem phenotype. Abnormal expression of CsWAX2 in transgenic cucumbers specifically affected both very long chain (VLC) alkanes and cutin biosynthesis. Furthermore, transgenic cucumber plants of CsWAX2 showed significant changes in pollen viability and fruit resistance to water loss and pathogens compared with the wild type. Collectively, these results indicated that CsWAX2 plays a pivotal role in wax biosynthesis, influencing pollen fertility and the plant's response to biotic and abiotic stresses.
Background: Stem cell–conditioned medium (CM) has been increasingly used in regenerative medicine. However, its effect on graft-host integration after anterior cruciate ligament (ACL) reconstruction (ACLR) remains unclear. Purpose: To examine the effect of human bone marrow stem cell (hBMSC)–CM on graft-bone integration and graft midsubstance ligamentization in a rat model of ACLR. Study Design: Controlled laboratory study. Methods: CM was obtained from the supernatant of commercially available hBMSCs in serum-free Dulbecco’s modified Eagle medium (DMEM). In a rat model of an ACL injury, isometric ACLR was performed. Three groups were established: CM injection group (CM; n = 40), control injection group (CI; n = 40) with serum-free DMEM injections, and no injection group (NI; n = 40). An intra-articular injection was performed weekly. Micro–computed tomography was conducted at 2, 4, and 8 weeks postoperatively. Histological and biomechanical analyses were conducted at 4 and 8 weeks postoperatively. The NIH3T3 fibroblast was utilized as a model in vitro to examine the effect of CM using the cell counting kit–8 (CCK-8) assay and immunofluorescence staining of Ki-67, α–smooth muscle actin (α-SMA), and collagen 1 (Col 1). Results: At 4 and 8 weeks, the femoral and tibial bone tunnel areas as well as the interface between the graft and host bone were smaller, while the bone volume/total volume ratio was higher, in the CM group. Sharpey-like fibers formed at 8 weeks in the CM group. At 4 and 8 weeks, more Col 1 was noticed in the CM group than in the NI group (both P < .001) or CI group (both P < .001). Immunohistochemically, the α-SMA–positive area was up-regulated at the graft-bone interface at 4 weeks ( P < .001) and declined at 8 weeks ( P < .001) in the CM group compared with the other 2 groups. At the midsubstance, α-SMA expression decreased from 4 to 8 weeks in all groups and was significantly lower in the CM group than in the NI group ( P < .01) or CI group ( P < .05) at 8 weeks. The CCK-8 assay showed that CM increased NIH3T3 viability ( P < .001) and the level of Ki-67 ( P < .05), α-SMA ( P < .001), and Col 1 ( P < .001) in CM-educated NIH3T3 cells. Conclusion: hBMSC-CM accelerates graft-bone incorporation and midsubstance ligamentization and enhances the proliferation, differentiation, and collagen synthesis of fibroblasts. Clinical Relevance: Graft-host integration is essential after ACLR. The current study identified a novel agent, that is, hBMSC-CM, as a candidate for promoting integration.
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