Disturbance Observation and Suppression in an Airborne Electro-Optical Stabilized Platform Based on a Generalized High-Order Extended State Observer.

Active disturbance rejection control (ADRC) is widely used in airborne optoelectronic stabilization platforms due to its minimal reliance on the mathematical model of the controlled object. The extended state observer (ESO) is the core of ADRC, which treats internal parameter variations and external disturbances as total disturbances, observes the disturbances as extended states, and then compensates them into the control loop to eliminate their effects. However, the ESO can only achieve a precise estimation of constant or slowly varying disturbances. When the disturbance is periodically changing, satisfactory results cannot be obtained. In this paper, a generalized high-order extended state observer (GHOESO) is proposed to achieve the precise estimation of known frequency sinusoidal disturbance signals and improve disturbance suppression levels. Through numerical simulations, a traditional ESO and GHOESO are compared in terms of disturbance observation capability and disturbance suppression ability for single and compound disturbances based on our prior knowledge of disturbance frequency. The effectiveness of the proposed GHOESO method is verified. Finally, the algorithm is applied to an airborne optoelectronic stabilization platform for a 1°/1 Hz swing experiment on a space hexapod swing table. The experimental results demonstrate the superiority of the GHOESO proposed in this paper.

Bepotastine Sensitizes Ovarian Cancer to PARP Inhibitors through Suppressing NF-κB-Triggered SASP in Cancer-Associated Fibroblasts.

Therapy-induced senescence (TIS) is common in tumor cells treated with PARP inhibitors (PARPis) and can serve as a promising target for improving PARPi efficacy. However, whether stromal components within the tumor microenvironment undergo TIS caused by PARPis and contribute to consequential treatment failure remain unclear. We previously revealed that PARPis triggered a senescence-like secretory phenotype in stromal fibroblasts. Here, we further explored PARPi-induced senescence in the stroma, its contribution to PARPi resistance, and opportunities to leverage stromal TIS for improved PARPi sensitivity. In this study, we demonstrated that tumor tissues from patients treated with neoadjuvant PARPis showed a significant senescence-like phenotype in the stroma. Moreover, PARPi-induced senescent cancer-associated fibroblasts (CAFs) displayed a senescence-associated secretory phenotype (SASP) profile that was sufficient to induce tumor resistance to PARPis in both homologous recombination-deficient (HRD) and -proficient ovarian cancer cells. Using the GLAD4U database, we found that bepotastine, an approved H1-antihistamine, inhibited the SASP of PARPi-primed CAFs at clinical serum concentrations. We further demonstrated that bepotastine attenuated fibroblast-facilitated tumor resistance to PARPis in three-dimensional organotypic cultures and HRD-positive patient-derived xenograft models. Mechanistically, bepotastine suppressed PARPi-triggered SASP by inhibiting NF-κB signaling independent of the histamine H1 receptor. Taken together, our results highlight the importance of stromal TIS and SASP in PARPi resistance, and targeting SASP with bepotastine may be a promising therapeutic option for improving PARPi sensitivity in ovarian cancer.

The structural and functional characteristics of soluble dietary fibers modified from tomato pomace with increased content of lycopene.

The tomato pomace, a by-product of tomato processing, was rich in nutrients such as lycopene (Lyc), vitamins, phenols and soluble dietary fibers (SDF). Homogenization combined with enzymatic hydrolysis (HE) was firstly applied to obtain HE-pomace. The yield of Lyc was raised by 57.2% after HE treatment by the optimal condition. The extraction rate of HE-SDF was increased by 73.4%. In order to clarify the relationship between the SDF and the release of Lyc, SDFs were characterized by structural analysis and morphological determination. The results suggested that HE-SDF possessed smaller molecular weight and loose microstructure with shorter chains. It implied that the degradation of dietary fiber led to the release of Lyc molecules. Besides, HE-SDF exhibited stronger capacity of water-holding, glucose adsorption and bile acid binding. In conclusion, HE treatment possessed the potential to be applied as an excellent modification method, which improved the nutritional and economic value of tomato pomace.

Serum semaphorin 4C as a diagnostic biomarker in breast cancer: A multicenter retrospective study.

BACKGROUND: To date, there is no approved blood-based biomarker for breast cancer detection. Herein, we aimed to assess semaphorin 4C (SEMA4C), a pivotal protein involved in breast cancer progression, as a serum diagnostic biomarker. METHODS: We included 6,213 consecutive inpatients from Tongji Hospital, Qilu Hospital, and Hubei Cancer Hospital. Training cohort and two validation cohorts were introduced for diagnostic exploration and validation. A pan-cancer cohort was used to independently explore the diagnostic potential of SEMA4C among solid tumors. Breast cancer patients who underwent mass excision prior to modified radical mastectomy were also analyzed. We hypothesized that increased pre-treatment serum SEMA4C levels, measured using optimized in-house enzyme-linked immunosorbent assay kits, could detect breast cancer. The endpoints were diagnostic performance, including area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. Post-surgery pathological diagnosis was the reference standard and breast cancer staging followed the TNM classification. There was no restriction on disease stage for eligibilities. RESULTS: We included 2667 inpatients with breast lesions, 2378 patients with other solid tumors, and 1168 healthy participants. Specifically, 118 patients with breast cancer were diagnosed with stage 0 (5.71%), 620 with stage I (30.00%), 966 with stage II (46.73%), 217 with stage III (10.50%), and 8 with stage IV (0.39%). Patients with breast cancer had significantly higher serum SEMA4C levels than benign breast tumor patients and normal controls (P < 0.001). Elevated serum SEMA4C levels had AUC of 0.920 (95% confidence interval [CI]: 0.900-0.941) and 0.932 (95%CI: 0.911-0.953) for breast cancer detection in the two validation cohorts. The AUCs for detecting early-stage breast cancer (n = 366) and ductal carcinoma in situ (n = 85) were 0.931 (95%CI: 0.916-0.946) and 0.879 (95%CI: 0.832-0.925), respectively. Serum SEMA4C levels significantly decreased after surgery, and the reduction was more striking after modified radical mastectomy, compared with mass excision (P < 0.001). The positive rate of enhanced serum SEMA4C levels was 84.77% for breast cancer and below 20.75% for the other 14 solid tumors. CONCLUSIONS: Serum SEMA4C demonstrated promising potential as a candidate biomarker for breast cancer diagnosis. However, validation in prospective settings and by other study groups is warranted.

TAGLN mediated stiffness-regulated ovarian cancer progression via RhoA/ROCK pathway.

BACKGROUND: Ovarian cancer (OC) progression is an unmet medical challenge. Since omental metastases were palpated harder than their primary counterparts during cytoreductive surgery of patients with epithelial ovarian cancer (EOC), we were inspired to investigate OC progression from the perspective of biomechanics. METHODS: Atomic Force Microscope (AFM) was used to measure the Young's modulus of tissues. The collagen-coated polyacrylamide hydrogel (PA gel) system was prepared to mimic the soft and stiff substrates in vitro. The effect of TAGLN was evaluated both in vitro and in vivo using transwell assay, immunofluorescence, western blot analysis and immunohistochemistry. RESULTS: We quantitatively confirmed that omental metastases were stiffer and more abundant in desmoplasia compared with paired primary tumors, and further demonstrated that matrix stiffness could notably regulate OC progression. Remarkably, TAGLN, encoding an actin cross-linking/gelling protein, was identified as a potent mechanosensitive gene that could form a regulation loop with Src activation reacting to environmental stiffness, thus mediating stiffness-regulated OC progression through regulating RhoA/ROCK pathway. CONCLUSIONS: These data demonstrate that targeting extra-cellular matrix (ECM) stiffness could probably hamper OC progression, and of note, targeting TAGLN might provide promising clinical therapeutic value for OC therapy.

PARP inhibitors promote stromal fibroblast activation by enhancing CCL5 autocrine signaling in ovarian cancer.

Cancer-associated fibroblasts (CAFs) play significant roles in drug resistance through different ways. Antitumor therapies, including molecular targeted interventions, not only effect tumor cells but also modulate the phenotype and characteristics of CAFs, which can in turn blunt the therapeutic response. Little is known about how stromal fibroblasts respond to poly (ADP-ribose) polymerase inhibitors (PARPis) in ovarian cancer (OC) and subsequent effects on tumor cells. This is a study to evaluate how CAFs react to PARPis and their potential influence on PARPi resistance in OC. We discovered that OC stromal fibroblasts exhibited intrinsic resistance to PARPis and were further activated after the administration of PARPis. PARPi-challenged fibroblasts displayed a specific secretory profile characterized by increased secretion of CCL5, MIP-3α, MCP3, CCL11, and ENA-78. Mechanistically, increased secretion of CCL5 through activation of the NF-κB signaling pathway was required for PARPi-induced stromal fibroblast activation in an autocrine manner. Moreover, neutralizing CCL5 partly reversed PARPi-induced fibroblast activation and boosted the tumor inhibitory effect of PARPis in both BRCA1/2-mutant and BRCA1/2-wild type xenograft models. Our study revealed that PARPis could maintain and improve stromal fibroblast activation involving CCL5 autocrine upregulation. Targeting CCL5 might offer a new treatment modality in overcoming the reality of PARPi resistance in OC.

Targeting INHBA in Ovarian Cancer Cells Suppresses Cancer Xenograft Growth by Attenuating Stromal Fibroblast Activation.

INHBA-encoded inhibin ß A is a member of the transforming growth factor-ß (TGF-ß) superfamily. INHBA has been reported to be implicated in the progression of multiple types of cancer including ovarian cancer (OC). However, the mechanisms by which INHBA affects OC progression are not well-characterized. The aim of our study was to explore the prognostic value of INHBA for different stages and grades of OC and to identify the possible mechanisms by which INHBA promotes OC progression. Our results demonstrated that INHBA was specifically expressed in OC epithelium, and higher expression was associated with higher risk of mortality in patients with advanced and higher-grade serous OC (SOC). In addition, knockdown of INHBA in cancer cells impaired cancer xenograft growth through reducing OC stromal fibroblast activation in vivo. Further results confirmed that Smad2 signaling pathway was involved in INHBA-induced stromal fibroblast activation, and inhibiting this pathway could effectively reverse activation of stromal fibroblasts. In summary, our results showed that blocking INHBA in cancer cells may be a potential therapeutic strategy to inhibit SOC progression.

Targeting YAP suppresses ovarian cancer progression through regulation of the PI3K/Akt/mTOR pathway.

Ovarian cancer (OC) is highly metastatic due to frequent peritoneal dissemination, and its treatment poses a major challenge in clinical practice. Yes­associated protein (YAP) is known to be associated with the development of multiple tumors. However, whether targeting YAP can restrain OC progression and the underlying mechanisms have yet to be fully elucidated. In the present study, YAP was found to be highly expressed in OC, and its expression was correlated with the prognosis of OC patients. Moreover, silencing of YAP markedly inhibited the malignant behavior of OC cells, possibly through regulation of the PI3K/Akt/mTOR pathway. Notably, peptide 17, a YAP inhibitor, exerted a significant attenuating effect on OC progression by diminishing the activation of the PI3K/Akt/mTOR pathway in vitro as well as in vivo. Taken together, these findings demonstrated that targeting YAP attenuated OC progression and suggested the potential application of peptide 17 in OC therapy, thus providing new insights into improving the treatment of OC.

Correction: Targeting Leptin as a Therapeutic Strategy against Ovarian Cancer Peritoneal Metastasis.

The authors would like to correct Fig. 1, Fig. 3 and Fig. 5G, as errors were introduced in the preparation of these figures for publication. The authors declare that these corrections do not change the results or conclusions of this paper. We sincerely apologize for having this error in the article, and apologize for any inconvenience caused. The authors have provided corrected version of Fig. 1, Fig. 3 and Fig. 5G here.

Mechanical cues modulate cellular uptake of nanoparticles in cancer via clathrin-mediated and caveolae-mediated endocytosis pathways.

AIM: To investigate the influence of tissue mechanics on the cellular uptake efficiency of nanoparticles (NPs) in cancer. MATERIALS & METHODS: Collagen-coated polyacrylamide gels were prepared as model substrates. Coumarin 6-loaded poly(lactic-co-glycolic) acid micelles (C6-NPs) were prepared to investigate the cellular uptake of NPs. RESULTS: We demonstrated that substrate stiffness modulated the cellular uptake of NPs of cancer. Mechanistically, mechanical cues exerted influence on the clathrin-mediated endocytosis and caveolae-mediated endocytosis pathways, which mediated stiffness-regulated cellular uptake of NPs. CONCLUSION: Our findings shed light on the regulatory role of the mechanical cues on the cellular uptake of NPs and will facilitate the selection of clinical patients who might benefit from a given nanotherapy.

Heterotypic CAF-tumor spheroids promote early peritoneal metastatis of ovarian cancer.

High-grade serous ovarian cancer (HGSOC) is hallmarked by early onset of peritoneal dissemination, which distinguishes it from low-grade serous ovarian cancer (LGSOC). Here, we describe the aggressive nature of HGSOC ascitic tumor cells (ATCs) characterized by integrin α5high (ITGA5high) ATCs, which are prone to forming heterotypic spheroids with fibroblasts. We term these aggregates as metastatic units (MUs) in HGSOC for their advantageous metastatic capacity and active involvement in early peritoneal dissemination. Intriguingly, fibroblasts inside MUs support ATC survival and guide their peritoneal invasion before becoming essential components of the tumor stroma in newly formed metastases. Cancer-associated fibroblasts (CAFs) recruit ITGA5high ATCs to form MUs, which further sustain ATC ITGA5 expression by EGF secretion. Notably, LGSOC is largely devoid of CAFs and the resultant MUs, which might explain its metastatic delay. These findings identify a specialized MU architecture that amplifies the tumor-stroma interaction and promotes transcoelomic metastasis in HGSOC, providing the basis for stromal fibroblast-oriented interventions in hampering OC peritoneal propagation.

C/EBPß enhances platinum resistance of ovarian cancer cells by reprogramming H3K79 methylation.

Chemoresistance is a major unmet clinical obstacle in ovarian cancer treatment. Epigenetics plays a pivotal role in regulating the malignant phenotype, and has the potential in developing therapeutically valuable targets that improve the dismal outcome of this disease. Here we show that a series of transcription factors, including C/EBPß, GCM1, and GATA1, could act as potential modulators of histone methylation in tumor cells. Of note, C/EBPß, an independent prognostic factor for patients with ovarian cancer, mediates an important mechanism through which epigenetic enzyme modifies groups of functionally related genes in a context-dependent manner. By recruiting the methyltransferase DOT1L, C/EBPß can maintain an open chromatin state by H3K79 methylation of multiple drug-resistance genes, thereby augmenting the chemoresistance of tumor cells. Therefore, we propose a new path against cancer epigenetics in which identifying and targeting the key regulators of epigenetics such as C/EBPß may provide more precise therapeutic options in ovarian cancer.

Metformin Suppresses Tumor Progression by Inactivating Stromal Fibroblasts in Ovarian Cancer.

Ovarian cancer is a devastating disease due to its high incidence of relapse and chemoresistance. The tumor microenvironment, especially the tumor stroma compartment, was proven to contribute tremendously to the unsatisfactory chemotherapeutic efficacy in ovarian cancer. Cytotoxic agents not only effect tumor cells, but also modulate the phenotype and characteristics of the vast stromal cell population, which can in turn alter the tumor cell response to chemointervention. In this study, we focused on the tumor stroma response to cytotoxic agents and the subsequent effect on the ovarian cancer tumor cells. First, we found a significant stromal overexpression of IL6 in patient samples that received cisplatin-based treatment, which was further validated in purified fibroblasts challenged with cisplatin. Stromal fibroblast-derived IL6 was proven to mediate ovarian cancer tumor cell chemoresistance. For the first time, we found that the tumor stroma of patients with routine metformin administration exhibited lower IL6 expression. Thus, we presumed that metformin was a potent alleviator of stromal inflammation in ovarian cancer. We found that metformin partly reversed cisplatin-stimulated IL6 secretion in the stromal fibroblasts and attenuated fibroblast-facilitated tumor growth in 3D organotypic cocultures and murine xenograft models. Mechanistically, we found that metformin inhibited IL6 secretion via suppressing NFκB signaling, an upstream controller of stromal inflammation. Collectively, our findings introduced a novel mechanism of metformin in suppressing ovarian cancer progression through diminishing chemotherapy-induced stromal activation. Therefore, we provide an alternative therapeutic option in targeting stromal inflammation and a potential scheme of combination therapy to improve the chemosensitivity in ovarian cancer. Mol Cancer Ther; 17(6); 1291-302. ©2018 AACR.

Quercetin suppresses DNA double-strand break repair and enhances the radiosensitivity of human ovarian cancer cells via p53-dependent endoplasmic reticulum stress pathway.

Quercetin is proven to have anticancer effects for many cancers. However, the role of tumor suppressor p53 on quercetin's radiosensitization and regulation of endoplasmic reticulum (ER) stress response in this process remains obscure. Here, quercetin exposure resulted in ER stress, prolonged DNA repair, and the expression of p53 protein; phosphorylation on serine 15 and 20 increased in combination with X-irradiation. Quercetin pretreatment could potentiate radiation-induced cell death. The combination of irradiation and quercetin treatment aggravated DNA damages and caused typical apoptotic cell death; as well the expression of Bax and p21 elevated and the expression of Bcl-2 decreased. Knocking down of p53 could reverse all the above effects under quercetin in combination with radiation. In addition, quercetin-induced radiosensitization was through stimulation of ATM phosphorylation. In human ovarian cancer xenograft model, combined treatment of quercetin and radiation significantly restrained the growth of tumors, accompanied with the activation of p53, CCAAT/enhancer-binding protein homologous protein, and γ-H2AX. Overall, these results indicated that quercetin acted as a promising radiosensitizer through p53-dependent ER stress signals.

Dicer reprograms stromal fibroblasts to a pro-inflammatory and tumor-promoting phenotype in ovarian cancer.

Inflammation and host stromal activation contribute significantly to ovarian cancer (OC) initiation and malignant progression. However, the complex reciprocal interactions between them are largely unknown. Here, we discovered that the tumor suppressor gene Dicer was paradoxically overexpressed in ovarian tumor stroma, and induced fibroblast activation and stromal inflammation. Dicer transformed normal fibroblasts to a carcinoma-associated fibroblast (CAF)-like state, which was morphologically spread out and functionally activated to fuel tumor invasion and metastasis. Attenuation of Dicer hampered CAF characteristics, diminished stromal inflammation and the role of fibroblasts in supporting tumor growth. Moreover, Dicer drove the expression of an "inflammatory signature" in fibroblasts that could be used to discriminate normal and cancerous stroma and predict the survival of patients with OC. Finally, the nuclear factor κ B (NFκB) signaling was demonstrated to be responsible for Dicer effect on fibroblast activation and stromal inflammation, through microRNA (miR)-6780b. Our study represents the first report that characterizes Dicer expression and function in the tumor stroma, and highlights its pro-metastatic role in this context. Additionally, we suggest that the Dicer-miR6780b-NFκB cascade is an attractive target of choice in stroma-oriented OC therapy.

Reprogramming of stromal fibroblasts by SNAI2 contributes to tumor desmoplasia and ovarian cancer progression.

BACKGROUND: Molecular profiling in ovarian cancer (OC) revealed that the desmoplasia subtype presented the poorest prognosis, highlighting the contribution of stromal fibroblasts in tumor progression. This study aimed to investigate the molecular characteristics of SNAI2 driving the transcriptional reprogramming of fibroblasts within tumors. METHODS: SNAI2 expression was evaluated in microdissected profiles of various cancers and in various molecular subtypes of OC. Gene set enrichment analysis (GSEA) and single sample GSEA (ssGSEA) were performed to explore the correlation between SNAI2 and stromal fibroblast activation. The SNAI2 defined signature in the mesenchymal OC subtype was identified through an integrative analysis of the TCGA and the Tothill datasets. The predictive value of this signature was validated in independent datasets. SNAI2 expression alteration influence of tumor growth in primary CAFs was evaluated in 3D organotypic and murine xenograft models. RESULTS: We demonstrated that SNAI2 was frequently activated in the tumor stroma, correlated with fibroblast activation and worse patient outcome in OC. SNAI2 transformed normal fibroblasts to a CAF-like state and boosted their tumor-supporting role in 3D organotypic culture and in OC xenograft model. SNAI2 drove a transcriptional signature in the mesenchymal subtype of OC that contributed to tumor desmoplasia, which fed back to increase SNAI2 expression and sustain fibroblast activation. CONCLUSIONS: Our results address the role of SNAI2 in reprogramming stromal fibroblasts. The identified SNAI2 mesenchymal signature has both a predictive value and biological relevance and might be a therapeutic target for stroma-oriented therapy against the desmoplasia OC subtype.

Isoform expression patterns of EPHA10 protein mediate breast cancer progression by regulating the E-Cadherin and ß-catenin complex.

Overexpression of EPHA10 protein was reported in concomitance with clinical severity of breast cancer. In this study, we annotate overexpression of EPHA10 protein with changes of isoform expression as EphA10s (EPHA10 isoform 2) and EphA10 (EPHA10 isoform 3). In the process of malignant transformation, secretory protein EphA10s is in low expression, and pseudo-kinase EphA10 is overexpressed and cytoplasmically enriched. Down-regulated EphA10s blunts stabilization of membrane-associate ß-catenin via the interaction with ephrin A5. Cytoplasmic EphA10 maintains phosphorylation of E-cadherin. Restoring isoform expression pattern by up-regulated EphA10s and down-regulated cytoplasmic EphA10 inhibits cell invasion and lymph node metastasis by strengthening the stability of the complex of E-cadherin and ß-catenin in membrane. Taken together, we defined the novel interaction via expression patterns of EphA10s and EphA10 that promote malignant transformation of breast cancer, and demonstrated the potential benefit in clinical usage.