Protein Tyrosine Phosphatases as Potential Regulators of STAT3 Signaling

The signal transducer and activator of transcription 3 (STAT3) protein is a major transcription factor involved in many cellular processes, such as cell growth and proliferation, differentiation, migration, and cell death or cell apoptosis. It is activated in response to a variety of extracellular stimuli including cytokines and growth factors. The aberrant activation of STAT3 contributes to several human diseases, particularly cancer. Consequently, STAT3-mediated signaling continues to be extensively studied in order to identify potential targets for the development of new and more effective clinical therapeutics. STAT3 activation can be regulated, either positively or negatively, by different posttranslational mechanisms including serine or tyrosine phosphorylation/dephosphorylation, acetylation, or demethylation. One of the major mechanisms that negatively regulates STAT3 activation is dephosphorylation of the tyrosine residue essential for its activation by protein tyrosine phosphatases (PTPs). There are seven PTPs that have been shown to dephosphorylate STAT3 and, thereby, regulate STAT3 signaling: PTP receptor-type D (PTPRD), PTP receptor-type T (PTPRT), PTP receptor-type K (PTPRK), Src homology region 2 (SH-2) domain-containing phosphatase 1(SHP1), SH-2 domain-containing phosphatase 2 (SHP2), MEG2/PTP non-receptor type 9 (PTPN9), and T-cell PTP (TC-PTP)/PTP non-receptor type 2 (PTPN2). These regulators have great potential as targets for the development of more effective therapies against human disease, including cancer

The EPOCH Project: I. Periodic variable stars in the EROS-2 LMC database

The EPOCH (EROS-2 periodic variable star classification using machine learning) project aims to detect periodic variable stars in the EROS-2 light curve database. In this paper, we present the first result of the classification of periodic variable stars in the EROS-2 LMC database. To classify these variables, we first built a training set by compiling known variables in the Large Magellanic Cloud area from the OGLE and MACHO surveys. We crossmatched these variables with the EROS-2 sources and extracted 22 variability features from 28 392 light curves of the corresponding EROS-2 sources. We then used the random forest method to classify the EROS-2 sources in the training set. We designed the model to separate not only $\delta$ Scuti stars, RR Lyraes, Cepheids, eclipsing binaries, and long-period variables, the superclasses, but also their subclasses, such as RRab, RRc, RRd, and RRe for RR Lyraes, and similarly for the other variable types. The model trained using only the superclasses shows 99% recall and precision, while the model trained on all subclasses shows 87% recall and precision. We applied the trained model to the entire EROS-2 LMC database, which contains about 29 million sources, and found 117 234 periodic variable candidates. Out of these 117 234 periodic variables, 55 285 have not been discovered by either OGLE or MACHO variability studies. This set comprises 1 906 $\delta$ Scuti stars, 6 607 RR Lyraes, 638 Cepheids, 178 Type II Cepheids, 34 562 eclipsing binaries, and 11 394 long-period variables. A catalog of these EROS-2 LMC periodic variable stars will be available online at http://stardb.yonsei.ac.kr and at the CDS website (http://vizier.u-strasbg.fr/viz-bin/VizieR).Comment: 18 pages, 20 figures, suggseted language-editing by the A&A editorial office is applie

Detecting Variability in Massive Astronomical Time-series Data. II. Variable Candidates in the Northern Sky Variability Survey

We present variability analysis of data from the Northern Sky Variability Survey (NSVS). Using the clustering method, which defines variable candidates as outliers from large clusters, we cluster 16,189,040 light curves having data points at more than 15 epochs as variable and non-variable candidates in 638 NSVS fields. Variable candidates are selected depending on how strongly they are separated from the largest cluster and how rarely they are grouped together in eight-dimensional space spanned by variability indices. All NSVS light curves are also cross-correlated with IRAS , AKARI, Two Micron All Sky Survey, Sloan Digital Sky Survey (SDSS), and GALEX objects, as well as known objects in the SIMBAD database. The variability analysis and cross-correlation results are provided in a public online database, which can be used to select interesting objects for further investigation. Adopting conservative selection criteria for variable candidates, we find about 1.8 million light curves as possible variable candidates in the NSVS data, corresponding to about 10% of our entire NSVS sample. Multi-wavelength colors help us find specific types of variability among the variable candidates. Moreover, we also use morphological classification from other surveys such as SDSS to suppress spurious cases caused by blending objects or extended sources due to the low angular resolution of the NSVS.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98631/1/1538-3881_143_3_65.pd

Adjuvant Coil Assisted Glue Embolization of Vein of Galen Aneurysmal Malformation in Pediatric Patients

PurposeAdjuvant coils may offer advantages in flow control during glue embolization of high flow vein of Galen aneurysmal malformation (VGAM) patients but involves specific issues such as feasibility, durability and coil mass effect. The purpose of this study is to assess the outcome of adjuvant coils in addition to transarterial glue embolization for treatment of these patients.Materials and MethodsFive pediatric VGAM patients (age range; 11 weeks to 2 yrs 2 mos) with high flow fistulous angioarchitecture were treated with adjuvant coils 1) in the distal feeding artery and/or 2) in the vein of Galen followed by glue embolization of the shunt. The angiographic / clinical outcomes were assessed.ResultsAdjuvant coils were deployed in the distal feeding artery (n=3), vein of Galen pouch plus distal feeding artery (n=2). Additional transarterial glue embolization of the fistulae was successfully performed (n=4). Complete occlusion was achieved with coils in one case. Complete occlusion was achieved for all mural type cases (n=4). Residual feeders remained in a case of choroidal type of VGAM. No complications were noted related to the treatment. All patients showed normal development on follow up (range: 7.6 to 88.8 mo, mean 49.3 mo). Initial hydrocephalus improved on follow up despite coil mass effect in dilated vein of Galen.ConclusionAdjuvant coils for flow control with glue embolization may be a safe and effective treatment method for VGAM patients with high flow fistulous feeders

Targeted disruption of TC-PTP in the proliferative compartment augments STAT3 and AKT signaling and skin tumor development

Tyrosine phosphorylation is a vital mechanism that contributes to skin carcinogenesis. It is regulated by the counter-activities of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Here, we report the critical role of T-cell protein tyrosine phosphatase (TC-PTP), encoded by Ptpn2, in chemically-induced skin carcinogenesis via the negative regulation of STAT3 and AKT signaling. Using epidermal specific TC-PTP knockout (K14Cre.Ptpn2fl/fl) mice, we demonstrate loss of TC-PTP led to a desensitization to tumor initiator 7,12-dimethylbenz[a]anthracene (DMBA)-induced apoptosis both in vivo epidermis and in vitro keratinocytes. TC-PTP deficiency also resulted in a significant increase in epidermal thickness and hyperproliferation following exposure to the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA). Western blot analysis showed that both phosphorylated STAT3 and phosphorylated AKT expressions were significantly increased in epidermis of TC-PTP-deficient mice compared to control mice following TPA treatment. Inhibition of STAT3 or AKT reversed the effects of TC-PTP deficiency on apoptosis and proliferation. Finally, TC-PTP knockout mice showed a shortened latency of tumorigenesis and significantly increased numbers of tumors during two-stage skin carcinogenesis. Our findings reveal that TC-PTP has potential as a novel target for the prevention of skin cancer through its role in the regulation of STAT3 and AKT signaling

Cordycepin induces apoptosis by caveolin-1-mediated JNK regulation of Foxo3a in human lung adenocarcinoma

Forkhead transcription factor (Foxo3a) is a downstream effector of JNK-induced tumor suppression. However, it is not clear whether the caveolin-1 (CAV1)-mediated JNK/Foxo3a pathway is involved in cancer cell apoptosis. We found that cordycepin upregulates CAV1 expression, which was accompanied by JNK phosphorylation (p-JNK) and subsequent Foxo3a translocation into the nucleus, resulting in the upregulation of Bax protein expression. Furthermore, we found that CAV1 overexpression upregulated p-JNK, whereas CAV1 siRNA downregulated p-JNK. Additionally, SP600125, a specific JNK inhibitor, significantly increased Foxo3a phosphorylation, which downregulated Foxo3a translocation into the nucleus, indicating that CAV1 mediates JNK regulation of Foxo3a. Foxo3a siRNA downregulated Bax protein and attenuated A549 apoptosis, indicating that the CAV1-mediated JNK/Foxo3a pathway induces the apoptosis of A549 lung cancer cells. Cordycepin significantly decreased tumor volume in nude mice. Taken together, these results indicate that cordycepin promotes CAV1 upregulation to enhance JNK/Foxo3a signaling pathway activation, inducing apoptosis in lung cancer cells, and support its potential as a therapeutic agent for lung cancer

Epidermal-specific deletion of TC-PTP promotes UVB-induced epidermal cell survival through the regulation of Flk-1/JNK signaling

UVB exposure can contribute to the development of skin cancer by modulating protein tyrosine kinase (PTK) signaling. It has been suggested that UVB radiation increases the ligand-dependent activation of PTKs and induces PTP inactivation. Our recent studies have shown that T-cell protein tyrosine phosphatase (TC-PTP) attenuates skin carcinogenesis induced by chemical regimens, which indicates its critical role in the prevention of skin cancer. In the current work, we report that TC-PTP increases keratinocyte susceptibility to UVB-induced apoptosis via the downregulation of Flk-1/JNK signaling. We showed that loss of TC-PTP led to resistance to UVB-induced apoptosis in vivo epidermis. We established immortalized primary keratinocytes (IPKs) from epidermal-specific TC-PTP-deficient (K14Cre.Ptpn2fl/fl) mice. Immortalized TC-PTP-deficient keratinocytes (TC-PTP/KO IPKs) showed increased cell survival against UVB-induced apoptosis which was concomitant with a UVB-mediated increase in Flk-1 phosphorylation, especially on tyrosine residue 1173. Inhibition of Flk-1 by either its specific inhibitors or siRNA in TC-PTP/KO IPKs reversed this effect and significantly increased cell death after UVB irradiation in comparison with untreated TC-PTP/KO IPKs. Immunoprecipitation analysis using the TC-PTP substrate-trapping mutant TCPTP-D182A indicated that TC-PTP directly interacts with Flk-1 to dephosphorylate it and their interaction was stimulated by UVB. Following UVBmediated Flk-1 activation, the level of JNK phosphorylation was also significantly increased in TC-PTP/KO IPKs compared to control IPKs. Similar to our results with Flk-1, treatment of TC-PTP/KO IPKs with the JNK inhibitor SP600125 significantly increased apoptosis after UVB irradiation, confirming that the effect of TC-PTP on UVB-mediated apoptosis is regulated by Flk-1/JNK signaling. Western blot analysis showed that both phosphorylated Flk-1 and phosphorylated JNK were significantly increased in the epidermis of TC-PTP-deficient mice compared to control mice following UVB. Our results suggest that TC-PTP plays a protective role against UVB-induced keratinocyte cell damage by promoting apoptosis via negative regulation of Flk-1/JNK survival signaling

Angiosarcomas of the Bilateral Breast and Heart: Which One is the Primary Site?

A 29-year-old pregnant woman with recurrent pericardial effusion and a cardiac tumor, diagnosed as an angiosarcoma, was treated with surgical resection of the tumor followed by radiotherapy. Immediately after completion of radiotherapy, she developed bilateral breast masses, which were also confirmed as angiosarcomas. We thought this might be the first case of bilateral angiosarcoma of the breast metastasizing to heart mimicking a primary cardiac angiosarcoma, although we could not conclude with certainty that angiosarcoma of the heart was not the primary site

Cordycepin promotes apoptosis by modulating the ERK-JNK signaling pathway via DUSP5 in renal cancer cells

Constitutive activation of extracellular signal regulated kinase (ERK)-Jun NH2-terminal kinase (JNK) signaling commonly occurs in tumors. The activation of ERK promotes cell proliferation, whereas that of JNK induces cell apoptosis. However, the apoptotic mechanism of ERK-JNK signaling in cancer is not well understood. Recently, we identified that apoptosis and activation of the JNK signaling pathway were induced after cordycepin treatment in human renal cancer, suggesting that JNK signaling might contribute to TK-10 cell apoptosis. We investigated the apoptotic effects of cordycepin by evaluating the activation of the ERK-JNK signaling pathway in renal cancer TK-10 cells. We found that cordycepin downregulated ERK and DUSP5, upregulated phosphorylated-JNK (p-JNK), and induced apoptosis. Moreover, we showed that siRNA-mediated inhibition of ERK downregulated DUSP5, whereas ERK overexpression upregulated DUSP5, and that DUSP5 knockdown by siRNA upregulated p-JNK. The JNK-specific inhibitor SP600125 upregulated nuclear translocation of β-catenin, and downregulated Dickkopf-1 (Dkk1), which has been shown to be a potent inhibitor of Wnt signaling. Dkk1 knockdown by siRNA upregulated nuclear β-catenin, suggesting the involvement of the Wnt/β-catenin signaling pathway. DUSP5 overexpression in TK-10 cells decreased p-JNK and increased nuclear β-catenin. The decreased Bax activation markedly protected against cordycepin-induced apoptosis. Bax subfamily proteins induced apoptosis through caspase-3. Taken together, we show that JNK signaling activation by cordycepin mediated ERK inhibition, which might have induced Bax translocation and caspase-3 activation via regulation of DUSP5 in TK-10 cells, thereby promoting the apoptosis of TK-10 cells. Targeting ERK-JNK signaling via the apoptotic effects of cordycepin could be a potential therapeutic strategy to treat renal cancer