The possible role of ribosomal protein S6 kinase 4 in the senescence of endothelial progenitor cells in diabetes mellitus

<p>Abstract</p> <p>Background</p> <p>The decrease and dysfunction of endothelial progenitor cells (EPCs) has been assumed as an important cause/consequence of diabetes mellitus (DM) and its complications, in which the senescence of EPCs induced by hyperglycemia may play an immensurable role. However, the mechanisms of EPCs senescence has not been fully investigated. Recently, ribosomal protein S6 kinase 4 (RSK4), a member of serine/threomine (Ser/Thr) kinase family and p53-related gene, is reported to regulate the replicative and stress-induced senescence of different cells.</p> <p>Presentation of the hypothesis</p> <p>These above lead to consideration of an evidence-based hypothesis that RSK4 may serve as a mediator of EPCs senescence in DM.</p> <p>Testing the hypothesis</p> <p>EPCs of healthy subjects and DM patients are isolated from peripheral blood and incubated with high glucose (HG). Then, the EPCs senescence would be detected by senescence associated β-galactosides (SA-β-gal) staining. Meanwhile, the RSK4 expression is assessed by RT-PCR and western blot. Moreover, overexpressing or RNA interfering of RSK4 in EPCs to investigate the relationship between RSK4 expression and the senescence of EPCs are necessary to substantiate this hypothesis. Also, studies on possible upstream and downstream factors of RSK4 would be explored to reveal the RSK4-mediated senescence pathway in EPCs.</p> <p>Implications of the hypothesis</p> <p>If proved, this hypothesis will provide another mediator of EPCs senescence, and may establish a novel pathogenesis for DM and further benefit to the management of DM.</p

CD133: a potential indicator for differentiation and prognosis of human cholangiocarcinoma.

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.BACKGROUND: CD133 is known to be a cancer stem cell (CSC) marker. However, recent studies have revealed that CD133 is not restricted to CSC but to be expressed not only in human normal tissues but also in some cancers and could serve as a prognostic factor for the patients. Nevertheless, the expression of CD133 in human cholangiocarcinoma (CC) is rare and our study is to detect the expression and explore the potential functions of CD133 in human CC. METHODS: Fifty-nine cases, comprised of 5 normal liver tissues and 54 consecutive CC specimens (21 well-differentiated, 12 moderately-differentiated and 21 poorly-differentiated), were included in the study. Immunohistochemical stainning with CD133 protein was carried out, and statistical analyses were performed. RESULTS: CD133 was found to express in all 5 normal livers and 40 out of 54 (74%) CC tissues with different subcellular localization. In the well, moderately and poorly differentiated cases, the numbers of CD133 positive cases were 19 (19 of 21, 90%), 10 (10 of 12, 83%) and 11 (11 of 21, 52%) respectively. Further statistical analyses indicated that the expression and different subcellular localization of CD133 were significantly correlated with the differentiation status of tumors (P = 0.004, P = 0.009). Among 23 patients followed up for survival, the median survival was 4 months for fourteen CD133 negative patients but 14 months for nine CD133 positive ones. In univariate survival analysis, CD133 negative expression correlated with poor prognosis while CD133 positive expression predicted a favorable outcome of CC patients (P = 0.001). CONCLUSIONS: Our study demonstrates that CD133 expression correlates with the differentiation of CC and indicates that CD133 is a potential indicator for differentiation and prognosis of human CC.Published versio

Genomic Mutation Profile of Primary Gastrointestinal Diffuse Large B-Cell Lymphoma.

Primary gastrointestinal diffuse large B-cell lymphoma (GI-DLBCL) is the most common gastrointestinal lymphoma, but its genetic features are poorly understood. We performed whole-exome sequencing of 25 primary tumor samples from patients with GI-DLBCL and 23 matched normal tissue samples. Oncogenic mutations were screened, and the correlations between genetic mutations and clinicopathological characteristics were analyzed. Twenty-five patients with GI-DLBCL were enrolled in the genetic mutation analysis with a median of 184 (range 79-382) protein-altering variants per patient. We identified recurrent oncogenic mutations in GI-DLBCL, including those in TP53, MUC16, B2M, CCND3, HIST1H1C, NEB, and ID3. Compared with nodal DLBCL, GI-DLBCL exhibited an increased mutation frequency of TP53 and reduced mutation frequencies of PIM1, CREBBP, BCL2, KMT2D, and EZH2. Moreover, GI-DLBCL exhibited fewer MYD88 and CD79B mutations than DLBCL in the testis and central nervous system. GI-DLBCLs with HLA-B, MEF2A, RHOA, and NAV3 mutations exhibited a tendency toward a high proliferation index. MUC16 and ETV6 mutations often occurred in tumors with early clinical staging. Our data provide a comprehensive understanding of the landscape of mutations in a small subset of GI-DLBCLs. The genetic mutation profiles of GI-DLBCL differ from those of nodal DLBCL and DLBCL in immune-privileged sites. The different mutated genes are related to the NF-κB and JAK-STAT pathways, and the different pathogenetic mechanisms leading to the development of DLBCL may be influenced by the tissue microenvironment. Differences in genetic alterations might influence the clinicopathological characteristics of GI-DLBCL

FTY720 protects cardiac microvessels of diabetes: a critical role of S1P1/3 in diabetic heart disease.

BACKGROUND: Diabetes is associated with an increased risk of cardiac microvascular disease. The mechanisms by which this damage occurs are unknown. However, research suggests that signaling through the sphingosine-1-phosphates receptor 1 and 3 (S1P1/3) by FTY720, a sphiongolipid drug that is structually similar to SIP, may play a role in the treatment on cardiac microvascular dysfunction in diabetes. We hypothesized that FTY720 might exert the cardioprotective effects of S1P1 and S1P3 viaprotein kinase C-beta (PKCβ II) signaling pathway. METHODOLOGY/PRINCIPAL FINDINGS: Transthoracic echocardiography was performed to detect the change of cardiac function. Scanning and transmission electron microscope with lanthanum tracer were used to determine microvascular ultrastructure and permeability in vivo. Apoptosis was detected by TUNEL and CD31 dual labeling in paraffin-embedded sections. Laser capture miscrodissection was used to assess cardiac micovascular endothelial cells (CMECs) in vivo. RT-PCR and Western blot analysis were used to determine the mRNA levels and protein expression of S1P1, S1P3, and PKCβ II. In the diabetic rats vs. controls, cardiac capillaries showed significantly higher density; CD31 positive endothelial cells were significantly reduced; the apoptosis index of cardiac endothlial cells was significantly higher. And FTY720 could increase the expressional level of S1P1 and boost S1P3 trasnslocation from membrane to nuclear, then ameliorate cardiac microvascular barrier impairment and pathologic angiogenesis induced by diabetes. In addition, overexpression of PKCβ II significantly decreased the protective effect of FTY720. CONCLUSIONS: Our study represents that the deregulation of S1P1 and S1P3 is an important signalresponsible for cardiac microvascular dysfunction in diabetes. FTY720 might be competent to serve as a potential therapeutic approach for diabetic heart disease through ameliorating cardiac microvascular barrier impairment and pathologic angiogenesis, which might be partly dependent on PKCβII-mediated signaling pathway

A clinicopathologic study of paragangliomas of the urinary bladder: can the clinical behavior of the tumor be predicted?

Paraganglioma of the urinary bladder is rare but even more unusual as no singular histologic feature is consistently characteristic of malignancy. Additionally, paragangliomas can manifest in hypertensive crisis for clinicians resecting the tumors in unusual locations without proper histologic diagnosis. Herein we report nine cases of paraganglioma of the urinary bladder with immunohistologic study and follow-up information, including one rare malignant case with liver metastasis. Comparison of the immunohistologic features reveal that the malignant case shows the common features suggested by both the Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) and Grading of Adrenal Pheochromocytoma and Extraadrenal Paraganglioma (GAPP) system. The predominant histopathologic features of malignant cases were large irregular nests with focal spindle tumor cells and a diffusely infiltrative growth pattern between smooth muscle of the urinary bladder wall with multiple necrotic areas and a high proliferative index. Eight cases without metastasis showed the classic zellballen of benign paragangliomas without irregular nests and welldemarcated nodules either in the submucosa or between smooth muscle bundles with no diffuse infiltration. We discuss the histopathologic and immunohistochemical features detecting malignant behavior, and comprehensively review the previously published cases of malignant paraganglioma of the urinary bladder. In summary, we assess some clinicopathologic features which might help to predict which neoplasms are more likely to behave in a clinically aggressive manner to avoid adverse outcomes in this rare tumor’s resection

Poorly differentiated chordoma

Chordoma is a rare primary malignant bone tumor that is believed to develop from embryonic notochordal remnants. The current World Health Organization (WHO) classification system divides chordoma into three subtypes: conventional, dedifferentiated and poorly differentiated chordoma (PDC). PDC is a newly recognized subtype of chordoma with distinct clinicopathological features characterized by loss of SMARCB1 expression. It typically occurs in young adults and children, more commonly arises in the skull base and cervical spine, rarely in the sacrococcygeal region, and exhibits more aggressive clinical behavior. Histologically, PDC is composed of cohesive sheets of poorly differentiated epithelioid cells with scattered intracytoplasmic vacuoles and minimal myxoid stroma, which may evoke a broad spectrum of differential diagnoses. Molecularly, PDC bears chromosome 22q loss leading to SMARCB1/INI1 inactivation. Clinicopathological correlation, including ancillary studies to confirm the loss of SMARCB1 expression, is critical for reaching the correct diagnosis

MET-overexpressing myxofibrosarcoma frequently exhibit polysomy of chromosome 7 but not MET amplification, especially in high-grade cases: clinical and pathological review of 30 myxofibrosarcoma cases

Abstract Background Myxofibrosarcoma (MFS) is one of the most common soft tissue sarcomas. Previous studies have shown that MET protein overexpressed in MFS patients and can serve as a prognostic factor. The reasons for MET protein overexpression include amplification of the MET gene, which is located on chromosome 7q. Triggered by an index case harboring chromosome 7 polysomy rather than MET gene amplification in myxofibrosarcoma, we investigated chromosome 7 polysomy in more cases. Methods Immunohistochemistry and fluorescence in situ hybridization (FISH) were performed in 30 MFS cases (including 2 epithelioid variant) to detect the expression of MET protein and gene status. Results MET was overexpressed in 14 cases out of 30, while thirteen cases were in higher FNCLCC grades (Grade 2–3). FISH showed that 11 cases having 3 signals on average of Met and more than 3 signals (Mean: 4.6) of centromere 7q (CEP7q). The MET/CEP7 ratio was about 0.65 on average, suggesting that chromosome 7 polysomy, rather than Met gene amplification, leading to the overexpression of MET protein in MFS. MET overexpression and chromosome 7 polysomy are positively correlated with higher Ki-67 index and higher grade and might have a high risk of local recurrence and metastasis. Conclusions It might reveals another explain of MET overexpression in myxofibrosarcoma, providing a clue for the therapy of MFS