The presence of postmenopausal bleeding as prognostic parameter in patients with endometrial cancer: a retrospective multi-center study

Abstract Background To date, there is no consensus on the utility of screening procedures for the early detection of endometrial cancer. The value of transvaginal ultrasound for screening of asymptomatic endometrial cancer has been discussed controversially. This study was conducted to evaluate whether asymptomatic patients with endometrial cancer have a better prognosis than symptomatic patients with endometrial cancer diagnosed after postmenopausal bleeding. Methods In the present multi-center study, the effect of the presence of postmenopausal bleeding on prognosis was evaluated retrospectively in 605 patients with endometrial cancer using patients' files. 543 patients (133 patients were asymptomatic, 410 patients were symptomatic) with endometrioid endometrial cancer were enrolled in all further analysis. Student's t-test, Cox regression analysis and Kaplan-Meier analysis were used were appropriate. Results Presence/absence of a postmenopausal bleeding was not associated with tumor stage (p = 0.2) and age at diagnosis (p = 0.5). Asymptomatic patients with endometrial cancer had a significantly higher rate of well and moderate-differentiated tumors compared to symptomatic patients (p = 0.008). In univariable and multivariable survival analysis, tumor stage, tumor grade, and patients' age at diagnosis, but not presence/absence of a postmenopausal bleeding, were associated with disease free and overall survival. Conclusion Asymptomatic patients with endometrial cancer have a higher rate of well differentiated tumors compared to patients with a postmenopausal bleeding prior to diagnosis. The prognosis of both groups of patients was similar.</p

Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement

Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal-dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, joint hypermobility, and mild skin findings. A locus was mapped to an approximately 5.8 Mb region at 12p13.1 but no candidate gene was identified. In an international consortium we recruited 19 independent families comprising 107 individuals with pEDS to identify the locus, characterize the clinical details in those with defined genetic causes, and try to understand the physiological basis of the condition. In 17 of these families, we identified heterozygous missense or in-frame insertion/deletion mutations in C1R (15 families) or C1S (2 families), contiguous genes in the mapped locus that encode subunits C1r and C1s of the first component of the classical complement pathway. These two proteins form a heterotetramer that then combines with six C1q subunits. Pathogenic variants involve the subunit interfaces or inter-domain hinges of C1r and C1s and are associated with intracellular retention and mild endoplasmic reticulum enlargement. Clinical features of affected individuals in these families include rapidly progressing periodontitis with onset in the teens or childhood, a previously unrecognized lack of attached gingiva, pretibial hyperpigmentation, skin and vascular fragility, easy bruising, and variable musculoskeletal symptoms. Our findings open a connection between the inflammatory classical complement pathway and connective tissue homeostasis

Cyclin-dependent kinase 9 (CDK9) is a novel prognostic marker and therapeutic target in osteosarcoma.

BackgroundCyclin-dependent protein kinase 9 (CDK9) has been shown to play an important role in the pathogenesis of malignant tumors. However, the expression and function of CDK9 remain unknown in osteosarcomas. The purpose of this study is to assess the expression, function and clinical prognostic relationship of CDK9 in osteosarcomas.MethodsA tissue microarray of 70 patient specimens was analyzed by immunohistochemistry to measure CDK9 expression, which was further investigated for correlation with patient clinical characteristics. CDK9 expression in osteosarcoma cell lines and patient tissues was also evaluated by Western blotting. CDK9-specific siRNA and the CDK9 inhibitor were applied to determine the effect of CDK9 inhibition on osteosarcoma cell proliferation and anti-apoptotic activity. The clonogenicity and migration activity were also examined using clonogenic and wound healing assays. A 3D cell culture model was performed to mimic the in vivo osteosarcoma environment to further validate the effect of CDK9 inhibition on osteosarcoma cells.FindingsWe demonstrated that higher CDK9-expression is associated with significantly shortened patient survival by immunohistochemistry. Expression of CDK9 is inversely correlated to the percent of tumor necrosis post-neoadjuvant chemotherapy, which is the most important predictive factor of disease outcome for osteosarcoma patients. Knockdown of CDK9 with siRNA and inhibition of CDK9 activity with inhibitor decreased cell proliferation and induced apoptosis in osteosarcoma.InterpretationHigh expression of CDK9 is an independent predictor of poor prognosis in osteosarcoma patients. Our results suggest that CDK9 is a novel prognostic marker and a promising therapeutic target for osteosarcomas

Cyclin-dependent kinase 9 (CDK9) is a novel prognostic marker and therapeutic target in osteosarcomaResearch in context

Background: Cyclin-dependent protein kinase 9 (CDK9) has been shown to play an important role in the pathogenesis of malignant tumors. However, the expression and function of CDK9 remain unknown in osteosarcomas. The purpose of this study is to assess the expression, function and clinical prognostic relationship of CDK9 in osteosarcomas. Methods: A tissue microarray of 70 patient specimens was analyzed by immunohistochemistry to measure CDK9 expression, which was further investigated for correlation with patient clinical characteristics. CDK9 expression in osteosarcoma cell lines and patient tissues was also evaluated by Western blotting. CDK9-specific siRNA and the CDK9 inhibitor were applied to determine the effect of CDK9 inhibition on osteosarcoma cell proliferation and anti-apoptotic activity. The clonogenicity and migration activity were also examined using clonogenic and wound healing assays. A 3D cell culture model was performed to mimic the in vivo osteosarcoma environment to further validate the effect of CDK9 inhibition on osteosarcoma cells. Findings: We demonstrated that higher CDK9-expression is associated with significantly shortened patient survival by immunohistochemistry. Expression of CDK9 is inversely correlated to the percent of tumor necrosis post-neoadjuvant chemotherapy, which is the most important predictive factor of disease outcome for osteosarcoma patients. Knockdown of CDK9 with siRNA and inhibition of CDK9 activity with inhibitor decreased cell proliferation and induced apoptosis in osteosarcoma. Interpretation: High expression of CDK9 is an independent predictor of poor prognosis in osteosarcoma patients. Our results suggest that CDK9 is a novel prognostic marker and a promising therapeutic target for osteosarcomas. Keywords: CDK9, Osteosarcoma, Prognostic marker, Therapeutic target, Apoptosi

Advances in sarcoma gene mutations and therapeutic targets

•Specific gene mutations are important in driving the pathogenesis and progression of sarcomas.•p53, RB, PI3K and IDH gene mutations are the most prevalent mutations identified in sarcomas.•Gene mutation based preclinical studies and clinical trials in using targeted therapies may improve the treatment of sarcoma patients. Sarcomas are rare and complex malignancies that have been associated with a poor prognostic outcome. Over the last few decades, traditional treatment with surgery and/or chemotherapy has not significantly improved outcomes for most types of sarcomas. In recent years, there have been significant advances in the understanding of specific gene mutations that are important in driving the pathogenesis and progression of sarcomas. Identification of these new gene mutations, using next-generation sequencing and advanced molecular techniques, has revealed a range of potential therapeutic targets. This, in turn, may lead to the development of novel agents targeted to different sarcoma subtypes. In this review, we highlight the advances made in identifying sarcoma gene mutations, including those of p53, RB, PI3K and IDH genes, as well as novel therapeutic strategies aimed at utilizing these mutant genes. In addition, we discuss a number of preclinical studies and ongoing early clinical trials in sarcoma targeting therapies, as well as gene editing technology, which may provide a better choice for sarcoma patient management

Regulation of microRNAs function by circular RNAs in human cancer.

Circular RNAs (circRNAs) are a newly validated class of endogenous non-coding RNA, generated from the ligation of exons, introns, or both, which arise via a diverse number of cellular mechanisms. Due to rapid advances in the development of combined high-throughput sequencing and bioinformatics analyzing tools, many circRNAs have recently been discovered, revealing an expansive number of ubiquitously expressed mammalian circRNAs. Interestingly, it has recently been confirmed that circRNAs bind to microRNAs (miRs), as miR "sponges", acting to suppress miR function. As miRs are known to alter the development and progression of cancer, circRNAs may offer a novel diagnostic and prognostic biomarker for cancer. Indeed, recent evidence has shown that circRNAs are associated with many human cancers. Herein, we review the molecular characteristics and biogenesis of circRNAs, with a focus on newly identified circRNAs that may play an important role in human cancer, through their regulation of miR expression

Application of liquid biopsy in bone and soft tissue sarcomas: Present and future

Bone and soft tissue sarcomas account for approximately 1% of adult solid malignancies and 20% of pediatric solid malignancies. Sarcomas are divided into more than 50 subtypes. Each subtype is highly heterogeneous and characterized by significant morphological and phenotypic variability. Currently, sarcoma characterization is based on tissue biopsies. However, primary and invasive tissue biopsies may not accurately reflect the current disease condition following treatment as is may cause marked changes to the tumor cells. Liquid biopsy offers an alternative minimally invasive approach to provide dynamic tumor information, allowing for the application of precision medicine in the treatment of sarcomas. Recently, there have been numerous blood-based tumor components identified by liquid biopsy in sarcomas, including circulating tumor cells, circulating cell-free nucleic acids, tumor-derived exosomes and metabolites in circulation. Here, we summarize the current evolving technologies and then elaborate on emerging novel concepts that may further propel the field of liquid biopsy in sarcomas. We address the applications in the context of our current knowledge about liquid biopsy in sarcomas and highlight the potential of translating these recent advances into the clinic for more effective management strategies for sarcoma patients. •There are 50 different subtypes of sarcomas with different genetic and epigenetic make-up.•There are significant limitations to using tissue biopsies for sarcoma diagnosis.•Monitoring biologic behavior by liquid biopsy provides a dynamic method for sarcomas

Regulation of microRNAs function by circular RNAs in human cancer

Circular RNAs (circRNAs) are a newly validated class of endogenous non-coding RNA, generated from the ligation of exons, introns, or both, which arise via a diverse number of cellular mechanisms. Due to rapid advances in the development of combined high-throughput sequencing and bioinformatics analyzing tools, many circRNAs have recently been discovered, revealing an expansive number of ubiquitously expressed mammalian circRNAs. Interestingly, it has recently been confirmed that circRNAs bind to microRNAs (miRs), as miR “sponges”, acting to suppress miR function. As miRs are known to alter the development and progression of cancer, circRNAs may offer a novel diagnostic and prognostic biomarker for cancer. Indeed, recent evidence has shown that circRNAs are associated with many human cancers. Herein, we review the molecular characteristics and biogenesis of circRNAs, with a focus on newly identified circRNAs that may play an important role in human cancer, through their regulation of miR expression

Inhibition of cyclin-dependent kinase 4 as a potential therapeutic strategy for treatment of synovial sarcoma

Synovial sarcoma is a highly aggressive but rare form of soft tissue malignancy that primarily affects the extremities of the arms or legs, for which current chemotherapeutic agents have not been proven to be very effective. The cyclin-dependent kinase 4/6-retinoblastoma protein (CDK4/6-Rb) pathway of cell cycle control is known to be aberrant in a large proportion of cancers. Recently, CDK4 inhibitors have successfully been used pre-clinically for the treatment of many human cancers, and in 2015, following the success of clinical trials, the FDA approved the first selective CDK4/6 inhibitor, palbociclib, for the treatment of endocrine therapy resistant breast cancers. However, the expression and therapeutic potential of targeting CDK4 in synovial sarcoma remains unclear. In the present study, we report that CDK4 is highly expressed in human synovial sarcoma, and high CDK4 expressions are associated with poor prognosis in sarcomas patients and the clinical stage and the TNM grade in synovial sarcoma patients. Knockdown of CDK4 with specific small interference RNAs inhibits cell proliferation and enhances apoptotic effects in synovial sarcoma cells. CDK4 inhibitor palbociclib suppresses synovial sarcoma cell proliferation and growth in a dose and time-dependent manner. Palbociclib also inhibits the CDK4/6-Rb signaling pathway and promotes cell apoptosis without changing CDK4/6 protein levels, suggesting that palbociclib only represses the hyper-activation, not the expression of CDK4/6. Flow cytometry analysis reveals that palbociclib induces G1 cell-cycle arrest and apoptotic effects by targeting the CDK4/6-Rb pathway in synovial sarcoma cells. Furthermore, wound healing assays demonstrate that inhibition of the CDK4/6-Rb pathway by palbociclib significantly decreases synovial sarcoma cell migration in vitro. Our study highlights the importance of the CDK4/6-Rb pathway in human synovial sarcoma pathogenesis, and the role of the current selective CDK4/6 inhibitor, palbociclib, as a potential promising targeted therapeutic agent in the treatment of human synovial sarcoma

Inhibition of cyclin-dependent kinase 4 as a potential therapeutic strategy for treatment of synovial sarcoma.

Synovial sarcoma is a highly aggressive but rare form of soft tissue malignancy that primarily affects the extremities of the arms or legs, for which current chemotherapeutic agents have not been proven to be very effective. The cyclin-dependent kinase 4/6-retinoblastoma protein (CDK4/6-Rb) pathway of cell cycle control is known to be aberrant in a large proportion of cancers. Recently, CDK4 inhibitors have successfully been used pre-clinically for the treatment of many human cancers, and in 2015, following the success of clinical trials, the FDA approved the first selective CDK4/6 inhibitor, palbociclib, for the treatment of endocrine therapy resistant breast cancers. However, the expression and therapeutic potential of targeting CDK4 in synovial sarcoma remains unclear. In the present study, we report that CDK4 is highly expressed in human synovial sarcoma, and high CDK4 expressions are associated with poor prognosis in sarcomas patients and the clinical stage and the TNM grade in synovial sarcoma patients. Knockdown of CDK4 with specific small interference RNAs inhibits cell proliferation and enhances apoptotic effects in synovial sarcoma cells. CDK4 inhibitor palbociclib suppresses synovial sarcoma cell proliferation and growth in a dose and time-dependent manner. Palbociclib also inhibits the CDK4/6-Rb signaling pathway and promotes cell apoptosis without changing CDK4/6 protein levels, suggesting that palbociclib only represses the hyper-activation, not the expression of CDK4/6. Flow cytometry analysis reveals that palbociclib induces G1 cell-cycle arrest and apoptotic effects by targeting the CDK4/6-Rb pathway in synovial sarcoma cells. Furthermore, wound healing assays demonstrate that inhibition of the CDK4/6-Rb pathway by palbociclib significantly decreases synovial sarcoma cell migration in vitro. Our study highlights the importance of the CDK4/6-Rb pathway in human synovial sarcoma pathogenesis, and the role of the current selective CDK4/6 inhibitor, palbociclib, as a potential promising targeted therapeutic agent in the treatment of human synovial sarcoma