Patients with lung cancer who develop bone metastasis (BM) generally have an adverse prognosis. Although several clinical models have been used to predict BM in patients with lung cancer, the results are unsatisfactory. In this retrospective study, we investigated the role of 18F-2-fluoro-2-deoxyglucose (FDG) metabolic activity, serum tumor markers, and histopathological subtypes in predicting BM in patients with lung cancer.This study included 695 consecutive patients with lung cancer who underwent 18F-FDG positron emission tomography/computed tomography (PET/CT) and in whom serum tumor markers were detected prior to treatment. The maximum standardized uptake value of primary tumors (pSUVmax), metastatic lymph nodes (nSUVmax) and distant metastases (mSUVmax), 8 serum tumor markers [carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), squamous cell carcinoma-related antigen (SCCA), cytokeratin 19 fragment (CYFRA21-1), carbohydrate antigen (CA) 125, CA50, CA72-4, and ferritin], and histopathological subtypes were compared between patients with and without BM. Receiver operating characteristic (ROC) curve and multiple logistic regression analyses were performed to identify predictors of BM in patients with lung cancer.BM was identified in 133 (19.1%) patients and not in 562 (80.9%). Patients with BM had significantly higher pSUVmax, nSUVmax, and mSUVmax than did those without BM. High concentrations of 6 serum tumor markers (i.e., CEA, ferritin, NSE, CA50, CA125, and CYFRA21-1) were significantly associated with BM. There were significant differences in the proportion of histopathological subtypes between patients with and without BM (χ2=32.35; P<0.001). The area under ROC-derived curve based on metabolic parameters was 0.737 (95% CI: 0.644-0.829) and 0.884 (95% CI: 0.825-0.943) when combined with the 6 serum tumor markers and histopathological subtypes, respectively.High pSUVmax, nSUVmax, and mSUVmax favor the presence of BM in patients with lung cancer, and serum tumor markers and histopathological subtypes are important factors for predicting BM in these patients.
The aim of the present study was to investigate the mechanisms of CCAAT/enhancer-binding protein β (C/EBPβ) in cardiac myofibroblast (CMF) differentiation and in a rat model of cardiac fibrosis induced by experimental autoimmune myocarditis (EAM).In vitro studies performed in primary neonatal rat CMF revealed that silencing of C/EBPβ expression (via lentiviral mediated shRNA strategies) was sufficient to reduce C/EBPβ mRNA and protein levels as well as to decrease the expressions of actin cytoskeletal proteins, cofilin, and filamin A (FLNA). TGFβ increased IL-1β, IL-6 and TNF-a production in cardiac fibroblasts (CF), while C/EBPβ knockdown reduced the secretion of these inflammatory mediators. In vivo studies performed in rats exhibiting EAM revealed that lentiviral-mediated silencing of C/EBPβ was sufficient to reduce the expression of C/EBPβ as well as inflammation and fibrosis in the hearts of EAM rats, when compared to controls. Echocardiography further revealed that C/EBPβ knockdown was sufficient to significantly improve cardiac dimensions and function in EAM rats. Immunohistochemical results showed that C/EBPβ knockdown attenuated the expression of C/EBPβ protein as well as the expressions of collagen I, collagen III, MMP-2, MMP-9, and α-SMA in heart tissue sections from rats in the EAM + Lenti-shC/EBPβ group.Strategies targeted at inhibiting C/EBPβ expression can be potentially exploited to regulate cofilin and FLNA expression, thereby regulating actin polymerization/depolymerization, cytoskeleton rearrangement, and CF differentiation into CMF and the production of inflammatory cytokines. C/EBPβ knock down reduces the degree of inflammation-mediated myocardial fibrosis in a rat model of EAM.
The SWI/SNF complex plays an important role in mouse embryonic stem cells (mESCs), but it remains to be determined whether this complex is required for the pluripotency of human ESCs (hESCs). Using RNAi, we demonstrated that depletion of BRG1, the catalytic subunit of the SWI/SNF complex, led to impaired self-renewing ability and dysregulated lineage specification of hESCs. A unique composition of the BRG1-SWI/SNF complex in hESCs was further defined by the presence of BRG1, BAF250A, BAF170, BAF155, BAF53A, and BAF47. Genome-wide expression analyses revealed that BRG1 participated in a broad range of biological processes in hESCs through pathways different from those in mESCs. In addition, chromatin immunoprecipitation sequencing (ChIP-seq) demonstrated that BRG1 played a repressive role in transcriptional regulation by modulating the acetylation levels of H3K27 at the enhancers of lineage-specific genes. Our data thus provide valuable insights into molecular mechanisms by which transcriptional repression affects the self-renewal and differentiation of hESCs.
Abstract Increasing evidence shows the oncogenic function of FAM83D in human cancer, but how FAM83D exerts its oncogenic function remains largely unclear. Here, we investigated the importance of FAM83D/FBXW7 interaction in breast cancer (BC). We systematically mapped the FBXW7-binding sites on FAM83D through a comprehensive mutational analysis together with co-immunoprecipitation assay. Mutations at the FBXW7-binding sites on FAM83D led to that FAM83D lost its capability to promote the ubiquitination and proteasomal degradation of FBXW7; cell proliferation, migration, and invasion in vitro; and tumor growth and metastasis in vivo, indicating that the FBXW7-binding sites on FAM83D are essential for its oncogenic functions. A meta-evaluation of FAM83D revealed that the prognostic impact of FAM83D was independent on molecular subtypes. The higher expression of FAM83D has poorer prognosis. Moreover, high expression of FAM83D confers resistance to chemotherapy in BCs, which is experimentally validated in vitro. We conclude that identification of FBXW7-binding sites on FAM83D not only reveals the importance for FAM83D oncogenic function, but also provides valuable insights for drug target.
Meiotic programmed DNA double-strand break (DSB) repair is essential for crossing-over and viable gamete formation and requires removal of Spo11-oligonucleotide complexes from 5′ ends (clipping) and their resection to generate invasive 3′-end single-stranded DNA (resection). Ctp1 (Com1, Sae2, CtIP homolog) acting with the Mre11-Rad50-Nbs1 (MRN) complex is required in both steps. We isolated multiple S. pombe ctp1 mutants deficient in clipping but proficient in resection during meiosis. Remarkably, all of the mutations clustered in or near the conserved CxxC or RHR motif in the C-terminal portion. The mutants tested, like ctp1Δ, were clipping-deficient by both genetic and physical assays. But, unlike ctp1Δ, these mutants were recombination-proficient for Rec12 (Spo11 homolog)-independent break-repair and resection-proficient by physical assay. We conclude that the intracellular Ctp1 C-terminal portion is essential for clipping, while the N-terminal portion is sufficient for DSB end-resection. This conclusion agrees with purified human CtIP resection and endonuclease activities being independent. Our mutants provide intracellular evidence for separable functions of Ctp1. Some mutations truncate Ctp1 in the same region as one of the CtIP mutations linked to the Seckel and Jawad severe developmental syndromes, suggesting that these syndromes are caused by a lack of clipping at DSB ends that require repair.
Abstract Ubiquitin-specific-processing proteases 35 (USP35) is an under-characterized deubiquitinase and its role in colorectal cancer (CRC) remains unclear. Here, we focus on delineating the impact of USP35 on CRC cell proliferation and chemo-resistance, as well as the possible regulatory mechanism. By examining the genomic database and clinical samples, we found that USP35 was overexpressed in CRC. Further functional studies showed that enhanced USP35 expression promoted CRC cell proliferation and resistance to oxaliplatin (OXA) and 5-fluorouracil (5-FU), whereas USP35 depletion impeded cell proliferation and sensitized cells to OXA and 5-FU treatments. Then, to explore the possible mechanism underlying USP35-triggered cellular responses, we performed co-immunoprecipitation (co-IP) followed by mass spectrometry (MS) analysis and identified α-L-fucosidase 1 (FUCA1) as a direct deubiquitiation target of USP35. Importantly, we demonstrated that FUCA1 was an essential mediator for USP35-induced cell proliferation and chemo-resistance in vitro and in vivo. Finally, we observed that nucleotide excision repair (NER) components (e.g., XPC, XPA, ERCC1) were up-regulated by USP35-FUCA1 axis, indicating a potential mechanism for USP35-FUCA1-mediated platinum resistance in CRC. Together, our results for the first time explored the role and important mechanism of USP35 in CRC cell proliferation and chemotherapeutic response, providing a rationale for USP35-FUCA1-targeted therapy in CRC.
Recurrence of endometriosis after surgery constitutes a serious challenge. Whether there is an evolution of lesion subtypes with each recurrence and whether certain lesions subtypes tend to recur faster than others is not adequately addressed. Medical records of all patients who underwent surgery for endometriosis between 1997 and 2018 in the Department of Gynecology and Obstetrics, University of Bern, were reviewed. Inclusion criteria was surgically confirmed endometriosis recurrence, defined as a subsequent surgery for endometriosis after a previous complete surgical excision of endometriosis lesions. Three subtypes of endometriosis were defined: superficial peritoneal endometriosis (SUP), ovarian endometrioma (OMA), and deep infiltrating endometriosis (DIE). Time to recurrence and variation in endometriosis subtype between the first and recurrent surgeries were the primary outcome measures. Out of the 322 patients with recurrent surgery that were identified, for 234 of them, the endometriosis subtype at first surgery was confirmed and classified (SUP = 56, OMA = 124, DIE = 54). No statistically significant difference was found for time to recurrence between lesion subtypes. SUP compared to the other groups had a higher possibility of presenting with SUP at recurrence (Odds Ratio (OR): 3.65, 95% confidence interval (CI): 1.74–7.51) and OMA compared to the other groups had a higher possibility of presenting with OMA at recurrence (OR: 3.72, 95% CI: 2.04–6.74). Nevertheless, a large number of SUP patients subsequently presented with OMA (10/56: 17.9%) or DIE (27/56: 48.2%) lesions at recurrence. Similarly, a large number of OMA patients subsequently presented with DIE (49/124: 39.5%) lesions at recurrence. In conclusion, although SUP and OMA patients compared to the others are more likely to present with the same subtype at recurrence, increasing lesion subtype severity occurs in a substantial proportion of patients. Time to recurrence is independent from the lesion subtype at first surgery.
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