Enhanced Partial Discharge Signal Denoising Using Dispersion Entropy Optimized Variational Mode Decomposition.

This paper presents a new approach for denoising Partial Discharge (PD) signals using a hybrid algorithm combining the adaptive decomposition technique with Entropy measures and Group-Sparse Total Variation (GSTV). Initially, the Empirical Mode Decomposition (EMD) technique is applied to decompose a noisy sensor data into the Intrinsic Mode Functions (IMFs), Mutual Information (MI) analysis between IMFs is carried out to set the mode length K. Then, the Variational Mode Decomposition (VMD) technique decomposes a noisy sensor data into K number of Band Limited IMFs (BLIMFs). The BLIMFs are separated as noise, noise-dominant, and signal-dominant BLIMFs by calculating the MI between BLIMFs. Eventually, the noise BLIMFs are discarded from further processing, noise-dominant BLIMFs are denoised using GSTV, and the signal BLIMFs are added to reconstruct the output signal. The regularization parameter λ for GSTV is automatically selected based on the values of Dispersion Entropy of the noise-dominant BLIMFs. The effectiveness of the proposed denoising method is evaluated in terms of performance metrics such as Signal-to-Noise Ratio, Root Mean Square Error, and Correlation Coefficient, which are are compared to EMD variants, and the results demonstrated that the proposed approach is able to effectively denoise the synthetic Blocks, Bumps, Doppler, Heavy Sine, PD pulses and real PD signals.

Characteristics of 10-year survivors of high-grade serous ovarian carcinoma.

OBJECTIVE: High-grade serous carcinoma (HGSC) generally presents at an advanced stage with poor long-term (LT) survival. Here we describe clinical features found in women surviving HGSC for ten or more years. METHODS: A multi-center research consortium was established between five participating academic centers. Patient selection criteria included high-grade serous ovarian, fallopian tube, or peritoneal carcinoma with at least ten years of follow up. Non-serous, borderline tumors and low-grade serous subtypes were excluded. RESULTS: The 203 identified LT ten-year survivors with HGSC were diagnosed at a median age of 57years (range 37-84years). The majority of patients had stage IIIC (72.4%) disease at presentation. Of those who underwent primary cytoreductive surgery, optimal cytoreduction was achieved in 143 (85.6%) patients. After a median follow up of 144months, 88 (46.8%) patients did not develop recurrent disease after initial treatment. Unexpected findings from this survey of LT survivors includes 14% of patients having had suboptimal cytoreduction, 11% of patients having an initial platinum free interval of <12months, and nearly 53% of patients having recurrent disease, yet still surviving more than ten years after diagnosis. CONCLUSIONS: LT survivors of HGSC of the ovary generally have favorable clinical features including optimal surgical cytoreduction and primary platinum sensitive disease. The majority of patients will develop recurrent disease, however many remained disease free for more than 10years. Future work will compare the clinical features of this unusual cohort of LT survivors with the characteristics of HGSC patients having less favorable outcomes.

Early prediction of clinical benefit of treating ovarian cancer using quantitative CT image feature analysis.

BACKGROUND: In current clinical trials of treating ovarian cancer patients, how to accurately predict patients' response to the chemotherapy at an early stage remains an important and unsolved challenge. PURPOSE: To investigate feasibility of applying a new quantitative image analysis method for predicting early response of ovarian cancer patients to chemotherapy in clinical trials. MATERIAL AND METHODS: A dataset of 30 patients was retrospectively selected in this study, among which 12 were responders with 6-month progression-free survival (PFS) and 18 were non-responders. A computer-aided detection scheme was developed to segment tumors depicted on two sets of CT images acquired pre-treatment and 4-6 weeks post treatment. The scheme computed changes of three image features related to the tumor volume, density, and density variance. We analyzed performance of using each image feature and applying a decision tree to predict patients' 6-month PFS. The prediction accuracy of using quantitative image features was also compared with the clinical record based on the Response Evaluation Criteria in Solid Tumors (RECIST) guideline. RESULTS: The areas under receiver operating characteristic curve (AUC) were 0.773 ± 0.086, 0.680 ± 0.109, and 0.668 ± 0.101, when using each of three features, respectively. AUC value increased to 0.831 ± 0.078 when combining these features together. The decision-tree classifier achieved a higher predicting accuracy (76.7%) than using RECIST guideline (60.0%). CONCLUSION: This study demonstrated the potential of using a quantitative image feature analysis method to improve accuracy of predicting early response of ovarian cancer patients to the chemotherapy in clinical trials.

Phase III randomized trial of second-line ixabepilone versus paclitaxel or doxorubicin in women with advanced endometrial cancer.

OBJECTIVE: The purpose of this multicenter, open label, randomized phase III study was to determine whether ixabepilone resulted in improved overall survival (OS) compared with commonly used single-agent chemotherapy (doxorubicin or paclitaxel) in women with locally advanced, recurrent, or metastatic endometrial cancer with at least one failed prior platinum-based chemotherapeutic regimen. METHODS: Patients were randomized 1:1 to ixabepilone (40mg/m(2)), or either paclitaxel (175mg/m(2)) or doxorubicin (60mg/m(2)), every 21days. Patients that had previously received an anthracycline were randomized to ixabepilone or paclitaxel; all other patients were randomized to ixabepilone or doxorubicin. An interim analysis of futility for OS was planned. RESULTS: At the time of database lock, 496 patients were randomized to receive ixabepilone (n=248) or control (n=248); nine patients in the control arm were not treated. The interim analysis of futility for OS (219 events) favored the control chemotherapy arm (hazard ratio=1.3 [95% confidence interval: 1.0-1.7], stratified log rank test P=0.0397), indicating that the study would not meet its primary objective. The study was discontinued based on the interim OS results. The frequency of adverse events was comparable between the treatment arms. CONCLUSIONS: The study did not meet its primary objective of improving OS in the ixabepilone arm compared to the control chemotherapy arm. A favorable risk/benefit ratio was not observed for ixabepilone versus control at the time of the interim analysis. The safety results were consistent with the known safety profiles of ixabepilone and control.

Phase II study of the PI3K inhibitor pilaralisib (SAR245408; XL147) in patients with advanced or recurrent endometrial carcinoma.

OBJECTIVE: Patients with endometrial carcinoma who progress after first-line chemotherapy have a poor prognosis. Phosphoinositide 3-kinase (PI3K) inhibitors are investigational treatment options in this setting. This study evaluated the efficacy and safety of the PI3K inhibitor pilaralisib (SAR245408; XL147) in advanced or recurrent endometrial carcinoma. METHODS: This Phase II, multicenter, single-arm, open-label study enrolled patients with histologically confirmed advanced or recurrent endometrial carcinoma, who had received one or two prior chemotherapy regimens. Patients received pilaralisib 600mg capsules or 400mg tablets once daily. Primary endpoints were objective response rate (ORR), proportion of patients with progression-free survival (PFS) >6months and safety. Molecular profiling in archival tumor tissue and circulating tumor DNA were performed to identify molecular markers associated with response or resistance to pilaralisib. RESULTS: 67 patients were enrolled, of which 50 and 17 patients had received one or two prior regimens, respectively. Complete or partial tumor responses occurred in two patients each (ORR 6.0%); three had tumors with normal PTEN expression and PIK3R1 mutations and one had a tumor with PTEN protein deficiency. However, there was no association between molecular alterations and clinical activity. Rate of PFS>6months was 11.9%. The most commonly reported treatment-related adverse events (AEs) were rash (40.3%), diarrhea (37.3%) and fatigue (28.4%). The most commonly reported treatment-related grade ≥3 AEs were rash (9.0%), diarrhea (4.5%) and increased alanine aminotransferase (4.5%). CONCLUSIONS: Pilaralisib was associated with a favorable safety profile and minimal antitumor activity in advanced or recurrent endometrial carcinoma.

A first-in-human dose-escalation study of ME-143, a second generation NADH oxidase inhibitor, in patients with advanced solid tumors.

BACKGROUND: ME-143, a second-generation tumor-specific NADH oxidase inhibitor, is broadly active against human cancers in vitro and in vivo. This first-in-human dose-escalation study evaluated the dose-limiting toxicities (DLTs), pharmacokinetics, safety, tolerability, and preliminary anti-tumor activity of ME-143 in patients with advanced solid tumors. METHODS: Patients with advanced solid tumors were treated in a 3 + 3 escalation design. ME-143 was administered via intravenous infusion on days 1, 8, and 15 of the first 28-day cycle, and weekly thereafter; the final cohort received twice-weekly treatment. Samples for pharmacokinetic analysis were collected during cycle 1. Treatment continued until disease progression or unacceptable toxicity. RESULTS: Eighteen patients were treated: 2.5 mg/kg (n = 3); 5 mg/kg (n = 3); 10 mg/kg (n = 3); 20 mg/kg (n = 6); 20 mg/kg twice-weekly (n = 3). There were no DLTs observed. Nearly all treatment-related toxicities were grade 1/2, specifically (all grades) nausea (22 %) and fatigue (17 %). Two patients experienced infusion reactions at the 20 mg/kg dose level, one of which was grade 4. Stable disease was documented in three patients with colorectal cancer, cholangiocarcinoma, and anal cancer. Pharmacokinetic exposures were linear and dose-dependent, with a half-life of approximately 5 h. CONCLUSIONS: ME-143 was well-tolerated when administered intravenously at the maximally administered/recommended phase 2 dose of 20 mg/kg once weekly to patients with advanced solid tumors. Though limited clinical activity was observed with monotherapy, inhibitors of tumor-specific NADH oxidase such as ME-143 may derive their greatest benefit in combination with cytotoxic chemotherapy.

Enhanced Fano resonance of organic material films deposited on arrays of asymmetric split-ring resonators (A-SRRs).

Depositing very thin organic films on the surface of arrays of asymmetric split-ring resonators (A-SRRs) produces a shift in their resonance spectra that can be utilized for sensitive analyte detection. Here we show that when poly-methyl-methacrylate (PMMA) is used as an organic probe (analyte) on top of the A-SRR array, the phase and amplitude of a characteristic molecular Fano resonance associated with a carbonyl bond changes according to the spectral positions of the trapped mode resonance of the A-SRRs and their plasmonic reflection peaks. Furthermore, we localize blocks of PMMA at different locations on the A-SRR array to determine the effectiveness of detection of very small amounts of non-uniformly distributed analyte.

Phase III trial of induction gemcitabine or paclitaxel plus carboplatin followed by paclitaxel consolidation in ovarian cancer.

OBJECTIVE: The safety and efficacy of gemcitabine plus carboplatin (GC) or paclitaxel plus carboplatin (TC) induction regimens with or without paclitaxel consolidation therapy were assessed in ovarian cancer (OC). METHODS: Patients with stage IC-IV OC were randomized to either GC (gemcitabine 1,000 mg/m(2), days 1 and 8, plus carboplatin area under the curve [AUC] 5, day 1) or TC (paclitaxel 175 mg/m(2) plus carboplatin AUC 6, day 1) every 21 days for up to six cycles. Patients with complete response (CR) were allowed optional consolidation with paclitaxel 135 mg/m(2) every 28 days for ≤ 12 months. Patients without CR received single-agent crossover therapy at induction doses/schedules until CR, disease progression (PD), or unacceptable toxicity. PD or death in 636 patients was required to compare induction arms with 80% statistical power for progression-free survival (PFS), the primary endpoint. RESULTS: Randomized induction therapy was received by 820 of 919 patients enrolled; 352 patients with CR received paclitaxel consolidation whereas 155 patients without CR received single-agent crossover therapy. PFS was similar for GC and TC (median, 20.0 and 22.2 months, respectively; P=.199). Despite high censoring rates (>52%), overall survival was longer for TC (median, 57.3 versus 43.8 months for GC; P=.013). Controlling for patient characteristics including performance status, residual tumor size, and tumor stage, there was no statistical difference in a multivariate analysis (HR=1.22; 95% CI=0.99-1.52; P=.067). CONCLUSIONS: GC does not improve PFS over TC as first-line induction chemotherapy in OC. Although favoring TC, overall survival analyses were limited by the study design and high censoring rates.

Tolerability, efficacy, and safety of pegylated liposomal Doxorubicin in combination with Carboplatin versus gemcitabine-Carboplatin for the treatment of platinum-sensitive recurrent ovarian cancer: a systematic review.

OBJECTIVE: To compare the tolerability, efficacy, and safety profiles of pegylated liposomal doxorubicin in combination with carboplatin (PLD-Carbo) with those of gemcitabine-carboplatin (Gem-Carbo) for the treatment of patients with platinum-sensitive recurrent ovarian cancer (PSROC) by reviewing the published literature. METHODS: Using the PubMed database, a systematic review of peer-reviewed literature published between January 2000 and September 2009 was undertaken to identify studies related to the treatment of patients with PSROC with PLD-Carbo or Gem-Carbo. Studies reporting either response rate, progression-free survival (PFS), and/or overall survival (OS) were included. Treatment regimens, efficacy endpoints, and safety profiles were compared between the two combination therapies. RESULTS: Ten studies evaluating 608 patients (PLD-Carbo: 5 studies, 278 patients; Gem-Carbo: 5 studies, 330 patients) were identified. The mean planned doses were: PLD, 34.8 mg/m(2) and Gem, 993 mg/m(2). The dose intensity reported in Gem trials was lower (75% of the planned dose) than the dose intensity reported in PLD trials (93.7% of the planned dose), suggesting better tolerability for the PLD-Carbo regimen. Among patients receiving PLD-Carbo, 60.2% achieved a response (complete, 27.0%; partial, 33.2%), versus 51.4% of patients treated with Gem-Carbo (complete, 19.2%; partial, 32.2%). The median PFS times were 10.6 months and 8.9 months in the PLD-Carbo and the Gem-Carbo populations, respectively. The median OS was longer for the PLD-Carbo regimen (27.1 months) than for the Gem-Carbo regimen (19.7 months). The hematological safety profiles were comparable in the two groups, although grade III or IV anemia (PLD-Carbo, 13.6%; Gem-Carbo, 24.5%) and neutropenia (PLD-Carbo, 45.5%; Gem-Carbo, 62.9%) were more common in patients receiving Gem-Carbo. CONCLUSION: Results from this systematic analysis of peer-reviewed literature suggest that PLD-Carbo therapy is a rational alternative to Gem-Carbo for the treatment of patients with PSROC.

Magnetic response of split ring resonators (SRRs) at visible frequencies.

In this paper, we report on a substantial shift in the response of arrays of similarly sized Split Ring Resonators (SRRs), having a rectangular U-shaped form--and made respectively of aluminium and of gold. We also demonstrate that it is possible to obtain the polarization dependent LC peak in the visible spectrum--by using SRRs based on aluminium, rather than gold. The response of metallic SRRs scales linearly with size. At optical frequencies, metals stop behaving like nearly perfect conductors and begin displaying characteristically different behaviour, in accord with the Drude model. The response at higher frequencies, such as those in the visible and near infra-red, depends both on their size and on the individual properties of the metals used. A higher frequency limit has been observed in the polarization dependent response (in particular the LC resonance peak) of gold based SRRs in the near infrared region. By using aluminium based SRRs instead of gold, the higher frequency limit of the LC resonance can be further shifted into the visible spectrum.

A phase 2 evaluation of irofulven as second-line treatment of recurrent or persistent intermediately platinum-sensitive ovarian or primary peritoneal cancer: a Gynecologic Oncology Group trial.

This multicenter phase 2 trial was conducted by the Gynecologic Oncology Group to evaluate the activity and the safety of irofulven in patients with recurrent epithelial ovarian cancer. Eligible patients had documented recurrent ovarian cancer 6 to 12 months after receiving a front-line platinum-based regimen and no other chemotherapy. Patients were required to have measurable disease, performance status of 0 to 2, and adequate bone marrow, hepatic, and renal functions before study entry. The dose of irofulven was 0.45 mg/kg intravenously on days 1 and 8 every 21 days. Responses were defined by Response Evaluation Criteria in Solid Tumors. Fifty-five of 61 enrolled patients were evaluable for response and toxicity. There were 7 partial responses (12.7%), and 30 patients (54.6%) had stable disease. Median progression-free and overall survival were 6.4 months (1.3-37.5 months) and 22.1 months or more (2.8-57.8+ months), respectively. Patients received a median of 3 cycles (range, 1-21) of protocol therapy. Grade 4 hematologic toxicity was limited to reversible neutropenia and thrombocytopenia. Grade 4 nonhematologic toxicity was limited to one patient with anorexia and another with hypomagnesemia. Irofulven administered at this dose and schedule was well tolerated but had modest activity as a single agent.

Asymmetric split ring resonators for optical sensing of organic materials.

Asymmetric Split Ring Resonators are known to exhibit resonant modes where the optical electric field is strongest near the ends of the arms, thereby increasing the sensitivity of spectral techniques such as surface enhanced Raman scattering (SERS). By producing asymmetry in the structures, the two arms of the ring produce distinct plasmonic resonances related to their lengths - but are also affected by the presence of the other arm. This combination leads to a steepening of the slope of the reflection spectrum between the resonances that increases the sensitivity of the resonant behavior to the addition of different molecular species. We describe experimental results, supported by simulation, on the resonances of a series of circular split ring resonators with different gap and section lengths--at wavelengths in the mid-infra red regions of the spectrum--and their utilization for highly sensitive detection of organic compounds. We have used thin films of PMMA with different thicknesses, resulting in characteristic shifts from the original resonance. We also demonstrate matching of asymmetric split ring resonators to a molecular resonance of PMMA.

A phase I study of gemcitabine followed by cisplatin concurrent with whole pelvic radiation therapy in locally advanced cervical cancer: a Gynecologic Oncology Group study.

PURPOSE: To determine the maximum tolerated dose (MTD) of gemcitabine followed by cisplatin that can be administered weekly during pelvic radiation therapy in patients with locally advanced cervical cancer. METHODS: A phase I and feasibility study with dose escalation of gemcitabine in cohorts of three to six patients to determine the MTD (the dose level at which no more than one of six patients experienced a acute dose-limiting toxicity) was conducted. RESULTS: Thirteen patients were entered on the phase I trial. Acute dose-limiting toxicity occurred with weekly cisplatin at a dose of 40 mg/m(2) and gemcitabine at a dose of 100 mg/m(2). The study was modified, decreasing the dose of cisplatin to 30 mg/m(2) in an effort to dose escalate gemcitabine. Acute dose-limiting toxicity occurred again with weekly cisplatin at a dose of 30 mg/m(2) and gemcitabine at a dose of 75 mg/m(2) (dose level 3). In addition to acute hematologic and acute and late non-hematologic toxicities, late grade 3 and 4 GI and GU toxicities have occurred in two of six patients at dose level 3. Twelve of thirteen patients remained disease-free following treatment. CONCLUSION: The MTD found in this chemoradiation study was weekly gemcitabine 50 mg/m(2) followed by cisplatin 40 mg/m(2). The alternative drug sequence has been reported by others to allow higher doses of gemcitabine. However, at this dose level chronic toxicity was observed. Further expansion of the feasibility cohort of this study was suspended pending the efficacy and toxicity results of a large trial which has recently been completed.

MICU1 drives glycolysis and chemoresistance in ovarian cancer.

Cancer cells actively promote aerobic glycolysis to sustain their metabolic requirements through mechanisms not always clear. Here, we demonstrate that the gatekeeper of mitochondrial Ca2+ uptake, Mitochondrial Calcium Uptake 1 (MICU1/CBARA1) drives aerobic glycolysis in ovarian cancer. We show that MICU1 is overexpressed in a panel of ovarian cancer cell lines and that MICU1 overexpression correlates with poor overall survival (OS). Silencing MICU1 in vitro increases oxygen consumption, decreases lactate production, inhibits clonal growth, migration and invasion of ovarian cancer cells, whereas silencing in vivo inhibits tumour growth, increases cisplatin efficacy and OS. Mechanistically, silencing MICU1 activates pyruvate dehydrogenase (PDH) by stimulating the PDPhosphatase-phosphoPDH-PDH axis. Forced-expression of MICU1 in normal cells phenocopies the metabolic aberrations of malignant cells. Consistent with the in vitro and in vivo findings we observe a significant correlation between MICU1 and pPDH (inactive form of PDH) expression with poor prognosis. Thus, MICU1 could serve as an important therapeutic target to normalize metabolic aberrations responsible for poor prognosis in ovarian cancer.

Quantitative measurement of adiposity using CT images to predict the benefit of bevacizumab-based chemotherapy in epithelial ovarian cancer patients.

The present study aims to quantitatively measure adiposity-related image features and to test the feasibility of applying multivariate statistical data analysis-based prediction models to generate a novel clinical marker and predict the benefit of epithelial ovarian cancer (EOC) patients with and without maintenance bevacizumab-based chemotherapy. A dataset involving computed tomography (CT) images acquired from 59 patients diagnosed with advanced EOC was retrospectively collected. Among them, 32 patients received maintenance bevacizumab following primary chemotherapy, while 27 did not. A computer-aided detection scheme was developed to automatically segment visceral and subcutaneous fat areas depicted on CT images of abdominal sections, and 7 adiposity-related image features were computed. Upon combining these features with the measured body mass index, multivariate data analyses were performed using three statistical models (multiple linear, logistic and Cox proportional hazards regressions) to analyze the association between the model-generated prediction results and the treatment outcome, including progression-free survival (PFS) and overall survival (OS) of the patients. The results demonstrated that applying all three prediction models yielded a significant association between the adiposity-related image features and patients' PFS or OS in the group of the patients who received maintenance bevacizumab (P<0.010), while there was no significant difference when these prediction models were applied to predict both PFS and OS in the group of patients that did not receive maintenance bevacizumab. Therefore, the present study demonstrated that the use of a quantitative adiposity-related image feature-based statistical model may generate a novel clinical marker to predict who will benefit among EOC patients receiving maintenance bevacizumab-based chemotherapy.

Exploitation of Exosomes as Nanocarriers for Gene-, Chemo-, and Immune-Therapy of Cancer.

The bottleneck in current vector-based cancer therapy is the targeted and controlled release of therapeutics in tumors. Exosomes are submicron-sized vesicles that are secreted by all cell types and are involved in communication and transportation of materials between cells. Analogous in size and function to synthetic nanoparticles, exosomes offer many advantages, rendering them the most promising candidates for targeted drug or gene delivery vehicles. Patient-specific customized therapeutic strategies can be engineered using exosomes derived from the patient's own healthy cells. Therefore, exosome-based cancer therapy has the potential to become an important part of personalized medicine. Interest in exosomes as carrier organelles is relatively recent. Knowledge about exosomal biology and its applications remains limited. The present review is an attempt to describe the current status of the application of exosomes to cancer therapy and the potential challenges associated with their use.

A New Approach to Evaluate Drug Treatment Response of Ovarian Cancer Patients Based on Deformable Image Registration.

Although Response Evaluation Criteria in Solid Tumors (RECIST) is the current clinical guideline to assess size change of solid tumors after therapeutic treatment, it has a relatively lower association to the clinical outcome of progression free survival (PFS) of the patients. In this paper, we presented a new approach to assess responses of ovarian cancer patients to new chemotherapy drugs in clinical trials. We first developed and applied a multi-resolution B-spline based deformable image registration method to register two sets of computed tomography (CT) image data acquired pre- and post-treatment. The B-spline difference maps generated from the co-registered CT images highlight the regions related to the volumetric growth or shrinkage of the metastatic tumors, and density changes related to variation of necrosis inside the solid tumors. Using a testing dataset involving 19 ovarian cancer patients, we compared patients' response to the treatment using the new image registration method and RECIST guideline. The results demonstrated that using the image registration method yielded higher association with the six-month PFS outcomes of the patients than using RECIST. The image registration results also provided a solid foundation of developing new computerized quantitative image feature analysis schemes in the future studies.

Role of TGF-ß signaling in uterine carcinosarcoma.

Uterine carcinosarcomas (UCS) are rare (3-4%) but highly aggressive, accounting for a disproportionately high (16.4%) mortality among uterine malignancies. Transforming growth factor beta (TGFß) is a multifunctional cytokine that regulates important cellular processes including epithelial-mesenchymal transition (EMT). Existence of biphasic elements and a report demonstrating amplification of TGFß at 19q13.1 prompted us to investigate the role of TGFß signaling in UCS.Here we demonstrated the components of TGFß pathway are expressed and functional in UCS. TGFß-I induced significant Smad2/3 phosphorylation, migration and EMT responses in UCS cell lines which could be attenuated by the TGFß receptor I (TGFßR-I) or TGFß receptor I/II (TGFßR-I/II) inhibitor developed by Eli Lilly and company. Importantly, TGFß-I induced proliferation was c-Myc dependent, likely through activation of cell cycle. c-Myc was induced by nuclear translocation of nuclear factor of activated T cells (NFAT-1) in response to TGFß-I. Inhibition of NFAT-1 or TGFßR-I blocked c-Myc induction, cell cycle progression and proliferation in UCS. In corroboration, mRNA levels of c-Myc were elevated in recurrent versus the non-recurrent UCS patient samples. Interestingly, in the absence of exogenous TGFß the TGFßR-I/II inhibitor enhanced proliferation likely through non-Smad pathways. Thus, inhibition of TGFßR-I could be efficacious in treatment of UCS.

Exosomes: a role for naturally occurring nanovesicles in cancer growth, diagnosis and treatment.

Exosomes are 30-100 nm bodies secreted from almost all types of cells into the extracellular spaces. They enclose in their lumen active genetic information in the form of messenger RNA (mRNA), micro RNA (miRNA), DNA and active peptides that are representative of the parental cell and can be isolated from different body fluids. Exosomes can participate in inter-cellular communication by trafficking molecules to their target cells. Because they can stably carry cargo including miRNA, mRNA, and proteins and can pass through stringent biological barriers (e.g., blood brain barrier) without eliciting an immune response, they are considered as an ideal acellular vehicle for drug delivery. In this review, we describe the structure and biogenesis of exosomes and new directions related to their role in diagnosis and treatment of diseases, especially for cancer. We also discuss potential challenges associated with exosomes that should be addressed before exosome-based therapy can be applied to clinical settings.

Role of cystathionine beta synthase in lipid metabolism in ovarian cancer.

Elevated lipid metabolism is implicated in poor survival in ovarian cancer (OC) and other cancers; however, current lipogenesis-targeting strategies lack cancer cell specificity. Here, we identify a novel role of cystathionine beta-synthase (CBS), a sulphur amino acid metabolizing enzyme highly expressed in several ovarian cancer cell lines, in driving deregulated lipid metabolism in OC. We examined the role of CBS in regulation of triglycerides, cholesterol and lipogenic enzymes via the lipogenic transcription factors SREBP1 and SREBP2. CBS silencing attenuated the expression of number of key enzymes involved in lipid synthesis (FASN and ACC1). Additionally CBS abrogates lipid uptake in OC cells. Gene silencing of CBS or SREBPs abrogated cellular migration and invasion in OC, while ectopic expression of SREBPs can rescue phenotypic effects of CBS silencing by restoring cell migration and invasion. Mechanistically, CBS represses SREBP1 and SREBP2 at the transcription levels by modulating the transcription factor Sp1. We further established the roles of both CBS and SREBPs in regulating ovarian tumor growth in vivo. In orthotopic tumor models, CBS or SREBP silencing resulted in reduced tumor cells proliferation, blood vessels formation and lipid content. Hence, cancer-selective disruption of the lipid metabolism pathway is possible by targeting CBS and, at least for OC, promises a profound benefit.