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The emerging roles and therapeutic potential of exosomes in epithelial ovarian cancer
Xiaoduan Li1 &
Xipeng Wang1
Ovarian cancer (OC) is one of the three types of malignant tumors in the female reproductive system, and epithelial ovarian cancer (EOC) is its most typical form. Due to the asymptomatic nature of the early stages and resistance to chemotherapy, EOC has both a poor prognosis and a high fatality rate. Current treatments for OC are very limited, and the 5-years survival rate is approximately 30%. Exosomes, which are microvesicles ranging from approximately 30–100 nm in size that are secreted by living cells, can be produced from different cell types and detected in various body fluids. Cancer cells can secrete more exosomes than healthy cells, and more importantly, the content of cancer cell-derived exosomes is distinct. The exosomes shedding from tumor cells are considered to be involved in tumor progression and metastasis. As such, exosomes are expected to be potential tools for tumor diagnosis and treatment. In this review, we briefly present the emerging roles of exosomes in OC and summarize related articles about their roles as diagnostic or prognostic biomarkers and in the treatment and drug resistance of OC.
Epithelial ovarian cancer (EOC) is one of the most malignant tumors in the female reproductive system. As cancer statistics in China [1] revealed, the mortality rate of ovarian cancer (OC) has been rising for the past few years (comparing 2001–2003 with 2003–2011). In addition, this trend also existed in the United States, and the estimated mortality rates of OC would rank as the fifth highest based on existing data (2007–2011) [2]. Unlike other tumors, OC tumors tend to metastasize within the peritoneum but rarely disseminate through the vasculature [3], suggesting that OC may require treatment that is different from that for other tumors. Current clinical treatments for OC are very limited, and the surgery (cytoreduction or debulking), chemotherapy or treatment with a novel agent are the main therapeutic options. More than 75% of women have advanced disease (stage III or IV) at the time of diagnosis, that the 5-years survival rate among these patients is less than 25% [4]. Due to the asymptomatic nature of this disease during the early stages and resistance to chemotherapy, a poor prognosis can be expected [5].
Exosomes were proposed as products of membrane exfoliation at first. Johnstone first described and named them "exosomes" in 1987, and he suggested that exosomes might have specific membrane-related functions [6]. The potential primary function of exosomes is intercellular communication. Exosomes may have distinct biological activities, and their components depend on the cellular origin and are highly variable [7]. Exosomes contain many proteins, mRNAs, miRNAs, DNAs, lipids and transcriptional factors. In addition, a multitude of pathways can be activated because of cellular interactions with exosomal molecules, including mRNAs, miRNAs and proteins (e.g., heat shock proteins [HSPs] and adhesion molecules) [8].
It has been gradually accepted that cancer cells secrete more exosomes than healthy cells. Moreover, the contents of these exosomes have been found distinct from each other [9]. Remarkably, cancer cell-derived exosomes can provide a suitable microenvironment for cancer development, such as cell proliferation [10,11,12], drug resistance [13], angiogenesis and metastasis [14], immune modulation [15] and premetastatic niche formation [16]. In addition, these features are all present in OC. Therefore, exosomes are expected to be potential diagnostic, prognostic, and even therapeutic tools for EOC. Certainly, such applications are still under development and far from clinical translation. Exciting research has shown that exosomes can serve as drug delivery systems, similar to nanoparticles. Scientists loaded exosomes with chemotherapeutic drugs, which can be used to kill tumor cells effectively without typical side effects [17]. Based on current nanoparticle research, such drug delivery systems will have more applicability in clinic.
Although the field of exosomes is relatively new, they are involved in OC and expected to have applications in OC as well. In this review, we briefly present the emerging roles of exosomes in OC and summarize related articles about their roles as diagnostic or prognostic biomarkers and in the treatment and drug resistance of OC, especially EOC.
Exosomes as biomarkers of OC
The biomarker mainly used for the diagnosis and prognosis of EOC is CA125, which has low sensitivity and specificity. Recent studies have revealed that exosomes can transport enzymes from EOC cells. Furthermore, an increased level of exosomes in the peritoneal fluid has been found to be correlated with tumor progression [18, 19], indicating that the level of exosomes in the blood is correlated with the stage of OC. Thus, exosomes themselves and their contents have potential as tumor-specific markers. Although no exosomes-related indicator comparable with CA125 has been widely accepted. In addition, the lack of large-scale clinical trials and the immature purification and detection methods remain unresolved issues. The writers still believe that exosomes are promising as biomarkers of OC.
Exosomal miRNAs as diagnostic and prognostic biomarkers
Recent studies have shown that the role of exosomes was protecting miRNAs from RNases, which created conditions for using exosomal miRNAs to diagnose OC [20]. MiRNA levels are important and often detected. Eight particular miRNAs (e.g., miR-21) in exosomes isolated from the serum of women with benign disease or various stages of EOC demonstrated diagnostic promise, because they were not detectable in the normal controls [21]. Those findings indicate that miRNAs of circulating tumor-derived exosomes could potentially be used as surrogate diagnostic markers for biopsy profiling or extended to screening asymptomatic populations. A similar phenomenon was observed in miR-222-3p, compared with healthy individuals, the expression of exosomal miR-222-3p was significantly increased in the serum of EOC patients [22]. MiR-21 was involved in the oncogenesis of ovarian serous carcinoma (OSC). The exosomal transfer of miR-21 could promote oncogenic transformation in target cells distant from the primary tumor, and it could be used as a diagnostic tool [23]. The high concentrations of exosomes in EOC patients suggested excessive and active exosomal secretion. In a cohort of 163 EOC patients, the levels of miR-200b and miR-200c were higher in International Federation of Gynecologists and Obstetricians (FIGO) stage III-IV patients, including those with lymph node metastasis, than in FIGO stage I-II patients [24]. This analysis showed that these miRNAs were highly suitable for tumor staging, diagnosis and prognosis.
Exosomes in the urine have gained attention, and urinary exosomal miRNAs are easily available samples that have been recently explored, particularly in urological and gynecological diseases. Zavesky confirmed a significant up-regulation of miR-92a in OC urinary samples, which could use for diagnostic purposes [25]. In addition, miRNA microarray data showed that miR-30a-5p was up-regulated in the urine samples of ovarian serous adenocarcinoma (OSA) patients compared with healthy controls. Furthermore, lower urine levels of miR-30a-5p were found in gastric cancer (GC) and colon carcinoma (CC) patients, suggesting that urinary miR-30a-5p may be particular to OC and demonstrating the use of exosomal urinary miR-30a-5p as a specific diagnostic marker [26]. However, the diagnostic potential of exosomal urinary miRNAs may depend on the urine fraction and might be vulnerable to the external environment, which is an obvious constraint.
Considering that the sources of exosomal miRNAs were very extensive, and differed from one another, the type and expression level of miRNAs was very different. Moreover, the various studies mentioned before had gathered information on patients from different type of ovarian cancer, thus they presented different characteristics in the number of patients, varied specimen and quantity. Despite all the research with one table list, it was lack of inconsistency between different studies.
Exosome-related proteins as biomarkers
In this section, we summarize exosome-related proteins, such as endosomal membrane proteins, HSPs, enzymes, and globulins. These proteins are involved in adhesion, angiogenesis, proliferation, and metabolism [27]. In-depth proteomic analyses of OC cell line-derived exosomes revealed the differential enrichment of functional proteome categories [28]. When examining the protein profile of purified exosomes derived from two OC cell lines (OVCAR-3 and IGROV1), 1017 proteins were identified in both exosome types, including all the major exosomal protein markers. These data indicated that exosomes might serve as a resource of blood-based protein biomarkers in OC [29]. Comparing malignant and cirrhotic ascites, a proteomic analysis identified 424 proteins specific to malignant ascites. In addition, a functional analysis demonstrated that the major differences between them were the clusters of spliceosome proteins. The OC ascites proteome may provide markers for predicting patient survival and the effectiveness of different chemotherapy methods [30]. OC patient's plasma contains higher levels of exosomal proteins than that of benign tumor patients or healthy controls. Significantly, high exosomal protein levels were observed in both newly diagnosed OC patients and those with advanced stages of OC. In addition, the levels varied when examined during and after chemotherapy [31]. As a result, changes in exosomal protein levels might be useful for predicting responses to therapy and prognosis in OC patients when combined with clinical data.
Epithelial cell adhesion molecule (EpCAM) overexpression correlated with an escalation in epithelial cell proliferation during tumor development [32]. The exosomal EpCAM levels in normal individuals were very low, while an increase in the exosomal EpCAM level was found to be related to the stage and severity of ovarian carcinoma. These findings indicated that EpCAM could be useful for the diagnosis of OC with the detection of tumor-derived exosomes [21]. CD24 is an established marker of poor prognosis in ovarian and other types of carcinomas, and it has been identified in exosomes isolated from the ascites fluid of ovarian carcinoma patients. What is more, most of the CD24-positive exosomes are secreted by tumor cells [33]. EpCAM and CD24 in ovarian tumor-derived exosomes are promising alternatives for early detection [34]. In addition, they can distinguish OC-derived exosomes from vesicles originating from normal cells. Furthermore, as shown in a small set of pre- and post-treatment OC patient ascites samples, changes in the exosomal EpCAM and CD24 levels can accurately classify patients as being responsive or nonresponsive to therapy [35, 36], which has great value for evaluating prognosis. Activated leukocyte cell adhesion molecule (ALCAM) is involved in cell-cell interactions in cancer. Serum ALCAM levels have also been found to be significantly higher in EOC patients than in controls, and full-length transmembrane ALCAM was detected in exosomes extracted from EOC ascites samples. Studies have shown that ALCAM is a marker of EOC and correlates with more aggressive tumors [37].
Tumor-reactive immunoglobulins can also be used as diagnostic markers in OC. Serum samples from OC patients exhibited significantly greater immunoreactivity levels than samples from either normal controls or women with benign disease. Analyzing IgG recognition of specific exosomal antigens can distinguish benign ovarian masses from OC, as well as early- and late-stage OC. The quantitative assessment of IgG reactivity with tumor-derived exosomal proteins can be used as diagnostic markers for OC [38]. In addition, claudin proteins frequently overexpressed in OCs, and full-length claudins can be found in OC cell-derived exosomes. Moreover, nearly half of the plasma samples from OC patients exhibited the presence of claudin-4-containing exosomes [39]. Thus, claudin-4 can be used for the detection of OC.
A proteomics analysis of exosomes derived from two late-stage OC cell lines demonstrated that the pentose phosphate pathway was a dominant mechanism in exosome-mediated intracellular communication. Glucose-6-phosphate dehydrogenase (G6PD), transketolase (TK) and transaldolase 1 (TA1) are three key enzymes in the regulation of this pathway and may become diagnostic or prognostic biomarkers of OC [40]. The inhibition of N-glycosylation processing caused changes in the composition of extracellular vesicles and induced a decrease in the levels of several glycoproteins, which showed that the identified glycosignatures of extracellular vesicles could serve as novel biomarkers for OC [41].
Yong Zeng et al. found that the ExoSearch chip offers a method for the isolation and release of blood/plasma exosomes in various preparation volumes (10 μL to 10 mL). In addition, the blood-based diagnosis of OC via three exosomal protein markers for tumor (CA125, EpCAM, and CD24) showed significant diagnostic power [42] in that tumor testing with a drop of blood was possible. All biomarkers related to exosomes are summarized in Table 1.
Table 1 Exosomes serve as biomarkers of OC
Exosomes as prospctive therapeutic targets in OC
Exosomes are related to the immune system, which may provide the foundation for future immunotherapies
The limitations of current chemotherapies for OC have motivated the development of new treatments. Evidence has shown that exosomes released by a tumor can suppress the immune system of a patient and prepare niches for metastatic spread [43]. Cancer-related exosomes exhibit powerful influences that benefit tumors via a variety of biological mechanisms. Understanding the underlying and complex exosome-mediated immunosuppressive mechanisms is important to prevent the immune escape of tumor cells and identify novel treatments for cancer. The ability to block immunosuppressive factors in tumor microenvironments is expected to enhance antitumor immune responses in OC patients.
Myeloid-derived suppressor cells (MDSCs), whose main feature is the potent immunosuppressive effect, are a major component of the tumor microenvironment. MDSCs are a heterogeneous group that includes macrophages, tumor-associated macrophages (TAMs), dendritic cells (DCs), monocytes, and granulocytes [44]. Dendritic and lymphoid exosomes can regulate immune activation. Tumors can release exosomes mimicking membranous material, resulting in the deletion of reactive lymphocytes. In addition, these exosomes expressed many reactive molecules, which suppressed the expression of T cell activation signal components, thus suppressing the immune activity of T cells and inducing apoptosis [45]. Exosomes isolated from the malignant ascites of OC patients could be internalized by monocytes and induced the production of cytokines. Exosomes from ascites can trigger toll-like receptor (TLR)-dependent signaling pathways in monocyte-precursor cells, which are important for the induction of immunosuppressive mechanisms during cancer progression [46]. The function and differentiation of macrophages can also be adjusted by exosomes. EOC-derived exosomes can activate macrophages to exhibit a TAM-like phenotype, which can facilitate the progression of cancer. MiR-222-3p can transfer from EOC cells to macrophages by exosomes, thereby effectively regulating the polarization of tumor-promoting M2 macrophages [22]. In addition, EOC exosomes have shown to be involved in the immunosuppression of natural killer (NK) cells, which are confirmed to be important in two cytotoxic pathways for anticancer immunity, the NK C-type lectin-like receptor (NKG2D) receptor-ligand pathway and the CD226/DNAM-1-polio virus receptor/nectin-2 pathway [47].
In addition, exosomes isolated from malignant ascites can also impair the cytotoxic activity of peripheral blood mononuclear cells (PBMCs), and Fas ligand (FasL) has shown to be present in the exosomal suspension. Thus, anti-FasL antibody can decrease the percentage of DC and PBMC apoptosis [48]. The Fas/FasL system plays an important role in the immune privilege status of tumors by inducing Fas-mediated apoptosis in tumor-specific lymphocytes. Normal ovarian surface epithelial cells express but do not secret FasL, while EOC cells secrete FasL via the release of exosomes. The release of secreted FasL rather than the membrane-bound form facilitated the escape from immune surveillance and survival of the tumor cells [49]. Lysophosphatidic acid (LPA) can up-regulate FasL presentation on the surface of OC cells and stimulate the secretion of FasL-bearing exosomes, thereby contributing to an OC cell counterattack against activated T cells and promoting OC metastasis [50]. Ovarian carcinoma-derived exosomes have shown to carry phosphatidylserine (PS) on their surface, and PS appeared to be an important molecule for exosomal uptake by NK cells [51]. The PS present on the membrane of exosomes isolated from ovarian tumor tissues or ascites can reversibly inhibit the activation of T cells by arresting the T cell signaling cascade. The depletion or blockade of PS with anti-PS antibody could significantly block the inhibition of T cell function, which represents a potential therapeutic approach for patients with OC [52].
Scientists have leveraged the relation of exosomes to the immune system in antitumor research since 2005. One clinical trial employed an immunotherapeutic approach in conjunction with conventional first-line chemotherapy. The immunotherapy based on the use of a TLR3 agonist and tumor-derived exosomes carrying associated antigens, which could disrupt tumor immune tolerance and immunosuppressive effects. This therapy also exploited tumor-derived exosomes as a potential source of antigens for generating effective and lasting tumor antigen-specific T cell immunity [53]. In another study, metastatic ovarian carcinoma-derived exosomes presented tumor-specific antigens to DCs derived from umbilical cord blood, and these DCs could then stimulate common T cells to differentiate and effectively induce cytotoxicity, thereby providing a novel immunotherapy for OC [54] The potential targets for immunotherapy are listed in Table 2. Although there are currently few applications, the authors believe that the role of exosomes in tumor microenvironment immunity may have the most potential for treating OC.
Table 2 Exosomes provide potential targets for immunotherapy
Exosomes are related to the tumor microenvironment and promote progression and metastasis
OC patients have a poor prognosis and frequently experience recurrence and dissemination, even with chemotherapy or surgical debulking. Recent evidence revealed that the tumor microenvironment consists of stromal cells (including fibroblasts, macrophages, and MDSCs) and extracellular matrix components (including inflammatory cytokines and chemokine), which can promote cancer cell invasion and metastasis [55]. An increasing amount of evidence has shown that exosome-mediated interactions between tumor cells and their microenvironment are a key factor in tumor progression. Exosomes are key mediators of intercellular communication in the tumor microenvironment [56]. Intercellular communication is a function that progressively developed via a process of mutual cellular adaptation. Experiments showed that when cancer cells co-cultured with different individual mesenchymal stem cells (MSCs), the interactions between the MSCs and cancer cells depended on the exchange of exosomes. During these cellular interactions, varieties of functional changes were observed, particularly those promoting the growth of tumor cells [57].
As previously mentioned, urinary exosomal miR-30a-5p could be used as a high-specificity diagnostic marker of OC. At the same time, miR-30a-5p knockdown significantly inhibited OC cell proliferation and migration. Therefore, miR-30a-5p can also serve as a therapeutic target for OSA [26]. It has been found that exosomes, which present in the ascites and blood of ovarian carcinoma patients, contain different exosomal proteins frequently related to tumor progression, such as metalloproteinase inducers (EMMPRIN/CD147) and pro-heparanase. The application of patient-derived exosomes can promote the growth of human SKOV3ip carcinoma xenografts in mice [51]. Although this was just a preliminary animal experiment, the results suggested that the application of exosomes in the treatment of OC was feasible.
Exosome shedding, which is frequently observed in tumor cells, is suggested to be involved in several aspects of tumor progression. It demonstrated that exosomes isolated from invasive tumor cell lines as well as the bodily fluids of OC patients can deliver membrane-type 1 matrix metalloprotease (MT1-MMP), which is involved in matrix degradation and disease progression [58]. Extracellular matrix degradation played an important role in OC metastasis. In OC, ascites-derived exosomes were found to contain gelatin lysis enzymes. In addition, exosome-associated proteolytic activity in the tumor vicinity might augment tumor cell invasion into the stroma. Fractionation of malignant ascites revealed exosomes containing localized extracellular matrix-degrading proteinases. The activation of proteinases, such as MMPs and urokinase-type plasminogen activator (uPA), led to increased extracellular matrix degradation, which may facilitate tumor cell invasion and metastasis [59]. Human OC cell lines (CABA I and A2780) shed exosomes carrying MMPs into the extracellular medium, demonstrating a mechanism for regulating focalized proteolytic activity and interacting with the microenvironment [60]. The L1 adhesion molecule (CD171) overexpressed in EOC and associated with a poor prognosis. Although expressed as a transmembrane molecule, L1 was released from carcinoma cells in a soluble form. Tumor-derived vesicles may be an important source of soluble L1 that can regulate tumor cell function in an autocrine-paracrine fashion. Soluble L1 from ascites showed to be a potent inducer of cell migration [61].
More researches are required to provide insight into the mechanisms underlying exosome-induced invasion and migration. Recent studies revealed that LIN28, an RNA-binding protein, could be highly expressed in the exosomes of OC cells (IGROV1) and be internalized by non-tumor cells. When taken up by HEK293 cells, these exosomes led to significant increases in the expression of genes involved in the epithelial-to-mesenchymal transition (EMT) and induced HEK293 cell invasion and migration [62]. The exosomal release of various miRNAs significantly correlated to the invasive potential of cancer cells, and some miRNAs showed significant associations with effusion site and tumor stage. For example, high miR-21, miR-23b and miR-29a levels were associated with poor progression-free survival, whereas high miR-21 expression was correlated to poor overall survival [63]. OC cells specifically secrete exosomes with miRNAs. Then, these exosomes communicate with mesothelial cells to allow tumor dissemination through the peritoneal cavity. When comparing OC cell lines with high (Skov-3) and low (OVCaR-3) invasive potential, transcripts of the miR-let-7 family were more abundant in OVCaR-3 cells than Skov-3 cells. In contrast, they were more abundant in exosomes from Skov-3 cells than OVCaR-3 cells. Transcripts from the miR-200 family was only identified in OVCaR-3 cells and their exosomes [64]. These findings might because miR-let-7 suppresses cell proliferation by transporting more exosomes outside of cells, while miR-200 suppresses the EMT.
Malignant ascites is a natural medium for cell communication. A cluster of spliceosomal proteins identified in ascites as prognostic markers for the prediction of patient survival. Furthermore, they played a role in communication between cancer cells [30]. As previously mentioned, the pentose phosphate pathway is a dominant mechanism mediating intracellular communication via exosomes excreted from OC cells. Therefore, G6PD, TK, and TA1 are key proteins that could become therapeutic targets of OC [40].
A novel concept for the treatment of OC based on impairing the crosstalk between metastatic ovarian cells and their environment has been tested. And a tumor cell capture device was fabricated with exosomes and a three-dimensional scaffold (metastatic trap [M-Trap]). M-Trap transformed a systemic disease into a focalized disease, in which proven therapeutic approaches, such as surgery, can extend survival [65]. Certainly, there are exosomes that directly possess antitumor effects, such as disintegrin and metalloproteinase 15 (ADAM15)-rich exosomes. ADAM15 can be released into the extracellular space as a component cleaved from released exosomes, and this effectively inhibited cancer cell migration and activation [66]. In another study, exosomes from MSCs inhibited cell cycle progression in all tested cell lines and induced Skov-3 cell necrosis. An increase in the number of cells in the G0-G1 phase was observed, suggesting a block in cell cycle progression. These results indicated that exosomes could halt proliferation, thus leading to cell death by apoptosis or necrosis [67]. The functions of exosomes described previously are showed in Table 3.
Table 3 Exosomes related to tumor progression, metastasis and angiogenesis
Exosomes are related to angiogenesis
To date, curative therapies for OC remain under development, and anti-angiogenesis approaches may provide alternative strategies. Tumor-derived exosomes are essential for tumor angiogenesis.
High-grade OC-derived exosomes have a more profound impact on angiogenesis than those derived from low-grade OC. Proteomic profiles revealed that the constituents of high-grade OC-derived exosomes, such as activating transcription factor 2 (ATF2) and metastasis-associated protein 1 (MTA1), among others, had a profound impact on angiogenesis and may play a key role in enhancing tumor development [27]. CD147 is a membrane molecule that is highly expressed in tumor cells and is involved in the progression of malignancies by regulating MMP expression in peritumoral stromal cells. A recent study showed that CD147 expressed in exosomes derived from EOC cells and that CD147-positive vesicles shed by OC cells may induce angiogenesis activities in human umbilical vein endothelial cells [68].
Anti-angiogenesis effects may serve as the mechanisms of some chemotherapy drugs and be expected to provide targets for the treatment of OC. Recently, a study demonstrated the anti-neoplastic effect of Amla extract (Emblica officinalis, AE) on OC in vitro and in vivo. The underlying mechanism was that AE could down-regulate pro-angiogenic molecules, such as insulin-like growth factor 1 receptor (IGF1R), via up-regulating cellular and exosomal miR-375 in human OC cells [69], explaining why AE attenuated angiogenesis and had an antitumor effect.
Exosomes are related to drug resisitance
There is no doubt that OC is the most lethal gynecological malignancy. Most OC patients are initially sensitively responsive to the preferred chemotherapy with platinum and paclitaxel (PTX). Unfortunately, most patients experience recurrence within 6–12 months and die of progressively chemotherapy-resistant disease [70].
One study showed that cancer-associated adipocytes (CAAs) or fibroblasts (CAFs) can secrete exosomes to transfer miR-21 into neighboring cancer cells, thereby increasing the chemo-resistance of these cells to PTX via the down-regulation of the direct target apoptotic protease-activating factor 1 (APAF1). Exosomal miR-21 can enhance OC cell PTX-resistance and decrease OC cell apoptosis [71]. The relationship between endogenous miR-433 expression and resistance to PTX was also been investigated in OC cell lines. Moreover, miR-433 mediated the down-regulation of cyclin-dependent kinase 6 (CDK6) [72]. Interestingly, miR-21-3p induced cisplatin (CIS) resistance in ovarian tumors, potentially by targeting the neuron navigator 3 (NAV3) gene. Exosomes released by CIS-resistant cells were also capable of increasing resistance in other cells [73].
In addition to miRNAs, exosomal proteins are also involved in the process of tumor drug resistance. After being shed, exosomes can transfer their contents to recipient cells at the membrane-bound protein level. For example, P-glycoprotein (P-gp) shared between human OC cells via intercellular exosomal transfer, resulting in enhanced cellular resistance to PTX [74]. Jie Y et al. found that increased annexin A3 expression was a mechanism for platinum resistance in OC cells [75]. Further research showed that serum annexin A3 levels were significantly higher in platinum-resistant patients than in platinum-sensitive patients. It was also found that annexin A3 was associated with exosomal release from platinum-resistant OC cells, which was supported by OC cells expressing higher levels of annexin A3 releasing increased numbers of exosomes [76]. Proteins may be transports or carriers of chemotherapy drugs. The lysosomal proteins ATPase copper-transporting alpha and beta (ATP7A and ATP7B), which are putative CIS-export transporters, can enhance the exosomal export of platinum in drug-resistant human ovarian carcinoma cells [77].
Now, the supporting role on drug resistance of exosomes sourced from tumor microenvironment has, gain more and more attention, such as exosomes from CAAs or CAFs. Although there are few related research in ovarian cancer, we believe that they will increase rapidly, thus we still listed them separately in Table 4.
Table 4 Exosomes related to drug resistance
Due to the asymptomatic nature of this disease during the early stages and resistance to chemotherapy, OC, particularly EOC, has a poor prognosis [5]. The distinct components and biological activities of exosomes must be explored to identify novel high-sensitivity and high-specificity biomarkers for the early diagnosis of EOC. Such exosomal biomarkers should significantly increase in OC patients compared with healthy individuals, which are higher in patients with advanced-stage disease than early-stage disease. Some miRNAs meet these requirements, such as miR-222-3p [22], miR-200b and miR-200c [24]. However, as previously mentioned, related therapies remain in the laboratory stage and there is a lack of large-scale clinical trials. In addition, the diagnostic potential of any biomarker depends on the sample type (e.g., serum and urine, among others), and the maturity of the purification and detection methods will be a constraint. The limitations of current clinical OC therapies require the development of new treatments. Cancer-related exosomes exhibit powerful influences on tumors by a variety of biological mechanisms, and it is important to understand the underlying mechanisms of exosome-mediated immunosuppression and tumor progression, metastasis and angiogenesis. The ability of exosomes block factors in tumor microenvironments should enhance antitumor responses in OC. Most EOC patients died of progressively chemotherapy-resistant disease notably [70]. In addition to miRNAs, exosomal proteins are also involved in the process of drug resistance in OC patients. In order to retain patient sensitivity to platinum and PTX, the mechanism of drug resistance should be more thoroughly understood, and exosomes provide a novel perspective in that context.
In summary, the emerging field of exosomes has created new perspectives on diagnosis, prognosis, treatment, and drug resistance in OC (Fig. 1). Exosomes represent a mobile source of information regarding the molecular makeup of parental tumors. However, the exosomal knowledgebase has thus far been limited to the findings of a few persuasive studies. In addition, high-throughput exosomal isolation and analysis remains difficult. Much more research on exosomes needs to be perform to reveal breakthroughs in diagnosing and treating OC.
A summary of the roles of exosomes in ovarian cancer
a disintegrin and metalloproteinase
ALCAM:
Activated leukocyte cell adhesion molecule
APAF1:
Apoptotic protease-activating factor 1
ATF2:
Activating transcription factor 2
ATP7A:
ATPase copper-transporting alpha
ATP7B:
ATPase copper-transporting beta
CAAs:
Cancer-associated adipocytes
CAFs:
Cancer-associated fibroblasts
Colon carcinoma
CDK6:
Cyclin-dependent kinase 6
DCs:
DNAM-1:
EMMPRIN:
Metalloproteinase-inducer
EMT:
Epithelial-to-mesenchymal transition
EpCAM:
Epithelial cell adhesion molecule
FasL:
Fas ligand
G6PD:
Glucose-6-phosphate dehydrogenase
GC:
HIF-1α:
Hypoxia-inducible factor-1 alpha
IGF1R:
LPA:
M2:
Macrophage 2 phenotypes
MDSCs:
MSCs:
MT1-MMP:
Membrane-type 1 matrix metalloprotease
MTA1:
Metastasis-associated protein 1
NAV3:
Neuron navigator 3
NK:
Natural killer
NKG2D:
NK C-type lectin-like receptor
OC:
Ovarian serous adenocarcinoma
OSC:
Ovarian serous carcinoma
PBMCs:
Peripheral blood mononuclear cells
P-gp:
P-glycoprotein
PTX:
TA1:
Transaldolase 1
Transketolase
TLR:
Toll-like receptor
uPA:
urokinase-type plasminogen activator
VAMP3:
Vesicle-associated membrane protein 3
Wild type
Wanqing C, Rongshou Z, Baade PD. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66:115–32.
Siegel LR, Miller KD, Jemal A, DVM. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29.
Stack MS, Fishman DA. Ovarian Cancer, Cancer Treatment and Research, vol. 149. US: Springer; 2010.
Cancer Research UK. Cancer stats report–ovarian cancer. 2011. accessed July 3, 2014.
Coleman RL, Monk BJ, Sood AK, Herzog TJ. Latest research and treatment of advanced-stage epithelial ovarian cancer. Nat Rev Clin Oncol. 2013;10:211–24.
Johnstone RM, Adam M, Hammond JR, Orr L, Turbide C. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem. 1987;262:9412–20.
Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013;200:373–83.
Giusti I, D'Ascenzo S, Dolo V. Microvesicles as potential ovarian cancer biomarkers. Biomed Res Int. 2013;2013:703048.
Lara M, Amit S, George M, Megha S, Amiji MM. Exosome mediated communication within the tumor microenvironment. J Control Release. 2015;219:278–94.
Hong BS, Cho JH, Kim H, et al. Colorectal cancer cell-derived microvesicles are enriched in cell cycle-related mRNAs that promote proliferation of endothelial cells. BMC Genom. 2009;10:556.
Kogure T, Lin WL, Yan IK, Braconi C, Patel T. Intercellular nanovesicle-mediated microRNA transfer: a mechanism of environmental modulation of hepatocellular cancer cell growth. Hepatology. 2011;54:1237–48.
Zhang L, Zhang S, Yao J, et al. Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature. 2015;527:100–4.
Challagundla KB, Wise PM, Neviani P, et al. Exosome‐mediated transfer of microRNAs within the tumor microenvironment and neuroblastoma resistance to chemotherapy. J Natl Cancer Inst. 2015;107:djv135.
Kosaka N, Iguchi H, Hagiwara K, Yoshioka Y, Takeshita F, Ochiya T. Neutral sphingomyelinase 2 (nSMase2) -dependent exosomal transfer of angiogenic microRNAs regulate cancer cell metastasis. J Biol Chem. 2013;288:10849–59.
Fabbri M, Paone A, Calore F, et al. MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc Natl Acad Sci U S A. 2012;109:E2110–6.
Fong MY, Zhou W, Liu L, et al. Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis. Nat Cell Biol. 2015;17:183–94.
Tang K, Zhang Y, Zhang H, Xu P, Liu J, Ma J, Lv M. Delivery of chemotherapeutic drugs in tumour cell-derived microparticles. Nat Commun. 2012;3:1282.
Graves LE, Ariztia EV, Navari JR, et al. Proinvasive properties of ovarian cancer ascites-derived membrane vesicles. Cancer Res. 2004;64:7045–9.
Kajdos M, Janas L, Kolasa-Zwierzchowska D, Wilczyński JR, Stetkiewicz T. Microvesicles as a potential biomarker of neoplastic diseases and their role in development and progression of neoplasm. Prz Menopauzalny. 2015;14(4):283–91.
Mikaelian I, Scicchitano M, Mendes O, et al. Frontiers in preclinical safety biomarkers: microRNAs and messenger RNAs. Toxicol Pathol. 2013;41:18–31.
Taylor DD, Gercel-Taylor C. MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol. 2008;110(1):13–21.
Xiang Y, Quanfeng W, Xiaoli W, Qinyi Z, Xinjing W, Lu J, Xin C. Epithelial ovarian cancer-secreted exosomal miR-222-3p induces polarization of tumor-associated macrophages. Oncotarget. 2016;7(28):43076–87.
Cappellesso R, Tinazzi A, Giurici T, Simonato F, Guzzardo V, Ventura L, Crescenzi M. Programmed cell death 4 and microRNA 21 inverse expression is maintained in cells and exosomes from ovarian serous carcinoma effusions. Cancer Cytopathol. 2014;122(9):685–93.
Meng X, Müller V, Milde-Langosch K, Trillsch F, Pantel K, Schwarzenbach H. Diagnostic and prognostic relevance of circulating exosomal miR-373, miR-200a, miR-200b and miR-200c in patients with epithelial ovarian cancer. Oncotarget. 2016;7(13):16923–35.
Zavesky L, Jandakova E, Turyna R, Langmeierova L, Weinberger V, Minar L. Supernatant versus exosomal urinary microRNAs. Two fractions with different outcomes in gynaecological cancers. Neoplasma. 2016;63(1):121–32.
Zhou J, Gong G, Tan H, Dai F, Zhu X, Chen Y, Wang J. Urinary microRNA-30a-5p is a potential biomarker for ovarian serous adenocarcinoma. Oncol Rep. 2015;33(6):2915–23.
Yi H, Ye J, Yang XM, Zhang LW, Zhang ZG, Chen YP. High-grade ovarian cancer secreting effective exosomes in tumor angiogenesis. Int J Clin Exp Pathol. 2015;8:5062–70.
Sinha A, Ignatchenko V, Ignatchenko A, Mejia-Guerrero S, Kislinger T. In-depth proteomic analyses of ovarian cancer cell line exosomes reveal differential enrichment of functional categories compared to the NCI 60 proteome. Biochem Biophys Res Commun. 2014;445(4):694–701.
Liang B, Peng P, Chen S, Li L, Zhang M, Cao D, Yang J. Characterization and proteomic analysis of ovarian cancer-derived exosomes. J Proteomics. 2013;80:171–82.
Shender VO, Pavlyukov MS, Ziganshin RH, Arapidi GP, Kovalchuk SI, Anikanov NA, Altukhov IA. Proteome-metabolome profiling of ovarian cancer ascites reveals novel components involved in intercellular communication. Mol Cell Proteomics. 2014;13(12):3558–71.
Szajnik M, Derbis M, Lach M, Patalas P, Michalak M, Drzewiecka H, Szpurek D. Exosomes in Plasma of Patients with Ovarian Carcinoma: Potential Biomarkers of Tumor Progression and Response to Therapy. Gynecol Obstet (Sunnyvale). 2013;Suppl 4:3.
Fan Q, Cheng JC, Qiu X, Chang HM, Leung PC. EpCAM is up-regulated by EGF via ERK1/2 signaling and suppresses human epithelial ovarian cancer cell migration. Biochem Biophys Res Commun. 2015;457(3):256–61.
Runz S, Keller S, Rupp C, Stoeck A, Issa Y, Koensgen D, Mustea A. Malignant ascites-derived exosomes of ovarian carcinoma patients contain CD24 and EpCAM. Gynecol Oncol. 2007;107(3):563–71.
Beach A, Zhang HG, Ratajczak MZ, Kakar SS. Exosomes: an overview of biogenesis, composition and role in ovarian cancer. J Ovarian Res. 2014;7:14.
Speicher MR, Pantel K. Tumor signatures in the blood. Nat Biotechnol. 2014;32(5):441–3.
Im H, Shao H, Yong Il P, Peterson VM, Castro CM, Ralph W. Label-free detection and molecular profiling of exosomes with a nano-plasmonic sensor. Nat Biotechnol. 2014;32:488–93.
Carbotti G, Orengo AM, Mezzanzanica D, Bagnoli M, Brizzolara A, Emionite L, Puppo A. Activated leukocyte cell adhesion molecule soluble form: a potential biomarker of epithelial ovarian cancer is increased in type II tumors. Int J Cancer. 2013;132(11):2597–605.
Taylor DD, Gercel-Taylor C, Parker LP. Patient-derived tumor-reactive antibodies as diagnostic markers for ovarian cancer. Gynecol Oncol. 2009;115(1):112–20.
Li J, Sherman-Baust CA, Tsai-Turton M, Bristow RE, Roden RB, Morin PJ. Claudin-containing exosomes in the peripheral circulation of women with ovarian cancer. BMC Cancer. 2009;9:244.
Yi H, Zheng X, Song J, Shen R, Su Y, Lin D. Exosomes mediated pentose phosphate pathway in ovarian cancer metastasis: a proteomics analysis. Int J Clin Exp Pathol. 2015;8(12):15719–28.
Gomes J, Gomes-Alves P, Carvalho SB, Peixoto C, Alves PM, Altevogt P. Costa JExtracellular Vesicles from Ovarian Carcinoma Cells Display Specific Glycosignatures. Biomolecules. 2015;5(3):1741–61.
Zhao Z, Yang Y, Zeng Y, He M. A microfluidic ExoSearch chip for multiplexed exosome detection towards blood-based ovarian cancer diagnosis. Lab Chip. 2016;16(3):489–96.
Filipazzi P, Bürdek M, Villa A, Rivoltini L, Huber V. Recent advances on the role of tumor exosomes in immunosuppression and disease progression. Semin Cancer Biol. 2012;22:342–9.
Kumar V, Patel S, Tcyganov E, Gabrilovich DI. The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol. 2016;37(3):208–20.
Taylor DD, Gerçel-Taylor C. Tumour-derived exosomes and their role in cancer-associated T-cell signalling defects. Br J Cancer. 2005;92(2):305–11.
Bretz NP, Ridinger J, Rupp AK, Rimbach K, Keller S, Rupp C, Marmé F. Body fluid exosomes promote secretion of inflammatory cytokines in monocytic cells via Toll-like receptor signaling. J Biol Chem. 2013;288(51):36691–702.
Labani-Motlagh A, Israelsson P, Ottander U, Lundin E, Nagaev I, Nagaeva O, Dehlin E. Differential expression of ligands for NKG2D and DNAM-1 receptors by epithelial ovarian cancer-derived exosomes and its influence on NK cell cytotoxicity. Tumour Biol. 2016;37(4):5455–66.
Peng P, Yan Y, Keng S. Exosomes in the ascites of ovarian cancer patients: origin and effects on anti-tumor immunity. Oncol Rep. 2011;25(3):749–62.
Abrahams VM, Straszewski SL, Kamsteeg M, Hanczaruk B, Schwartz PE, Rutherford TJ, Mor G. Epithelial ovarian cancer cells secrete functional Fas ligand. Cancer Res. 2003;63(17):5573–81.
Meng Y, Kang S, Fishman DA. Lysophosphatidic acid stimulates fas ligand microvesicle release from ovarian cancer cells. Cancer Immunol Immunother. 2005;54(8):807–14.
Keller S, König AK, Marmé F, Runz S, Wolterink S, Koensgen D, Mustea A. Systemic presence and tumor-growth promoting effect of ovarian carcinoma released exosomes. Cancer Lett. 2009;278(1):73–81.
Kelleher Jr RJ, Balu-Iyer S, Loyall J, Sacca AJ, Shenoy GN, Peng P, Iyer V. Extracellular vesicles present in human ovarian tumor microenvironments induce a phosphatidylserine-dependent arrest in the T-cell signaling cascade. Cancer Immunol Res. 2015;3(11):1269–78.
Adams M, Navabi H, Croston D, Coleman S, Tabi Z, Clayton A, Jasani B. The rationale for combined chemo/immunotherapy using a Toll-like receptor 3 (TLR3) agonist and tumour-derived exosomes in advanced ovarian cancer. Vaccine. 2005;23(17–18):2374–8.
Li QL, Bu N, Yu YC, Hua W, Xin XY. Exvivo experiments of human ovarian cancer ascites-derived exosomes presented by dendritic cells derived from umbilical cord blood for immunotherapy treatment. Clin Med Oncol. 2008;2:461–7.
Luo Z, Wang Q, Lau WB, Lau B, Xu L, Zhao L, Yang H. Tumor microenvironment: the culprit for ovarian cancer metastasis? Cancer Lett. 2016;377(2):174–82.
Tang MK, Wong AS. Exosomes: emerging biomarkers and targets for ovarian cancer. Cancer Lett. 2015;367(1):26–33.
Yang Y, Otte A, Hass R. Human mesenchymal stroma/stem cells exchange membrane proteins and alter functionality during interaction with different tumor cell lines. Stem Cells Dev. 2015;24(10):1205–22.
Clancy JW, Sedgwick A, Rosse C, Muralidharan-Chari V, Raposo G, Method M, Chavrier P. Regulated delivery of molecular cargo to invasive tumour-derived microvesicles. Nat Commun. 2015;6:6919.
Graves LE, Ariztia EV, Navari JR, Matzel HJ, Stack MS, Fishman DA. Proinvasive properties of ovarian cancer ascites-derived membrane vesicles. Cancer Res. 2004;64(19):7045–9.
Dolo V, D'Ascenzo S, Giusti I, Millimaggi D, Taraboletti G, Pavan A. Shedding of membrane vesicles by tumor and endothelial cells. Ital J Anat Embryol. 2005;110(2 Suppl 1):127–33.
Gutwein P, Stoeck A, Riedle S, Gast D, Runz S, Condon TP, Marmé A. Cleavage of L1 in exosomes and apoptotic membrane vesicles released from ovarian carcinoma cells. Clin Cancer Res. 2005;11(7):2492–501.
Enriquez VA, Cleys ER, Da Silveira JC, Spillman MA, Winger QA, Bouma GJ. High LIN28A expressing ovarian cancer cells secrete exosomes that induce invasion and migration in HEK293 cells. Biomed Res Int. 2015;2015:701390.
Vaksman O, Tropé C, Davidson B, Reich R. Exosome-derived miRNAs and ovarian carcinoma progression. Carcinogenesis. 2014;35(9):2113–20.
Kobayashi M, Salomon C, Tapia J, Illanes SE, Mitchell MD, Rice GE. Ovarian cancer cell invasiveness is associated with discordant exosomal sequestration of Let-7 miRNA and miR-200. J Transl Med. 2014;12:4.
de la Fuente A, Alonso-Alconada L, Costa C, Cueva J, Garcia-Caballero T, Lopez-Lopez R, Abal M. M-trap: exosome-based capture of tumor cells as a new technology in peritoneal metastasis. J Natl Cancer Inst. 2015;6:107(9).
Lee HD, Kim YH, Koo BH, Kim DS. The ADAM15 ectodomain is shed from secretory exosomes. BMB Rep. 2015;48(5):277–82.
Bruno S, Collino F, Deregibus MC, Grange C, Tetta C, Camussi G. Microvesicles derived from human bone marrow mesenchymal stem cells inhibit tumor growth. Stem Cells Dev. 2013;22(5):758–71.
Millimaggi D, Mari M, D'Ascenzo S, Carosa E, Jannini EA, Zucker S, Carta G. Tumor vesicle-associated CD147 modulates the angiogenic capability of endothelial cells. Neoplasia. 2007;9(4):349–57.
De A, Powers B, De A, Zhou J, Sharma S, Van Veldhuizen P, Bansal A. Emblica officinalis extract downregulates pro-angiogenic molecules via upregulation of cellular and exosomal miR-375 in human ovarian cancer cells. Oncotarget. 2016. doi: 10.18632/oncotarget.8966.
Cho KR, Shih IM. Ovarian cancer. Annu Rev Pathol. 2009;4:287–313.
Au Yeung CL, Co NN, Tsuruga T, Yeung TL, Kwan SY, Leung CS, Li Y. Exosomal transfer of stroma-derived miR21 confers paclitaxel resistance in ovarian cancer cells through targeting APAF1. Nat Commun. 2016;7:11150.
Weiner-Gorzel K, Dempsey E, Milewska M, McGoldrick A, Toh V, Walsh A, Lindsay S. Overexpression of the microRNA miR-433 promotes resistance to paclitaxel through the induction of cellular senescence in ovarian cancer cells. Cancer Med. 2015;4(5):745–58.
Pink RC, Samuel P, Massa D, Caley DP, Brooks SA, Carter DR. The passenger strand, miR-21-3p, plays a role in mediating cisplatin resistance in ovarian cancer cells. Gynecol Oncol. 2015;137(1):143–51.
Zhang FF, Zhu YF, Zhao QN, Yang DT, Dong YP, Jiang L, Xing WX. Microvesicles mediate transfer of P-glycoprotein to paclitaxel-sensitive A2780 human ovarian cancer cells, conferring paclitaxel-resistance. Eur J Pharmacol. 2014;738:83–90.
Yan XD, Yin J, Yao H, et al. Increased expression of annexin A3 is a mechanism of platinum resistance in ovarian cancer. Cancer Res. 2010;70:1616–24.
Yin J, Yan X, Yao X, Zhang Y, Shan Y, Mao N, Yang Y. Secretion of annexin A3 from ovarian cancer cells and its association with platinum resistance in ovarian cancer patients. J Cell Mol Med. 2012;16(2):337–48.
Safaei R, Larson BJ, Cheng TC, Gibson MA, Otani S, Naerdemann W, Howell SB. Abnormal lysosomal trafficking and enhanced exosomal export of cisplatin in drug-resistant human ovarian carcinoma cells. Mol Cancer Ther. 2005;4(10):1595–604.
We thank the board of the Shanghai First Maternity and Infant Hospital Corporation for their excellent technical assistance.
This study was supported by grants from the National Natural Science Foundation of China (81372787, 81072136), Shanghai Municipal Bureau of Health (20134033) Shanghai Health System joint research project (2013ZYJB0201) and Top 100 Medical Elite in Shanghai (XBR 2011065).
XDL designed the figures, researched appropriate references and was a major contributor in writing the manuscript. XPW developed the structure of the article and guided the selection of references. Both authors read and approved the final manuscript.
Both authors have approved the final manuscript for publication.
Department of Gynecology, Shanghai First Maternity and Infant Hospital Affiliated with Tongji University, Shanghai, China
Xiaoduan Li & Xipeng Wang
Xiaoduan Li
Xipeng Wang
Correspondence to Xipeng Wang.
Li, X., Wang, X. The emerging roles and therapeutic potential of exosomes in epithelial ovarian cancer. Mol Cancer 16, 92 (2017). https://doi.org/10.1186/s12943-017-0659-y
Received: 06 September 2016


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Sam Cooke's A Change Is Gonna Come, 1964
Aretha Franklin, The Queen of Soul - I never Loved A Man(the Way I love You)
Aretha Franklin, The Queen of Soul Has Passed Away
BlacKkKlansmanmovie
Felicien
Spike Lee's "BlacKkKlansman": A Movie About Contemporary Issues and Conversations
Black Panther movie
Black Panther Movie Highlights Challenges Faced by Resources Rich Africa and Blacks in the World
Michaela DePrince, an accomplished ballerina
Michaela DePrince: From African War Orphan to American World Renowned Ballerina
Rhiannon Giddens' Freedom Highway : Julie
Rhiannon Giddens' Freedom Highway Solo Album: From African akonting, to Enslaved Blacks' Banjo to American Experience.
James Baldwin, Black American author and civil rights activist
I Am Not Your Negro: A Movie I Invite All Americans to Watch
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Legs of Tornado: The Human Who Outran the Wind
Legs of Tornado - The Human Who Outran the Wind
Legs of Tornado: A Rwandan Tale
Authored by Felicien Kanyamibwa
Long ago, the people of Rwanda suffered through a terrible famine. The rains did not come to help the crops grow, the grass withered, and the soil became so dry that it cracked.
John McCain, Lakeville, Minnesota, Oct 2008
Reflecting on the Life of John McCain
David O'Brian
John McCain, the US Senator from Arizona, passed away on Saturday, August 25, 2018, at 91. AfroAmerica Network remembers a man who did so much for the US, an American Hero and a political role model. A man with strong moral values and principles, despite human flaws.
Aretha Franklin, the Queen of Soul , passed away in Detroit, Michigan, on August 16, 2018. She is known as one of the greatest signer of soul, gospel and other music genres. Aretha Franklin once said: "I always felt rock and roll was very, very wholesome music." Her music inspired people from all over the World for over 6 decades and left them feel whole.
Zindzi Mandela shares experiences with her mother Winnie Mandela-- Source SABC News - YouTube
Winnie Madikizela-Mandela: Anti-apartheid Hero and Mother of Nation, Dies at 81
South African anti-apartheid hero, known as Mother of the Nation, and former first lady Winnie Madikizela-Mandela has passed away. She was aged 81.
President Obama Calls Lead Plaintiff in Same-Sex Marriage Case, Jim Obergefell
Same-Sex Marriage: Equal Dignity in the Eyes of the Law, US Supreme Court Rules.
A day after a landmark ruling cementing the foundation of Obamacare, the US Supreme Court handed yet another victory to
President Obama's administration by ruling that same-sex marriage is a civil right that states cannot ban.
Until recently, legalizing same-sex marriage was unthinkable in the United States. This did not deter gay rights advocates who have
continued their struggle, supported mostly by Democrats and Civil Rights activists. Several prominent business executives, such as
US Supreme Court ACA ruling celebration
Patient Protection and Affordability Care Act, PPACA or Obamacare here to stay.
Patient Protection and Affordability Care Act, PPACA or known as Obamacare, has once again survived the challenge from Republicans, after a 6-3 decision ruling by the US Supreme Court, or SCOTUS. Obamacare will be the health care law that will solidify President Barack Obama's legacy for generations to come.
The ruling was about the provision in the PPACA authorizing federal tax credits for eligible Americans, whether they live in states
Tim Cook - Apple CEO
"I am proud to be gay", says Apple CEO Tim Cook; Cites Martin Luther King
"I'm proud to be gay, and I consider being gay among the greatest gifts God has given me, " Apple CEO Tim Cook has said in a letter written for Bloomberg Businessweek, while publicly coming out as gay and declaring his support for equality.
Tim Cook, though the CEO of perhaps the most prominent company in the World today, has managed to keep a low profile on his personal life. In the letter he says that his decision to publicly acknowledge his sexuality was intended to "bring comfort to anyone who feels alone" and to "inspire people to insist on their equality."
January 21, 2019 is Martin Luther King Jr Day. Tributes to civil rights leader Martin Luther King Jr. will be held in the Unites States nationwide,. The day will be marked by massive marches, protests, and statements from various groups, politicians, activists, and individuals. As we celebrate, let us listen to the 1964 song by Sam Cooke: A Change Is Gonna Come.
Africa has some of the most ruthless, repressive, and corrupt dictators in the World. The most notorious took power following an armed rebellion, claiming to fight against repressive regimes and promising democracy.
Who would have thought in their youth, during the armed struggle, and in their early years of power, that these so called "revolutionary" leaders would turn into ones of the worst dictators in the World?
Stacey Abrams may be mostly known for her unsuccessful Democratic bid to become governor of Georgia in 2018. She was narrowly defeated, almost becoming the first black to be elected governor of Georgia, and the first black woman anywhere in the United States.
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redpajama_set_name: RedPajamaCommonCrawl


Do you find that the question of how to get rid of a timeshare has consumed your life? Are you losing sleep because you can't figure out the best way out of your timeshare? If so, you have come to the right place. Read on to learn more about your timeshare exit options and figure out the best way for you to be rid of your timeshare, once and for all.
When you buy a timeshare, you are buying into an idea, a lifestyle, a fantasy. This fantasy very rarely becomes a reality. More often than not, timeshare owners are dissatisfied with their purchase and left wondering how to get rid of a timeshare.
If you are in this position, rest assured you are not alone. The number of timeshare scams out there is alarming, and many people fall for one without realizing it. And then they need to know how to get out, but the options for unloading a timeshare can seem overwhelming.
Let's look at how you can get rid of a timeshare and examine the pros and cons of each. This will allow you to evaluate your options and choose the best one for you.
One way to get rid of a timeshare is by doing a timeshare resale. This is pretty much exactly what it sounds like. You list your timeshare with a real estate agent, and you sell it. You pay commissions to realtors, and there are closing costs.
If you own a timeshare that has increased in value, this can be a good option because you might make a little bit of money. However, for most people, this is not the case, and often a timeshare resale ends in a huge loss.
Most new timeshares sell for around $30,000 while the average timeshare resale is about $8,000. That is not the kind of math we like to see, but it is the reality of selling a timeshare. In addition, it can take time to sell because finding the right buyer can be tricky.
During this time you continue to make payments and end up being more and more in the negative on your timeshare. As you can see, this is often not the best option for getting out of a timeshare.
A second answer to how to get rid of a timeshare is by donating it to a charity. If you need a tax write off, this can be a good option. Just be careful and make sure you are donating to a legitimate charity that will actually qualify for a write-off.
In many cases, people use a timeshare attorney to help them with the donation process which is an additional cost.
A third and arguably better way to get rid of a timeshare is through the process of timeshare cancellation. When you cancel a timeshare, it makes it like it never even happened.
When you choose this as the answer to how to get rid of a timeshare, I highly recommend you call a skilled timeshare exit team. They make the process much easier and smoother. And in some cases, they may be able to help you get a refund from the timeshare company.
You read that right, you might be entitled to a refund from the timeshare company.
to get rid of a timeshare, call the experts and let them do the hard work for you. We are here for you when you need us, and we are on your side.


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Disgruntled Promontory employee arrested after, police say, making threat to shoot people
Alexander Cramer
acramer@parkrecord.com
After being told he would lose his job, a Promontory employee threatened to shoot multiple people at a public place and "go down in a blaze of glory" in a gun battle with law enforcement, according to a report from the Summit County Sheriff's Office.
Deputies responded both to Promontory, where the threat was made, and to the man's residence, Lt. Andrew Wright said, which they searched and found no weapons. The incident happened around lunchtime Wednesday, according to the report.
Wright said the 35-year-old Park City man was remorseful for the panic he had caused and lacked the means to carry out his threat.
"In today's age … we don't take threats like that lightly," Wright said. "If someone is making a threat like that out of frustration but doesn't have the means to follow through, we don't know that when someone makes that kind of threat."
The man was arrested and booked into jail. He was charged with threat of violence, a class B misdemeanor.
A Promontory spokesperson in an email declined to comment on "internal human resource matters" and would not confirm what the man's job was or whether he was fired or had quit. Wright said the man is not allowed back on Promontory property.
The man said he was going to "snipe" people at a specific public place with an assault rifle, then shoot it out with police if Promontory hurt his family, according to the report.
The man had told management he was going to quit, and when he requested to retract that statement, they denied the request. He had also been disciplined for insubordination, according to the report. After that, the man made the threat.
Staff and management told the authorities they were frightened and took the threats seriously and reported them to the Sheriff's Office. The man had left the scene by the time deputies responded to Promontory, but another team of deputies found him at his house.
In cases when a person has made a "terroristic threat" of violence, Wright said, the first priority is to ensure the people who are being threatened or the place the threats are targeting is secure. At the same time, the office sends out deputies to see if the means exist for the threats to be carried out.
Since the man was encountered at his home, and consented to it being searched, deputies were able to ascertain the man didn't possess any weapons with which he could conduct a mass shooting.
Wright wasn't sure if deputies arrived at the home in larger numbers or with greater firepower than usual, or with their guns drawn, but he said it would not be unusual in a case like this. If the man had been driving or near the area he had threatened, deputies would have conducted a "high-risk" stop with a greater show of force and ordered the man to leave his vehicle at gunpoint, Wright said.
"It's one of those things that people need to remember — you can't even make those threats," he said. "We in law enforcement (and the) Sheriff's Office will take aggressive action against people who make these types of threats. In the climate we live in, the shootings that we see on a regular basis throughout our country. … The Summit County Sheriff's Office, we don't want to see it in our county and we'll take steps to prevent it."


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Wikipedia:Wikipedia Signpost/2018-06-29/Featured content
< Wikipedia:Wikipedia Signpost | 2018-06-29
New promotions: Enjoy the superb content.
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By Eddie891
This Signpost "Featured content" report covers material promoted from May 19 through June 18. Text may be adapted from the respective articles and lists; see their page histories for attribution.
18 featured articles were promoted.
Construction of Rockefeller Center, undertaken as an urban renewal project for Midtown Manhattan, was the largest private construction project at the time. Shown here partially completed in December 1933.
Lord Howe swamphen has been extinct since the early 19th century.
Tutupaca, a complex formed by three overlapping volcanoes in Peru's Central Volcanic Zone, reaches 5,815 metres.
Ceratosaurus cast at Natural History Museum of Utah
Edward the Elder (nominated by Dudley Miles) was King of the Anglo-Saxons from 899 until his death. He was the elder son of Alfred the Great and his wife Ealhswith. When Edward succeeded to the throne, he had to defeat a challenge from his cousin Æthelwold, who had a strong claim as the son of Alfred's elder brother and predecessor, Æthelred.
Ficus macrophylla (nominated by Cas Liber) is a large evergreen banyan tree of the family Moraceae native to eastern Australia, from the Wide Bay–Burnett region in the north to the Illawarra in New South Wales, as well as Lord Howe Island.
The Royal Naval Division War Memorial (nominated by HJ Mitchell) is a First World War memorial located on Horse Guards Parade in central London, and dedicated to members of the 63rd (Royal Naval) Division (RND) killed in that conflict. Sir Edwin Lutyens designed the memorial, which was unveiled on 25 April 1925—ten years to the day after the Gallipoli landings, in which the division suffered heavy casualties.
The Lord Howe swamphen (nominated by FunkMonk) is an extinct species of rail which lived on Lord Howe Island, east of Australia. It was first encountered when the crews of British ships visited the island between 1788 and 1790, and all contemporary accounts and illustrations were produced during this time. Today, two specimens exist: the holotype in the Natural History Museum of Vienna, and another in Liverpool's World Museum.
Construction of Rockefeller Center: (nominated by epicgenius) The construction of New York City's Rockefeller Center complex was conceived as an urban renewal project, spearheaded by John D. Rockefeller Jr., to help revitalize Midtown Manhattan. Rockefeller Center is located on one of Columbia University's former campuses and is bounded by Fifth Avenue to the east, Sixth Avenue (Avenue of the Americas) to the west, 48th Street to the south, and 51st Street to the north. The center occupies 22 acres (8.9 ha) in total, with some 17 million square feet (1.6×106 m2) of office space.
The Australian Air Corps (AAC) (nominated by Ian Rose) was a temporary formation of the Australian military that existed in the interval between the disbandment of the Australian Flying Corps (AFC) of World War I and the establishment of the Royal Australian Air Force (RAAF) in March 1921. Raised in January 1920, the AAC was commanded by Major William Anderson, a former AFC pilot.
Tutupaca (nominated by Jo-Jo Eumerus) is a volcano in the region of Tacna in Peru. It is part of the Peruvian segment of the Central Volcanic Zone, one of several volcanic belts in the Andes. Tutupaca consists of three overlapping volcanoes formed by lava flows and lava domes made out of andesite and dacite, which grew on top of older volcanic rocks. The highest of these is usually reported to be 5,815 metres (19,078 ft) high and was glaciated in the past.
Lazarus (nominated by Argento Surfer) is a dystopian science fiction comic book series created by writer Greg Rucka and artist Michael Lark.
The Black Hours, Morgan MS 493 (nominated by Ceoil) is an illuminated book of hours produced in Bruges between 1460 and 1475, although dates as late as 1480 have been suggested. It consists of 121 leaves, most containing blocks of Latin text written in Gothic minuscule script, arranged in rows of fourteen lines.
Antiochus X Eusebes (nominated by Attar-Aram syria) as a Hellenistic Seleucid monarch who reigned as the King of Syria between 95 and 92 or 89 BC.
The red warbler (nominated by MeegsC) is a small passerine bird of the New World warbler family Parulidae endemic to the highlands of Mexico, north of the Isthmus of Tehuantepec.
Guy Burgess (nominated by Brianboulton) was a British diplomat and Soviet agent, a member of the Cambridge Five spy ring that operated from the mid-1930s to the early years of the Cold War. His defection in 1951 to the Soviet Union, with his fellow-spy Donald Maclean, led to a serious breach in Anglo-United States intelligence co-operation, and caused long-lasting disruption and demoralisation in Britain's foreign and diplomatic services.
Nicholas Hoult (nominated by Numerounovedant) is an English actor. His body of work includes supporting work in big-budget mainstream productions and starring roles in independent projects in both the American and the English film industries. He has been nominated for such awards as a British Academy Film Award, a Critics Choice Award, and a Gold Derby Award. Hoult was included in Forbes magazine's 2012 list of 30 under 30.
Hoodening (nominated by Midnightblueowl) is a folk custom found in Kent, a county in south-eastern England. The tradition entails the use of a wooden hobby horse known as a hooden horse that is mounted on a pole and carried by an individual hidden under a sackcloth. Originally, the tradition was restricted to the area of East Kent, although in the twentieth century it spread into neighbouring West Kent. It represents a regional variation of a "hooded animal" tradition that appears in various forms throughout the British Isles.
The Gevninge helmet fragment (nominated by Usernameunique) is the dexter eyepiece of a Danish helmet from the Viking Age or end of the Nordic Iron Age. It was found in 2000 during the excavation of a Viking farmstead at Gevninge, near Lejre.
Ceratosaurus (nominated by Jens Lallensack) was a predatory theropod dinosaur in the Late Jurassic Period (Kimmeridgian to Tithonian).
Cleopatra (nominated by Pericles of Athens) was the last active ruler of the Ptolemaic Kingdom of Egypt, nominally survived as pharaoh by her son Caesarion. She was also a diplomat, naval commander, linguist, and medical author.
The Hudson Sesquicentennial half dollar (nominated by Wehwalt) is a commemorative fifty-cent piece struck by the United States Bureau of the Mint in 1935. The coin was designed by Chester Beach. Its obverse depicts Half Moon, flagship of Henry Hudson, after whom the city of Hudson is named. In addition to showing the ship, the coin depicts a version of the Hudson city seal, with Neptune riding a whale, a design that has caused commentary over the years.
18 featured lists were promoted.
Fomalhaut b (Dagon), 25 light-years away, is one of the nearest exoplanets, and has been directly imaged.
Billboard Latin Music Award for Hot Latin Song of the Year (nominated by Brankestein)
List of Hot Country Songs number ones of 2008 (nominated by ChrisTheDude)
Miike Snow discography (nominated by PancakeMistake)
Jimi Hendrix videography (nominated by Ojorojo)
List of Premier League winning players (nominated by Mattythewhite)
List of international goals scored by Cristiano Ronaldo (nominated by The Rambling Man)
List of Turkish football champions (nominated by Akocsg)
Timeline of Scottish football (nominated by ShugSty)
List of 1992 Winter Olympics medal winners (nominated by Courcelles)
Best Male Athlete with a Disability ESPY Award (nominated by MWright96)
List of games by Epic Games (nominated by PresN)
List of Local Nature Reserves in Kent (nominated by Dudley Miles)
List of municipalities in New Mexico (nominated by Mattximus)
List of ecclesiastical parishes in the Diocese of Bath and Wells (nominated by Rodw)
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The featured article section for the Hudson Sesquicentennial half dollar has an i missing from the word "is". Just though I'd let you know. Alduin2000 (talk) 17:13, 2 July 2018 (UTC)
Looks like its been fixed. L293D (☎ • ✎) 12:50, 4 July 2018 (UTC)
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Enjoying an elevated position, this well-established hotel is not only close to the sandy Seagulls Beach, but also Fuengirola's lively centre. Two swimming pools take pride of place in the well-maintained grounds and surrounded by a huge sun terrace it's a perfect spot for relaxing with a refreshing drink or snack from the pool bar. If you want to up the pace, there's plenty to get involved in. During the day table tennis and billiards are on the agenda, whilst at night you can expect occasional shows and live music. The hotel's great location makes getting out and about easy. A bus stop and the local train station lie a short stroll away, so you can explore the surrounding areas of Costa del Sol whenever you like! NB: Due to the elevated location, the hotel may not be suitable for the less mobile guests.
Meals: Full board with buffet-style breakfast, lunch and dinner. Hot and cold snacks 11am-12.30pm and 4pm-6.30pm. Ice-cream available 11am-10pm.
Drinks: Locally produced alcoholic drinks including beer and wine and non-alcoholic drinks including water, fruit juice (excluding fresh fruit juice), tea and coffee from the pool bar 11am-7.30pm (times may vary) and from the lounge bar 11am-11pm. Afternoon tea, coffee, cakes/biscuits 4pm-6.30pm. Selected drinks served during meal times.


A core scheme of the BZ reaction with Ce and BMA.
current 01:11, 25 July 2007 427 × 479 (11 KB) Anatol M. Zhabotinsky (Talk | contribs) A core scheme of the BZ reaction with Ce and BMA.
00:39, 19 July 2007 427 × 479 (10 KB) Anatol M. Zhabotinsky (Talk | contribs) A core scheme of the BZ reaction with Ce and BMA.


Aaron West's Technology Blog: Spoof Caller ID and Change Your Voice?
Spoof Caller ID and Change Your Voice?
During my commute to work this morning I was catching up on some old TWiT podcasts, listening to TWiT 40: Yellow Lasers. Towards the beginning of the Podcast Leo and company began discussing SpoofCard, a service that offers consumers the ability to make phone calls spoofing any number you want. Additionally, you can alter your own voice by selecting from a list of available voices. You use the SpoofCard service by purchasing calling cards from $10 (60 minutes of USA talk time) to $40 (240 minutes of USA talk time).
I have not tried this service but if anyone has, please let me know. Crazy.
This entry was posted by Aaron West on March 14, 2006 at 8:44 AM. It was filed in the following categories: General. It has been viewed 2661 times and has 1 comments.
1 Responses to Spoof Caller ID and Change Your Voice?


Emily Watson was born in England in 1967 and in War Horse, she magnificently portrays Rose, the mother of Albert Naraccott.
Watson attended the University of Bristol and got a BA in English. Later on, she trained at the Drama Studio London but as many other actors struggled in the beginnings of her career. Actually, her acting career began on stage, where she took part in various plays: The Children's Hours, Three Sisters, Much Ado About Nothing and so on. Later on, she joined the Royal Shakespeare Company with All's Well That Ends Well, The Changeling and A Jovial Crew, among the rest.
Her movie debut happened when she was cast to play Bess McNeill in Breaking the Waves in 1996, a rather controversial role for the time – she only got it because Helena Bonham Carter dropped out last minute!
Watson is so passionate about her roles that for her role as Jacqueline in Hilary and Jackie – another controversial role – she learned how to play the cello in mere three months! Other popular appearances of her include starring in the movies The Boxer, Red Dragon, Corpse Bride, Oranges and Sunshine and The Theory of Everything.
Among other significant nominations and awards, Watson received a nomination for the Academy Award for Best Actress for her leading role in Breaking the Waves. In 1998, she won the BIFA Award for Best Actress for her role as Jacqueline in Hilary and Jackie. She lives in London with her husband, whom she met at the Royal Shakespeare Company and their two children and finds great joy in actively supporting children charities.


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An immediate ban on the aerial use of 1080 poison is needed to prevent more kea deaths.
1. The Kea, the world's only mountain parrot, needs your help!
2. Why is the NZ Government poisoning Kea?
4. Why is TbFree Poisoning Kea Habitat?
Playing with these big parrots, in car parks and at ski fields, is one of the best experiences NZ has to offer animal lovers. But the kea's home, the alpine herb fields and rainforests of southern NZ, is being poisoned by the New Zealand Government.
Cinnamon-flavoured, cereal food pellets will be spread from the air, twice. The first time they will be just flavoured cereal. The second time, they will contain deadly 1080 poison.
Kea will eat the cereal baits and die. They will also be poisoned if they drink from ponds and alpine tarns where the baits lie, or scavenge poisoned carcasses or eat the dying insects surrounding the poisonous baits.
It was first recognised that the government's poisonings were killing kea in 1963.
In 2008, government monitoring of the kea began.
The monitoring showed that large numbers of kea were dying.
At one site (North Okarito) 77% of the monitored kea died.
1080 poisoning is very cruel. It causes extreme spasms and vomiting, with suffering for many hours or days.
Many kea are likely to die.
There are not many kea left.
In 1986 and 1992, it was estimated there were 1000-5000 kea, in total.
The Government poisonings will not only kill off precious kea.
There is solid evidence that the Government's 1080 poisonings kill many other native creatures and cause plagues of unwanted species. The whole ecology is at stake.


text:
Q: Email Fails to send with sms details The following code listens for an incoming sms, takes all the spaces out of the sms then emails the edited sms. Everything works fine, except that the app fails to send an email. Can anyone see what I am doing wrong and help me?
new Thread() {
    public void run() {

        try {

            DatagramConnection _dc =
                (DatagramConnection)Connector.open("sms://");

            for(;;) { //'For-Loop' used to listen continously for incoming sms's

                Datagram d = _dc.newDatagram(_dc.getMaximumLength());
                _dc.receive(d);  //The sms is received
                byte[] bytes = d.getData();
                String address = d.getAddress(); //The address of the sms is put on a string.
                String msg = new String(bytes); //The body of the sms is put on a string.
                String msg2 = (replaceAll(msg, " ",""))  ; //

                Store store = Session.getDefaultInstance().getStore();

                Folder[] folders = store.list(Folder.SENT);
                Folder sentfolder = folders[0]; //Retrieve the sent folder

                Message in = new Message(sentfolder);
                Address recipients[] = new Address[1];

                recipients[0]= new Address("me@yahoo.com", "user");

                in.addRecipients(Message.RecipientType.TO, recipients);

                in.setSubject("Incoming SMS"); //The subject of the message is added
                in.setContent("You have just received an SMS from: " + address + "/n" + "Message: " + msg2); //Here the body of the message is formed

                in.setPriority(Message.Priority.HIGH); //The priority of the message is set.

                Transport.send(in); //The message is sent

                in.setFlag(Message.Flag.OPENED, true);
                Folder folder = in.getFolder(); //The message is deleted from the sent folder
                folder.deleteMessage(in);
            }

        }catch (Exception me) { //All Exceptions are caught
        }
    }
};

public static String replaceAll(String front, String pattern, String back) {

    if (front == null)
    return "";

    StringBuffer sb = new StringBuffer(); //A StringBufffer is created
    int idx = -1;
    int patIdx = 0;

    while ((idx = front.indexOf(pattern, patIdx)) != -1) {
        sb.append(front.substring(patIdx, idx));
        sb.append(back);
        patIdx = idx + pattern.length();
    }

    sb.append(front.substring(patIdx));
    return sb.toString();
}

Thanks

A: This isn't really an answer to the problem, just an elaboration on my comment above, that might help.
Make sure do something in your exception catch block, so that problems in the code don't go unnoticed.  It's possible that your code is not encountering any exceptions, but in order for us to help, we need to try to eliminate potential problems, and since you say the code isn't working, but you have an empty exception handler, that's an easy area to fix first.
the simplest handler is just:
try {
   // try sending sms here
} catch (Exception e) {
   e.printStackTrace();
}

If you can run this in the debugger (which I highly suggest), then you can now put a breakpoint on the e.printStackTrace() line, and see if it ever gets hit.  If it does, inspect the value of e and tell us what it is.
Normally, in my programs, I don't actually use e.printStackTrace() in catch handlers, but I have a logging class that takes strings, and maybe a log level (e.g. info, warning, error, verbose), and writes to a log file.  The log file can be attached to emails the users send to tech support, or can be disabled for production if you only want to use the feature while developing.
Anyway, start with a simple printStackTrace() and see if it ever gets hit.  Then, report back.

Edit: from the symptoms you describe in the comments after your question, it seems like it's a possibility that
 String msg2 = (replaceAll(msg, " ",""))  ; //

is throwing an exception, and therefore never letting you get to where you'd send the email.  I can't see anything wrong with your implementation of replaceAll() upon initial inspection, but that might be a place to look.  Has that implementation been thoroughly unit-tested?
Also, I think you have a "/n" in your code where you probably want a "\n", right?

redpajama_set_name: RedPajamaStackExchange


text:
Proof Chief Justice Roberts Blackmailed? Sibel Edmonds Blows The Whistle On Government Blackmailing – The Corbett Report
Posted by Alexandra | Jun 27, 2013 | 2013, Conspiracy, Cabal, Education, Environment, Financial, Economy, Government Laws, Policies, Politicians, Military | 0 |
(Before It's News)
Was Supreme Court Justice John Roberts blackmailed into supporting Obamacare via information gained about him by the National Security Agency? The more US government crimes are being exposed by whistleblowers such as Edward Snowden, Bradley Manning, Russ Tice and Sibel Edmonds, the more I get the feeling that these criminal politicians and criminals in the state department are the ones who are slowly being boiled, not realizing that their crimes and lies have left them in extremely hot water.
In this remarkable conversation, Sibel Edmonds reflects on Russ Tice's recent revelations to Boiling Frogs Post and The Corbett Report that the NSA has wiretapped top government officials for years. Edmonds discusses from her own experience how the FBI collects dirt on Congressman and public officials for use as political leverage. We also talk about how this scandal proves that there is no "official channel" for whistleblowers to follow when they want to expose wrondoing because the system is being controlled from behind the scenes by the criminals in the national security establishment.
From Mike Adams and Natural News: Ten days ago, I publicly stated my belief that the NSA had used its spy apparatus to gather dirt on Supreme Court Justice John Roberts, then used that leverage to force him to change his vote on Obamacare.
Five days later, I also predicted the NSA was using its spy powers to surveil members of Congress and the U.S. Senate. In an article published on June 16, 2013, I wrote, "There could already be countless cases of the NSA using its god-like powers to blackmail people in key positions in the U.S. Senate (which is full of pedophiles and perverts), the House of Representatives, the State Department or even the US Supreme Court. There are virtually no limits to the abuses of this power."
Suddenly, new revelations prove this to be true. Russ Tice, a Bush-era NSA analyst-turned-whistleblower has sounded the alarm on the true depth of the NSA's surveillance abuses. In an interview on the Boiling Frogs Podcast, Tice stated:
"They went after — and I know this because I had my hands literally on the paperwork for these sort of things — they went after high-ranking military officers; they went after members of Congress, both Senate and the House, especially on the intelligence committees and on the armed services committees and some of the — and judicial…
They went after lawyers and law firms. All kinds of — heaps of lawyers and law firms. They went after judges. One of the judges is now sitting on the Supreme Court that I had his wiretap information in my hand. Two are former FISA court judges. They went after State Department officials. They went after people in the executive service that were part of the White House — their own people."
PreviousSpace World News 6.27.13
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text:
Q: Can we move SharePoint up in the site hierarchy? I have SharePoint with the local intranet link as http://shserver/Sites/LAPP/HR/LA. I want to move the site LA to the following location http://shserver/Sites/LAPP/LA.
Is this possible through some tool or the only way is to recreate the site altogether in the new url location.

A: STSAdmin should help out here - this article looks to cover what you would need


text:
Walleigh Bios
Walleighs' Travels
Brief Book Overview
Thought Leaders on Our Book
Wendy's Father's Africa in World War II
Zambia & Zimbabawe
Kenya: In and Around Nairobi Plus Office Colleagues
Approximately 10% of Kenya's population lives in Nairobi, population 4 million–about 4 times the total population of Swaziland. It sprawls over many miles with the characteristics of any major city in the world, consisting of the same contrasts of poverty, traffic, and crime vs. modern buildings, civilized neighborhoods, and cosmopolitan choices in food. Rick and Wendy had visited Nairobi in 1997 during their first safari adventure. When the Walleighs settled down to live there for TechnoServe in 2007, initially Nairobi didn't look and feel much different from their first, brief visit. However, during their year-long stay, it became clear how much had changed. Of course touring vs. living in a city or country is very different. But though it is still deservedly nicknamed "Nai-Robbery" for its crime, many parts of Nairobi had entered the Internet/Mobile Phone age, and had become entrepreneurial, more Westernized, and generally more sophisticated.
Nairobi had become notorious also for traffic jams, though during rush hour police did try to control the chaos. However, there are unique African flavors to Nairobi's traffic, e.g., people dart unexpectedly across very busy roads, cars create new
lanes of traffic whenever they chose, etc. Westlands is where the TechnoServe office is located and where the Walleighs lived in one of the many apartment buildings. Westlands' Sarit Centre is a huge shopping mall–one of many high-end facilities in Nairobi–that on first appearance could be in any U.S. city, with similar stores and facilities. However, carved giraffes supervise the crazy chaos of people trying to buy food, clothes, shoes, rugs, linens, etc.
Civilized Living Quarters
In January, 2007, the Walleighs moved into Prime Apartments, a complex on Rapta Road in Westlands, lined with many similar apartment complexes. It was nicer than most with a pool, gym, courtyards, small convenience store, and restaurant. They lived in a large three bedroom apartment with a spacious living/dining area. Typical of all Nairobi's one to four-story residential and commercial buildings, it was built with concrete blocks. They did observe next door's construction site with scaffolding that looked like skinny tree branches….Rick and Wendy hoped some reinforcement was included in their building, especially after they experienced a few of Nairobi's occasional earthquakes.
During the first rainy season in April, the apartment's interior walls became and stayed damp, despite supposed efforts by the Prime Apartment management. So in June, 2007, they moved into a brand new building in the newer Cates Apartment complex on School Road adjacent to the modern Sarit Centre shopping mall. No one had ever lived in this two-bedroom, two-bath apartment prior to the Walleighs, who greatly appreciated that all the furnishings were fresh and clean as well.
Crazy Kitengela Glass Factory
Near the Kenyatta Airport, down a very rutted dirt road lies Kitengela glass factory, established by a white woman named Nani Croze and her son, both artists. All of their glass is recycled, re-blown or re-formed into many whimsical products including mosaic tiles for floors or walls, sculptures, stained glass windows, drinking and eating utensils and plates as well as many other decorative pieces. There are several Kitengela retail stores in Nairobi, but a visit to the factory is amazing. Not only is the inventory much more extensive than any of the stores, but when they went with their friends Anna and Greg, the Walleighs got to meet the owner.
Behind the factory showroom is a small B & B covered in whimsical objects either painted on or in mosaic glass. There were amazing sculptures of glass or metal, including a multi-humped dragon in the outdoor pool. Also on the property were slightly domesticated, rescued, wild animals in pens near the house in which Mrs. Croze lived, which was also decorated with mosaic and painted figures.
Office Colleagues at TechnoServe Kenya
During their 2007 year-long residence in Nairobi, Rick and Wendy established many friendships with the TechnoServe colleagues there. As in any intensive experience, people become part of one's life for that period, but can often fade away over time. However, the Walleighs have stayed in touch with several colleagues-now-friends since their move back to California. Rick meets with the TechnoServe Country Directors each year in Washington D.C. Three female Kenyan friends from Nairobi also stayed with the Walleighs at their home before and after they attended a women's leadership conference nearby. And Wendy is in contact with Cecilia from the Young Women in Enterprise Program via Facebook and email. Each time Wendy has been in Nairobi–most recently April 2012 (see Cecilia's Success Story on a separate webpage), she and Cecilia get together. No matter what, Wendy and Rick will always have the memories of how these wonderful colleagues and friends impacted their lives. Their second career really changed them as much as they hoped they changed a few Kenyan lives!
Want to Stay Connected?
Click on the image above to sign up to receive our most recent updates and get a free preview of our book, From Silicon Valley to Swaziland: How One Couple Found Purpose and Adventure in an Encore Career.
Africa Asia-Pacific Australia Austria Blog Bosnia Herzegovina Botswana Canada Croatia Czech Republic Ecuador El Salvador Ethiopia Europe France Ghana Greece Honduras Hungary Kenya Latin America Montenegro Mozambique Namibia Nepal New Zealand Nicaragua North America Peru Slovenia South Africa Success Stories Swaziland Turkey Uganda Uncategorized United Kingdom United States Wendy's Father's Africa in World War II Zambia & Zimbabwe Zanzibar
Link to Stories
Entrepreneurs exist in developing countries where the Walleighs have visited, just as in developed countries. But they face many more challenges. TechnoServe enables entrepreneurship among: subsistence-level farmers to operate as cash-crop businesses; agricultural processors (e.g., grain mills) to efficiently process hundreds of smallholder farmers' crops; cooperatives to link to markets; and urban businesses to expand their horizons. Africa and Latin America's entrepreneurial spirit is the foundation for hope for the future.
Victoria on Vancouver Island, British Columbia
Backpacking in Sierra
Prague & Nearby Karlovy Vary in Czech Republic
Vienna, Austria – the Jewel of the Habsburg Empire
Budapest, Hungary–our favorite former Austro-Hungarian city
Slovenia's Charming Ljubljana & Lake Bled in Julian Alps
©2019 Rick and Wendy Walleigh. Website developed by Melody Sharp


Excellent opportunity to get into a very well maintained and secure condo association! Newly updated electrical panel and garbage disposal. This 2BR 2BA unit has a large living rm/dining rm combination and master bedroom suite. Other amenities include: gorgeous heated pool next to over-sized clubhouse that features: full kitchen, fitness area, underground parking, same floor laundry, storage unit, elevator and access to car wash port in garage! WOW! Water/hot water and heat are also included in the condo fee--why rent when you can own for less? Call today and start enjoying summer.


The name of a Company or LLP can be changed with Board of Directors and Shareholders approval. We at GoMunshi offers an easy process for changing Company or LLP name.
4) Any other document, if required, will be asked.
How Company name will be changed ?
Review of documents and prepartion of Board Resolutions.
Our experts will review MOA and AOA, and prepare necessary Board Resolutions for the procedure.
Once the Board Resolutions are passed, our Experts will prepare and file the necessary documents with the Ministry of Corporate Affairs after your approval.
Q. 1 Will I receive a new certificate of incorporation stating the new name of the company ?
Yes, the certificate states both the old and the new name of the company, along with the date of change of the name.
Q. 2 How will I know the name which I desire is available ?
Our expert will ask you and keep you in loop in every communication with the authorities. You don't have to worry. We at GoMunshi will give you our expert services that are beyond your expectations.
Q. 3 Whom should the notification of the Change in name be furnished ?
Apart from the registrar, the same should be notified to the banks, clients and other concerned relevant authorities.
Q. 4 What will be the effect of new name on my business ?
The change of name of a company or LLP however has no impact on the legal entity or its existence. Hence, all assets and liabilities of the entity would continue, while only the name of the company would have been changed.