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Background: Robots have the potential to assist older adults in their home-based daily living tasks. Previous studies indicated that older adults generally accept robot assistance. However, the preferences of older adults with different functional dependence levels are lacking. These older adults encounter varying levels of difficulty in daily living and may have distinct preferences for robot assistance. This study aimed to describe and compare the preferences for robot assistance on domestic tasks in older adults with different functional dependence levels., Methods: This cross-sectional descriptive study recruited a convenience sample of 385 older adults in Hong Kong. They were categorized as independent, partially dependent, and dependent using the Katz Index of Independence in Activities of Daily Living. Their preferences for robot assistance on a list of 48 domestic tasks under six categories were assessed through the Assistance Preference Checklist. Differences in preferences between the three groups were compared using one-way ANOVA test., Results: Findings revealed the differences and similarities in preferences between participants with different dependence levels. In most domestic tasks under the personal care category, dependent and partially dependent older adults reported a significantly lower preferences for human assistance or a higher preferences for robot assistance (p < 0.001), compared with the independent ones. The effect size varied from medium to large (eta squared = 0.07 to 0.52). However, participants, regardless of functional dependence levels, preferred human to assist in some domestic tasks under the health and leisure activities category and preferred robot to assist in most of the domestic tasks under the chores, information management, and manipulating objects category., Conclusions: Older adults with different levels of functional dependence exhibit different preferences for robotic assistance. To effectively use robots and assist older adults as they age, the specific preferences of older adults must be considered before designing and introducing robots in domestic care., (© 2024. The Author(s).)

Background: Uterine serous cancer (USC) is the most common non-endometrioid subtype of uterine cancer, and is also the most aggressive. Most patients will die of progressively chemotherapy-resistant disease, and the development of new therapies that can target USC remains a major unmet clinical need. This study sought to determine the molecular mechanism by which a novel unfavorable prognostic biomarker ryanodine receptor 1 (RYR1) identified in advanced USC confers their malignant phenotypes, and demonstrated the efficacy of targeting RYR1 by repositioned FDA-approved compounds in USC treatment., Methods: TCGA USC dataset was analyzed to identify top genes that are associated with patient survival or disease stage, and can be targeted by FDA-approved compounds. The top gene RYR1 was selected and the functional role of RYR1 in USC progression was determined by silencing and over-expressing RYR1 in USC cells in vitro and in vivo. The molecular mechanism and signaling networks associated with the functional role of RYR1 in USC progression were determined by reverse phase protein arrays (RPPA), Western blot, and transcriptomic profiling analyses. The efficacy of the repositioned compound dantrolene on USC progression was determined using both in vitro and in vivo models., Results: High expression level of RYR1 in the tumors is associated with advanced stage of the disease. Inhibition of RYR1 suppressed proliferation, migration and enhanced apoptosis through Ca 2+ -dependent activation of AKT/CREB/PGC-1α and AKT/HK1/2 signaling pathways, which modulate mitochondrial bioenergetics properties, including oxidative phosphorylation, ATP production, mitochondrial membrane potential, ROS production and TCA metabolites, and glycolytic activities in USC cells. Repositioned compound dantrolene suppressed USC progression and survival in mouse models., Conclusions: These findings provided insight into the mechanism by which RYR1 modulates the malignant phenotypes of USC and could aid in the development of dantrolene as a repurposed therapeutic agent for the treatment of USC to improve patient survival., (© 2022. The Author(s).)

Background: Bintrafusp alfa (BA) is a bifunctional fusion protein designed for colocalized, simultaneous inhibition of two immunosuppressive pathways, transforming growth factor-β (TGF-β) and programmed death-ligand 1 (PD-L1), within the tumor microenvironment (TME). We hypothesized that targeting PD-L1 to the tumor by BA colocalizes the TGF-β trap (TGF-βRII) to the TME, enabling it to sequester TGF-β in the tumor more effectively than systemic TGF-β blockade, thereby enhancing antitumor activity., Methods: Multiple technologies were used to characterize the TGF-β trap binding avidity. BA versus combinations of anti-PD-L1 and TGF-β trap or the pan-TGF-β antibody fresolimumab were compared in proliferation and two-way mixed lymphocyte reaction assays. Immunophenotyping of tumor-infiltrating lymphocytes (TILs) and RNA sequencing (RNAseq) analysis assessing stromal and immune landscape following BA or the combination therapy were performed in MC38 tumors. TGF-β and PD-L1 co-expression and their associated gene signatures in MC38 tumors and human lung carcinoma tissue were studied with single-cell RNAseq (scRNAseq) and immunostaining. BA-induced internalization, degradation, and depletion of TGF-β were investigated in vitro., Results: BA and fresolimumab had comparable intrinsic binding to TGF-β1, but there was an ~80× avidity-based increase in binding affinity with BA. BA inhibited cell proliferation in TGF-β-dependent and PD-L1-expressing cells more potently than TGF-β trap or fresolimumab. Compared with the combination of anti-PD-L1 and TGF-β trap or fresolimumab, BA enhanced T cell activation in vitro and increased TILs in MC38 tumors, which correlated with efficacy. BA induced distinct gene expression in the TME compared with the combination therapy, including upregulation of immune-related gene signatures and reduced activities in TGF-β-regulated pathways, such as epithelial-mesenchymal transition, extracellular matrix deposition, and fibrosis. Regulatory T cells, macrophages, immune cells of myeloid lineage, and fibroblasts were key PD-L1/TGF-β1 co-expressing cells in the TME. scRNAseq analysis suggested BA modulation of the macrophage phenotype, which was confirmed by histological assessment. PD-L1/TGF-β1 co-expression was also seen in human tumors. Finally, BA induced TGF-β1 internalization and degradation in the lysosomes., Conclusion: BA more effectively blocks TGF-β by targeting TGF-β trap to the tumor via PD-L1 binding. Such colocalized targeting elicits distinct and superior antitumor responses relative to single agent combination therapy., Competing Interests: Competing interests: YL, T-LY, HH, SS, MHJ, HW, JQ, GL, GQ, BM, HY, L-YC, AWG, MGD, MS, AS, HM, VS, FJ and K-ML are all employees of EMD Serono Research and Development Institute, Billerica, Massachusetts, USA, an affiliate of Merck KGaA, Darmstadt, Germany. AW is an employee of Merck KGaA, Darmstadt, Germany, and MT-A and DK are employees of Inter-lab, a subsidiary of Merck KGaA, Yavne, Israel. GL is an inventor on the US20210196822A1 patent held by Merck Patent GmbH, 'Treatment of triple negative breast cancer with targeted TGF-β inhibition.' K-ML is the inventor on the US Patent 9,676,863 B2, 'Targeted TGF-β inhibition,' issued on June 13, 2017, and held by the Merck Patent GmbH, covering M7824 (bintrafusp alfa), its methods of making, and its methods of use. All other authors disclose no competing interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Localized radiotherapy (RT) induces an immunogenic antitumor response that is in part counterbalanced by activation of immune evasive and tissue remodeling processes, e.g., via upregulation of programmed cell death-ligand 1 (PD-L1) and transforming growth factor β (TGF-β). We report that a bifunctional fusion protein that simultaneously inhibits TGF-β and PD-L1, bintrafusp alfa (BA), effectively synergizes with radiotherapy, leading to superior survival in multiple therapy-resistant murine tumor models with poor immune infiltration. The BA + RT (BART) combination increases tumor-infiltrating leukocytes, reprograms the tumor microenvironment, and attenuates RT-induced fibrosis, leading to reconstitution of tumor immunity and regression of spontaneous lung metastases. Consistently, the beneficial effects of BART are in part reversed by depletion of cytotoxic CD8 + T cells. Intriguingly, targeting of the TGF-β trap to PD-L1 + endothelium and the M2/lipofibroblast-like cell compartment by BA attenuated late-stage RT-induced lung fibrosis. Together, the results suggest that the BART combination has the potential to eradicate therapy-resistant tumors while sparing normal tissue, further supporting its clinical translation., Competing Interests: Declaration of interests Y.L., C.X., T.-L.Y., M.H.J., H.Y., B.M., G.Q., J.Q., G.L., M.G.D., F.J., and K.-M.L. are all employees of EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Darmstadt, Germany. K.-M.L. is the inventor on Patent Cooperation Treaty Publications WO2015/118115 and US 2015/0225483 held by applicant Merck Patent GmvH covering bintrafusp alfa, its methods of making, and its methods of use. J.D. has received research grants from Siemens Healthcare GmbH, Solution Akademia GmbH, ViewRay, The Clinical Research Institute GmbH, Accuray International Sàrl, RaySearch Laboratories AB, Vision RT, Merck Serono GmbH, Astellas Pharma GmbH, AstraZeneca GmbH, Ergomed, Quintiles GmbH, and Pharmaceutical Research Associates GmbH and declares grant support from EMD/Merck KGaA to his institution to conduct experiments directly related to the published study. A.A. has received research grants from Merck KGaA, FibroGen, and Bayer; has a consulting or advisory role with Roche, Merck KGaA, Merck Serono, FibroGen, BMS Brazil, Bayer Health, and BioMedX; and declares grant support from EMD/Merck KGaA to his institution to conduct experiments directly related to the published study. All other authors disclose no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Stromal and immune cells in the tumor microenvironment (TME) have been shown to directly affect high-grade serous ovarian cancer (HGSC) malignant phenotypes, however, how these cells interact to influence HGSC patients' survival remains largely unknown. To investigate the cell-cell communication in such a complex TME, we developed a SpatioImageOmics (SIO) pipeline that combines imaging mass cytometry (IMC), location-specific transcriptomics, and deep learning to identify the distribution of various stromal, tumor and immune cells as well as their spatial relationship in TME. The SIO pipeline automatically and accurately segments cells and extracts salient cellular features to identify biomarkers, and multiple nearest-neighbor interactions among tumor, immune, and stromal cells that coordinate to influence overall survival rates in HGSC patients. In addition, SIO integrates IMC data with microdissected tumor and stromal transcriptomes from the same patients to identify novel signaling networks, which would lead to the discovery of novel survival rate-modulating mechanisms in HGSC patients.

Uterine serous cancer (USC) is an aggressive subtype of endometrial cancer, with poor survival and high recurrence rates. The development of novel and effective therapies specific to USC would aid in its management. However, few studies have focused solely on this rare subtype. The current study demonstrated that the orally bioavailable, investigational new drug and novel imipridone ONC206 suppressed USC cell proliferation and induced apoptosis both in vitro and in vivo. Disruption of the DRD2-mediated p38MAPK/ERK/PGC-1α network by ONC206 led to metabolic reprogramming and suppression of both glycolysis and oxidative phosphorylation. ONC206 also synergized with paclitaxel in reducing USC cell viability. In addition, DRD2 overexpression correlated with poor overall survival in patients. This study provides the first evidence that ONC206 induced metabolic reprogramming in USC cells and is a promising therapeutic agent for USC treatment. These findings support further development of ONC206 as a promising therapeutic agent and improves survival rates in patients with USC.

Advanced ovarian cancer usually spreads to the omentum. However, the omental cell-derived molecular determinants modulating its progression have not been thoroughly characterized. Here, we show that circulating ITLN1 has prognostic significance in patients with advanced ovarian cancer. Further studies demonstrate that ITLN1 suppresses lactotransferrin's effect on ovarian cancer cell invasion potential and proliferation by decreasing MMP1 expression and inducing a metabolic shift in metastatic ovarian cancer cells. Additionally, ovarian cancer-bearing mice treated with ITLN1 demonstrate marked decrease in tumor growth rates. These data suggest that downregulation of mesothelial cell-derived ITLN1 in the omental tumor microenvironment facilitates ovarian cancer progression.

Uterine serous carcinoma (USC) is the most aggressive form of endometrial cancer, with poor survival rates and high recurrence risk. Therefore, the purpose of this study was to identify therapeutic targets that could aid in the management of USC. By analyzing endometrial cancer samples from The Cancer Genome Atlas (TCGA), we found Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1) to be highly expressed in USC and to correlate with poorer overall survival. UCHL1 silencing reduced cell proliferation in vitro and in vivo, cyclin B1 protein levels and cell cycle progression. Further studies showed that UCHL1 interacts with cyclin B1 and increases cyclin B1 protein stability by deubiquitination. Treatment of USC-bearing mice with the UCHL1-specific inhibitor reduced tumor growth and improved overall survival. Our findings suggest that cyclin B1 is a novel target of UCHL1 and targeting UCHL1 is a potential therapeutic strategy for USC.

Purpose: Recent studies demonstrate the role of the tumor microenvironment in tumor progression. However, strategies used to overcome the malignant phenotypes of cancer cells modulated by the microenvironment have not been thoroughly explored. In this study, we evaluated the therapeutic efficacy of a newly developed mAb targeting microfibril-associated protein 5 (MFAP5), which is secreted predominately by cancer-associated fibroblast (CAF), in ovarian and pancreatic cancer models. Experimental Design: MAbs were developed using human MFAP5 recombinant protein as an antigen in mice, and antibodies from hybridoma clones were evaluated for their specificity to human and murine MFAP5. An Octet RED384 system was used to determine the kinetics of binding affinity and the specificity of the antibody clones, which were followed by epitope mapping and functional characterization by in vitro assays. The therapeutic efficacy of a lead anti-MFAP5 antibody clone 130A in tumor suppression was evaluated by ovarian tumor- and pancreatic tumor-bearing mouse models., Results: Three hybridoma clones, which produced antibodies with high affinity and specificity to MFAP5, were selected for functional studies. Antibody clone 130A, which recognizes a common epitope shared between human and murine MFAP5 protein, was further selected for in vivo studies. Results showed that clone 130A downregulated MFAP5-induced collagen production in CAFs, suppressed intratumoral microvessel leakiness, and enhanced paclitaxel bioavailability in both ovarian and pancreatic cancer mouse models., Conclusions: These data suggest that MFAP5 blockade using an immunologic approach inhibits fibrosis, induces tumor vessel normalization, and enhances chemosensitivity in ovarian and pancreatic cancer, and can be used as a novel therapeutic agent., (©2019 American Association for Cancer Research.)

Chromatin accessibility data can elucidate the developmental origin of cancer cells and reveal the enhancer landscape of key oncogenic transcriptional regulators. We develop a computational strategy called PSIONIC (patient-specific inference of networks informed by chromatin) to combine chromatin accessibility data with large tumor expression data and model the effect of enhancers on transcriptional programs in multiple cancers. We generate a new ATAC-seq data profiling chromatin accessibility in gynecologic and basal breast cancer cell lines and apply PSIONIC to 723 patient and 96 cell line RNA-seq profiles from ovarian, uterine, and basal breast cancers. Our computational framework enables us to share information across tumors to learn patient-specific TF activities, revealing regulatory differences between and within tumor types. PSIONIC-predicted activity for MTF1 in cell line models correlates with sensitivity to MTF1 inhibition, showing the potential of our approach for personalized therapy. Many identified TFs are significantly associated with survival outcome. To validate PSIONIC-derived prognostic TFs, we perform immunohistochemical analyses in 31 uterine serous tumors for ETV6 and 45 basal breast tumors for MITF and confirm that the corresponding protein expression patterns are also significantly associated with prognosis.

Objective: To investigate the prognostic and biologic significance of immune-related gene expression in high grade serous ovarian cancer (HGSOC)., Methods: Gene expression dependent survival analyses for a panel of immune related genes were evaluated in HGSOC utilizing The Cancer Genome Atlas (TCGA). Prognostic value of LCK was validated using IHC in an independent set of 72 HGSOC. Prognostic performance of LCK was compared to cytolytic score (CYT) using RNAseq across multiple tumor types. Differentially expressed genes in LCK high samples and gene ontology enrichment were analyzed., Results: High pre-treatment LCK mRNA expression was found to be a strong predictor of survival in a set of 535 ovarian cancers. Patients with high LCK mRNA expression had a longer median progression free survival (PFS) of 29.4 months compared to 16.9 months in those without LCK high expression (p = 0.003), and longer median overall survival (OS) of 95.1 months versus 44.5 months (p = 0.001), which was confirmed in an independent cohort by IHC (p = 0.04). LCK expression was compared to CYT across tumor types available in the TCGA and was a significant predictor of prognosis in HGSOC where CYT was not predictive. Unexpectedly, LCK high samples also were enriched in numerous immunoglobulin-related and other B cell transcripts., Conclusions: LCK is a better prognostic factor than CYT in ovarian cancer. In HGSOC, LCK high samples were characterized by higher expression of immunoglobulin and B-cell related genes suggesting that a cooperative interaction between tumor infiltrating T and B cells may correlate with better survival in this disease.

Purpose : In response to the rising suicide trend in Hong Kong, the Centre for Suicide Research and Prevention ("CSRP") was established in 2002, with the aim to capitalize on the collective impact of research-support practices to prevent suicides. Method : The CSRP has since become an international knowledge hub that applies a public health approach and innovative strategies to address suicide-related problems at multiple levels. Results : The CSRP actively engages in research, teaching, and knowledge exchange with community stakeholders. These effort are associated with Hong Kong's more than 30% reduction in suicide rates between 2003 and 2016. Discussion : The rationale for and examples of the CSRP's practices in face of the suicide prevention challenges lay ahead were also discussed. Conclusion : The outcomes of these practices, which hold great potential for suicide prevention worldwide, have contributed to important academic debates in the field of suicidology.

Background: Bulk tumor tissue samples are used for generating gene expression profiles in most research studies, making it difficult to decipher the stroma-cancer crosstalk networks. In the present study, we describe the use of microdissected transcriptome profiles for the identification of cancer-stroma crosstalk networks with prognostic value, which presents a unique opportunity for developing new treatment strategies for ovarian cancer., Methods: Transcriptome profiles from microdissected ovarian cancer-associated fibroblasts (CAFs) and ovarian cancer cells from patients with high-grade serous ovarian cancer (n = 70) were used as input data for the computational systems biology program CCCExplorer to uncover crosstalk networks between various cell types within the tumor microenvironment. The crosstalk analysis results were subsequently used for discovery of new indications for old drugs in ovarian cancer by computational ranking of candidate agents. Survival analysis was performed on ovarian tumor-bearing Dicer/Pten double-knockout mice treated with calcitriol, a US Food and Drug Administration-approved agent that suppresses the Smad signaling cascade, or vehicle control (9-11 mice per group). All statistical tests were two-sided., Results: Activation of TGF-β-dependent and TGF-β-independent Smad signaling was identified in a particular subtype of CAFs and was associated with poor patient survival (patients with higher levels of Smad-regulated gene expression by CAFs: median overall survival = 15 months, 95% confidence interval [CI] = 12.7 to 17.3 months; vs patients with lower levels of Smad-regulated gene expression: median overall survival = 26 months, 95% CI = 15.9 to 36.1 months, P = .02). In addition, the activated Smad signaling identified in CAFs was found to be targeted by repositioning calcitriol. Calcitriol suppressed Smad signaling in CAFs, inhibited tumor progression in mice, and prolonged the median survival duration of ovarian cancer-bearing mice from 36 to 48 weeks (P = .04)., Conclusions: Our findings suggest the feasibility of using novel multicellular systems biology modeling to identify and repurpose known drugs targeting cancer-stroma crosstalk networks, potentially leading to faster and more effective cures for cancers., (© The Author(s) 2018. Published by Oxford University Press.)

Increased number of tumor-infiltrating CD8+ lymphocytes is associated with improved survival in patients with advanced stage high grade serous ovarian cancer (HGSOC) but the underlying molecular mechanism has not been thoroughly explored. Using transcriptome profiling of microdissected HGSOC tissue with high and low CD8+ lymphocyte count and subsequent validation studies, we demonstrated that significantly increased ISG15 (Interferon-stimulated gene 15) expression in HGSOC was associated with high CD8+ lymphocyte count and with the improvement in median overall survival in both univariate and multivariate analyses. Further functional studies showed that endogenous and exogenous ISG15 suppressed ovarian cancer progression through ISGylation of ERK in HGSOC, and activation of NK cells and CD8+ T lymphocytes. These data suggest that the development of treatment strategies based on up-regulating ISG15 in ovarian cancer cells or increased circulating ISG15 in ovarian cancer patients is warranted.

The molecular mechanism by which cancer-associated fibroblasts (CAFs) confer chemoresistance in ovarian cancer is poorly understood. The purpose of the present study was to evaluate the roles of CAFs in modulating tumor vasculature, chemoresistance, and disease progression. Here, we found that CAFs upregulated the lipoma-preferred partner (LPP) gene in microvascular endothelial cells (MECs) and that LPP expression levels in intratumoral MECs correlated with survival and chemoresistance in patients with ovarian cancer. Mechanistically, LPP increased focal adhesion and stress fiber formation to promote endothelial cell motility and permeability. siRNA-mediated LPP silencing in ovarian tumor-bearing mice improved paclitaxel delivery to cancer cells by decreasing intratumoral microvessel leakiness. Further studies showed that CAFs regulate endothelial LPP via a calcium-dependent signaling pathway involving microfibrillar-associated protein 5 (MFAP5), focal adhesion kinase (FAK), ERK, and LPP. Thus, our findings suggest that targeting endothelial LPP enhances the efficacy of chemotherapy in ovarian cancer. Our data highlight the importance of CAF-endothelial cell crosstalk signaling in cancer chemoresistance and demonstrate the improved efficacy of using LPP-targeting siRNA in combination with cytotoxic drugs.

Peritoneal dissemination is the primary metastatic route of ovarian cancer (OvCa), and is often accompanied by the accumulation of ascitic fluid. The peritoneal cavity is lined by mesothelial cells (MCs), which can be converted into carcinoma-associated fibroblasts (CAFs) through mesothelial-to-mesenchymal transition (MMT). Here, we demonstrate that MCs isolated from ascitic fluid (AFMCs) of OvCa patients with peritoneal implants also undergo MMT and promote subcutaneous tumour growth in mice. RNA sequencing of AFMCs revealed that MMT-related pathways - including transforming growth factor (TGF)-β signalling - are differentially regulated, and a gene signature was verified in peritoneal implants from OvCa patients. In a mouse model, pre-induction of MMT resulted in increased peritoneal tumour growth, whereas interfering with the TGF-β receptor reduced metastasis. MC-derived CAFs showed activation of Smad-dependent TGF-β signalling, which was disrupted in OvCa cells, despite their elevated TGF-β production. Accordingly, targeting Smad-dependent signalling in the peritoneal pre-metastatic niche in mice reduced tumour colonization, suggesting that Smad-dependent MMT could be crucial in peritoneal carcinomatosis. Together, these results indicate that bidirectional communication between OvCa cells and MC-derived CAFs, via TGF-β-mediated MMT, seems to be crucial to form a suitable metastatic niche. We suggest MMT as a possible target for therapeutic intervention and a potential source of biomarkers for improving OvCa diagnosis and/or prognosis. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland., (© 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.)

Transcription factors are master switches for various biochemical pathways. However, transcription factors involved in the pathogenesis of ovarian cancer have yet to be explored thoroughly. Therefore, in the present study, we assessed the prognostic value of the transcription factor E74-like factor 3 (ELF3) identified via transcriptome profiling of the epithelial components of microdissected ovarian tumor samples isolated from long- and short-term survivors and determined its roles in ovarian cancer pathogenesis. Immunohistochemical analysis of ELF3 in tumor tissue sections suggested that ELF3 was exclusively expressed by epithelial ovarian cancer cells. Furthermore, using 112 high-grade ovarian cancer samples isolated from patients and The Cancer Genome Atlas (TCGA) data, we found that downregulation of ELF3 expression was markedly associated with reduced survival. Functional studies demonstrated that overexpression of ELF3 in ovarian cancer cells suppressed proliferation and anchorage-dependent growth of the cells and that ELF3 silencing increased cell proliferation. Furthermore, upregulation of ELF3 increased expression of epithelial markers, decreased expression of mesenchymal markers, and mediated translocation of epithelial-mesenchymal transition (EMT) signaling molecules in ovarian cancer cells. Finally, we validated the tumor-inhibitory roles of ELF3 using animal models. In conclusion, ELF3 is a favorable prognostic marker for ovarian cancer. As a negative regulator of EMT, ELF3-modulated reversal of EMT may be a new effective modality in the treatment of ovarian cancer.

The conventional approach to assessing cancer invasion is primarily for end-point analysis, which does not provide temporal information on the invasion process or any information on the interactions between invading cells and the underlying adherent cells. To alleviate these limitations, the present study exploited electric cell-substrate impedance sensing (ECIS) to monitor the invasion of ovarian cancer cells (SKOV-3) through an adherent monolayer of human umbilical vein endothelial cells (HUVECs). Impedance was measured at 4 kHz of AC voltage or was measured as a function of AC frequency (25 Hz to 60 kHz). By measuring impedance at 4-kHz AC, we found that the invasion of SKOV-3 cells through the HUVEC monolayer was manifested as a rapid decrease in transendothelial electrical resistance in real time. The invasion was augmented in the presence of hepatocyte growth factor (HGF). The enhancing effect of HGF was attenuated by c-Met inhibitor (SU11274). By measuring the frequency-dependent impedance of SKOV-3 cells over time, we found that HGF-enhanced SKOV-3 cell invasion was accomplished with reduced junctional resistance (R b ), increased average cell-substrate separation (h), and increased micromotion. SU11274 attenuated the effects of HGF on R b , h, and micromotion in the SKOV-3 monolayer. SU11274 also increased the barrier function of the HUVEC monolayer by increasing R b and decreasing h In conclusion, this study demonstrated an improved method for monitoring and studying the interactions between cancer cells and the underlying adherent cells during invasion in real time. Alterations in cellular biophysical properties (R b , h) associated with cancer transendothelial invasion were detected., (Copyright © 2016 the American Physiological Society.)

Reactive stromal cells are an integral part of tumor microenvironment (TME) and interact with cancer cells to regulate their growth. Although targeting stromal cells could be a viable therapy to regulate the communication between TME and cancer cells, identification of stromal targets that make cancer cells vulnerable has remained challenging and elusive. Here, we identify a previously unrecognized mechanism whereby metabolism of reactive stromal cells is reprogrammed through an upregulated glutamine anabolic pathway. This dysfunctional stromal metabolism confers atypical metabolic flexibility and adaptive mechanisms in stromal cells, allowing them to harness carbon and nitrogen from noncanonical sources to synthesize glutamine in nutrient-deprived conditions existing in TME. Using an orthotopic mouse model for ovarian carcinoma, we find that co-targeting glutamine synthetase in stroma and glutaminase in cancer cells reduces tumor weight, nodules, and metastasis. We present a synthetic lethal approach to target tumor stroma and cancer cells simultaneously for desirable therapeutic outcomes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: We report a case of peripheral pigmentary retinopathy and visual field loss following topiramate use for uncontrolled seizures. Such side effects have not been well documented despite the increasing use of topiramate in the past 10 years. A thorough search of available English literature revealed only a small number of reports of topiramate-induced retinopathy or visual field defects in humans. One similar case has been described. We are concerned about the possible rare instances of this occurrence in future patients and hence would like to propose a presumed correlation., Case Presentation: A 48-year-old Chinese woman developed blurred vision after 9 months of topiramate use. Her visual acuity dropped from 1.2 to 0.7 in both eyes, with bilateral diffuse pigmentary retinopathy and a constricted visual field. Despite an improvement in visual acuity after cessation of the drug, the other clinical findings remained. The temporal relationship between the initiation of topiramate and the visual disturbance suggests that topiramate could be the cause of such signs and symptoms., Conclusion: Topiramate potentially causes pigmentary retinopathy and constricted visual field.

Advanced ovarian cancer usually spreads to the visceral adipose tissue of the omentum. However, the omental stromal cell-derived molecular determinants that modulate ovarian cancer growth have not been characterized. Here, using next-generation sequencing technology, we identify significantly higher levels of microRNA-21 (miR21) isomiRNAs in exosomes and tissue lysates isolated from cancer-associated adipocytes (CAAs) and fibroblasts (CAFs) than in those from ovarian cancer cells. Functional studies reveal that miR21 is transferred from CAAs or CAFs to the cancer cells, where it suppresses ovarian cancer apoptosis and confers chemoresistance by binding to its direct novel target, APAF1. These data suggest that the malignant phenotype of metastatic ovarian cancer cells can be altered by miR21 delivered by exosomes derived from neighbouring stromal cells in the omental tumour microenvironment, and that inhibiting the transfer of stromal-derived miR21 is an alternative modality in the treatment of metastatic and recurrent ovarian cancer.

Ovarian cancer is a histologically, clinically, and molecularly diverse disease with a five-year survival rate of less than 30%. It has been estimated that approximately 21,980 new cases of epithelial ovarian cancer will be diagnosed and 14,270 deaths will occur in the United States in 2015, making it the most lethal gynecologic malignancy. Ovarian tumor tissue is composed of cancer cells and a collection of different stromal cells. There is increasing evidence that demonstrates that stromal involvement is important in ovarian cancer pathogenesis. Therefore, stroma-specific signaling pathways, stroma-derived factors, and genetic changes in the tumor stroma present unique opportunities for improving the diagnosis and treatment of ovarian cancer. Cancer-associated fibroblasts (CAFs) are one of the major components of the tumor stroma that have demonstrated supportive roles in tumor progression. In this review, we highlight various types of signaling crosstalk between ovarian cancer cells and stromal cells, particularly with CAFs. In addition to evaluating the importance of signaling crosstalk in ovarian cancer progression, we discuss approaches that can be used to target tumor-promoting signaling crosstalk and how these approaches can be translated into potential ovarian cancer treatment.

Ovarian cancer is the most lethal gynecological malignancy. It is usually diagnosed at a late stage, with a 5-yr survival rate of <30%. The majority of ovarian cancer cases are diagnosed after tumors have widely spread within the peritoneal cavity, limiting the effectiveness of debulking surgery and chemotherapy. Owing to a substantially lower survival rate at late stages of disease than at earlier stages, the major cause of ovarian cancer deaths is believed to be therapy-resistant metastasis. Although metastasis plays a crucial role in promoting ovarian tumor progression and decreasing patient survival rates, the underlying mechanisms of ovarian cancer spread have yet to be thoroughly explored. For many years, researchers have believed that ovarian cancer metastasizes via a passive mechanism by which ovarian cancer cells are shed from the primary tumor and carried by the physiological movement of peritoneal fluid to the peritoneum and omentum. However, the recent discovery of hematogenous metastasis of ovarian cancer to the omentum via circulating tumor cells instigated rethinking of the mode of ovarian cancer metastasis and the importance of the "seed-and-soil" hypothesis for ovarian cancer metastasis. In this review we discuss the possible mechanisms by which ovarian cancer cells metastasize from the primary tumor to the omentum, the cross-talk signaling events between ovarian cancer cells and various stromal cells that play crucial roles in ovarian cancer metastasis, and the possible clinical implications of these findings in the management of this deadly, highly metastatic disease.

Ovarian cancer is the most lethal gynaecologic malignancy in the United States, and advanced serous ovarian adenocarcinoma is responsible for most ovarian cancer deaths. However, the stroma-derived molecular determinants that modulate patient survival are yet to be characterized. Here we identify a stromal gene signature for advanced high-grade serous ovarian cancer using microdissected stromal ovarian tumour samples and find that stromal microfibrillar-associated protein 5 (MFAP5) is a prognostic marker for poor survival. Further functional studies reveal that FAK/CREB/TNNC1 signalling pathways mediate the effect of MFAP5 on ovarian cancer cell motility and invasion potential. Targeting stromal MFAP5 using MFAP5-specific siRNA encapsulated in chitosan nanoparticles significantly decreases ovarian tumour growth and metastasis in vivo, suggesting that it may be a new modality of ovarian cancer treatment.

TGF-β has limited effects on ovarian cancer cells, but its contributions to ovarian tumor growth might be mediated through elements of the tumor microenvironment. In the present study, we tested the hypothesis that TGF modulates ovarian cancer progression by modulating the contribution of cancer-associated fibroblasts (CAF) that are present in the microenvironment. Transcriptome profiling of microdissected stromal and epithelial components of high-grade serous ovarian tumors and TGF-β-treated normal ovarian fibroblasts identified versican (VCAN) as a key upregulated target gene in CAFs. Functional evaluations in coculture experiments showed that TGF-β enhanced the aggressiveness of ovarian cancer cells by upregulating VCAN in CAFs. VCAN expression was regulated in CAFs through TGF-β receptor type II and SMAD signaling. Upregulated VCAN promoted the motility and invasion of ovarian cancer cells by activating the NF-κB signaling pathway and by upregulating expression of CD44, matrix metalloproteinase-9, and the hyaluronan-mediated motility receptor. Our work identified a TGF-β-inducible gene signature specific to CAFs in advanced high-grade serous ovarian tumors, and showed how TGF-β stimulates ovarian cancer cell motility and invasion by upregulating the CAF-specific gene VCAN. These findings suggest insights to develop or refine strategies for TGF-β-targeted therapy of ovarian cancer.

Purpose: To evaluate the prognostic value of fibroblast growth factor receptor 4 (FGFR4) protein expression in patients with advanced-stage, high-grade serous ovarian cancer, delineate the functional role of FGFR4 in ovarian cancer progression, and evaluate the feasibility of targeting FGFR4 in serous ovarian cancer treatment., Experimental Design: Immunolocalization of FGFR4 was conducted on 183 ovarian tumor samples. The collected FGFR4 expression data were correlated with overall survival using Kaplan-Meier and Cox regression analyses. The effects of FGFR4 silencing on ovarian cancer cell growth, survival, invasiveness, apoptosis, and FGF1-mediated signaling pathway activation were evaluated by transfecting cells with FGFR4-specific siRNAs. An orthotopic mouse model was used to evaluate the effect of injection of FGFR4-specific siRNAs and FGFR4 trap protein encapsulated in nanoliposomes on ovarian tumor growth in vivo., Results: Overexpression of FGFR4 protein was significantly associated with decreased overall survival durations. FGFR4 silencing significantly decreased the proliferation, survival, and invasiveness and increased apoptosis of ovarian cancer cells. Also, downregulation of FGFR4 significantly abrogated the mitogen-activated protein kinase (MAPK), nuclear factor-κB (NF-κB), and WNT signaling pathways, which are activated by FGF1. Targeting FGFR4 with the FGFR4-specific siRNAs and FGFR4 trap protein significantly decreased ovarian tumor growth in vivo., Conclusions: FGFR4 is a prognostic marker for advanced-stage, high-grade serous ovarian carcinoma. Silencing FGFR4 and inhibiting ligand-receptor binding significantly decrease ovarian tumor growth both in vitro and in vivo, suggesting that targeting ovarian cancer cells with high levels of FGFR4 protein expression is a new therapeutic modality for this disease and will improve survival of it., (©2012 AACR.)

Immediate early response 3 interacting protein 1 (IER3IP1) is an endoplasmic reticulum protein with its potential cellular function involved in cell differentiation and cell death processes. In this report, we investigated the molecular mechanism by which the expression of IER3IP1 gene is regulated by cloning the 5' flanking region of the human IER3IP1 gene for various promoter studies. Deletion analysis was used to identify the basal promoter activity retained at -298/-59 region and mutation analysis proved that Sp1 is a transcriptional activator of this gene expression. As an early response gene, IER3IP1 showed an increase in transcription in response to tumor necrosis factor alpha (TNF-alpha) in a time- and dose-dependent manner. This inducible response to TNF-alpha is mediated by the demonstration of nuclear factor kappaB (NF-kappaB) responsive element on IER3IP1 promoter sequence. From our results, we suggest that IER3IP1 gene is involved in TNF-alpha-mediated cellular response to stressful conditions., (2009 John Wiley & Sons, Ltd.)