Surgery outcomes of lamellar macular eyes with or without lamellar hole-associated epiretinal proliferation: a meta-analysis.

BACKGROUND: Given the two different kinds of epiretinal membranes, this study aimed to compare both the structural and functional outcomes of lamellar macular holes with and without lamellar hole-associated epiretinal proliferation (LHEP) after surgery. METHOD: Publications up to July 2020 that compared the surgical outcomes of lamellar macular hole with and without LHEP were included. Forest plots were created by using a weighted summary of proportion meta-analysis. Fixed or random effects models were used on the basis of I2 heterogeneity estimates. Meanwhile, to evaluate the stability of the meta-analysis, a sensitivity analysis was carried out. RESULTS: Eight pertinent publications that contained a total of 176 eyes without LHEP and 173 eyes with LHEP were included. They were all retrospective studies and had a follow-up of at least 6 months. In all studies, the preoperative best corrected visual acuity showed no significant differences between the two groups, and the visual acuity improved in both groups after surgery. The pooled result for the improved best corrected visual acuity was 0.18 (95% confidence interval (CI), 0.10 to 0.26; P < 0.01) between the with and without LHEP groups. The restored ellipsoid zone odds ratio was 0.80 (95% CI, 0.26 to 2.44; P = 0.69) for the group with LHEP compared to the group without LHEP. CONCLUSION: Patients without LHEP had better postoperative visual acuity than patients with LHEP. No significant difference in restored ellipsoid zone was found between the two groups.

Prognostic significance of helicobacter pylori-infection in gastric diffuse large B-cell lymphoma.

BACKGROUND: Helicobacter pylori (H. pylori) is thought to have an oncogenic effect on the development of gastric malignancies. However, the effect of H. pylori status on the prognosis of gastric diffuse large B-cell lymphoma (DLBCL) remains unconfirmed. This study aimed to identify the prognostic importance of H. pylori infection in de novo gastric DLBCL. METHODS: One hundred and twenty-nine patients diagnosed with primary de novo gastric DLBCL at the West China Hospital of Sichuan University from 1st January 2009 to 31st May 2016 were included. The clinical features of the patients were documented. H. pylori status was assessed via urease breath tests and histologic examinations. The prognostic value of H. pylori was verified via univariate and multivariate analyses. RESULTS: Over a median follow-up of 52.2 months (range 4-116), the 5-year overall survival (OS) for all patients was 78.7%. Patients with H. pylori infections had significantly better 5-year PFS and OS than did the H. pylori-negative subgroup (5-year PFS, 89.3% vs. 74.1%, P = 0.040; 5-year OS, 89.7% vs. 71.8%, P = 0.033). Negative H. pylori status and poor ECOG performance were independent negative prognostic indicators for both PFS and OS (PFS, P = 0.045 and P = 0.001, respectively; OS, P = 0.021 and P < 0.001, respectively). CONCLUSIONS: H. pylori status in de novo gastric DLBCL can be a promising predictor of disease outcome, and patients with negative H. pylori status require careful follow-up since they tend to have a worse outlook.

Expression Profile Analysis of Circular RNAs in Ovarian Endometriosis by Microarray and Bioinformatics.

BACKGROUND Endometriosis is a common gynecologic disorder with enigmatic etiopathogenesis and is characterized by tumor-like biological behaviors. Recently, circular RNAs (circRNAs) have attracted considerable attention because they exert very important functions in the progression of human cancers. However, little is known about the functions and molecular mechanism of circRNAs in endometriosis. MATERIAL AND METHODS A total of 20 patients with ovarian endometriosis and 4 normal endometrium from women free of endometriosis were included in this study. Ectopic endometrium tissues and paired eutopic endometrium tissues were collected from ovarian endometriosis patients. We assessed the expression profiles of circRNAs in endometriosis by microarray analysis. Expression of selected circRNAs in those tissues was detected by quantitative real-time PCR (qRT-PCR). Based on the target prediction, we constructed a circRNA-miRNA-mRNA competing endogenous RNA (ceRNA) network and elucidated circRNAs through Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses. RESULTS We detected 2237 circRNAs, differentially expressed among 3 groups, and then found 8 circRNAs that may be involved in the epithelial-mesenchymal transition process. The qRT-PCR validation suggested that circ_103470 and circ_101102 matched the microarray results. The functional analysis revealed 17 pathways, such as the mTOR signaling pathway, the Hippo signaling pathway, and the HIF-1 signaling pathway, which may be associated with the pathogenesis and development of endometriosis. CONCLUSIONS In general, our results suggest that 2 downregulated circRNAs (circ_103470 and circ_101102) may regulated epithelial-mesenchymal transition in endometriosis via miR-141-5p, which may be a promising therapeutic target in the future.

p53-regulated lncRNAs in cancers: from proliferation and metastasis to therapy.

Long non-coding RNAs (lncRNAs) have been identified as master gene regulators through various mechanisms such as transcription, translation, protein modification and RNA-protein complexes. LncRNA dysregulation is frequently associated with a variety of biological functions and human diseases including cancer. The p53 network is a key tumor-suppressive mechanism that transcriptionally activates target genes to suppress cellular proliferation in human malignancies. Recent research indicates that lncRNAs play an important role in the p53 signaling pathway. In this review, we summarize the current knowledge of lncRNAs in p53-relevant functions and provide an overview of how these altered lncRNAs contribute to tumor initiation and progression. We also discuss the association between lncRNA and up- or downstream genes of p53. These findings imply that lncRNAs can help identify cellular vulnerabilities that may prove to be promising potential biomarkers and therapeutic targets for cancer treatment.

Profiling the metabolome of uterine fluid for early detection of ovarian cancer.

Ovarian cancer (OC) causes high mortality in women because of ineffective biomarkers for early diagnosis. Here, we perform metabolomics analysis on an initial training set of uterine fluid from 96 gynecological patients. A seven-metabolite-marker panel consisting of vanillylmandelic acid, norepinephrine, phenylalanine, beta-alanine, tyrosine, 12-S-hydroxy-5,8,10-heptadecatrienoic acid, and crithmumdiol is established for detecting early-stage OC. The panel is further validated in an independent sample set from 123 patients, discriminating early OC from controls with an area under the curve (AUC) of 0.957 (95% confidence interval [CI], 0.894-1). Interestingly, we find elevated norepinephrine and decreased vanillylmandelic acid in most OC cells, resulting from excess 4-hydroxyestradiol that antagonizes the catabolism of norepinephrine by catechol-O-methyltransferase. Moreover, exposure to 4-hydroxyestradiol induces cellular DNA damage and genomic instability that could lead to tumorigenesis. Thus, this study not only reveals metabolic features in uterine fluid of gynecological patients but also establishes a noninvasive approach for the early diagnosis of OC.

Long non-coding RNA HIF1A-As2 and MYC form a double-positive feedback loop to promote cell proliferation and metastasis in KRAS-driven non-small cell lung cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide. KRAS is the main oncogenic driver in lung cancer that can be activated by gene mutation or amplification, but whether long non-coding RNAs (lncRNAs) regulate its activation remains unknown. Through gain and loss of function approaches, we identified that lncRNA HIF1A-As2, a KRAS-induced lncRNA, is required for cell proliferation, epithelial-mesenchymal transition (EMT) and tumor propagation in non-small cell lung cancer (NSCLC) in vitro and in vivo. Integrative analysis of HIF1A-As2 transcriptomic profiling reveals that HIF1A-As2 modulates gene expression in trans, particularly regulating transcriptional factor genes including MYC. Mechanistically, HIF1A-As2 epigenetically activates MYC by recruiting DHX9 on MYC promoter, consequently stimulating the transcription of MYC and its target genes. In addition, KRAS promotes HIF1A-As2 expression via the induction of MYC, suggesting HIF1A-As2 and MYC form a double-regulatory loop to strengthen cell proliferation and tumor metastasis in lung cancer. Inhibition of HIF1A-As2 by LNA GapmeR antisense oligonucleotides (ASO) significantly improves sensitization to 10058-F4 (a MYC-specific inhibitor) and cisplatin treatment in PDX and KRASLSLG12D-driven lung tumors, respectively.

PG545 sensitizes ovarian cancer cells to PARP inhibitors through modulation of RAD51-DEK interaction.

PG545 (Pixatimod) is a highly sulfated small molecule known for its ability to inhibit heparanase and disrupt signaling mediated by heparan-binding-growth factors (HB-GF). Previous studies indicated that PG545 inhibits growth factor-mediated signaling in ovarian cancer (OC) to enhance response to chemotherapy. Here we investigated the previously unidentified mechanisms by which PG545 induces DNA damage in OC cells and found that PG545 induces DNA single- and double-strand breaks, reduces RAD51 expression in an autophagy-dependent manner and inhibits homologous recombination repair (HRR). These changes accompanied the ability of PG545 to inhibit endocytosis of the heparan-sulfate proteoglycan interacting DNA repair protein, DEK, leading to DEK sequestration in the tumor microenvironment (TME) and loss of nuclear DEK needed for HRR. As a result, PG545 synergized with poly (ADP-ribose) polymerase inhibitors (PARPis) in OC cell lines in vitro and in 55% of primary cultures of patient-derived ascites samples ex vivo. Moreover, PG545/PARPi synergy was observed in OC cells exhibiting either de novo or acquired resistance to PARPi monotherapy. PG545 in combination with rucaparib also generated increased DNA damage, increased antitumor effects and increased survival of mice bearing HRR proficient OVCAR5 xenografts compared to monotherapy treatment in vivo. Synergistic antitumor activity of the PG545/rucaparib combination was likewise observed in an immunocompetent syngeneic ID8F3 OC model. Collectively, these results suggest that targeting DEK-HSPG interactions in the TME through the use of PG545 may be a novel method of inhibiting DNA repair and sensitizing cells to PARPis.

Multi-omics approaches for biomarker discovery in early ovarian cancer diagnosis.

Ovarian cancer (OC) is a heterogeneous disease with the highest mortality rate and the poorest prognosis among gynecological malignancies. Because of the absence of specific early symptoms, most OC patients are often diagnosed at late stages. Thus, improved biomarkers of OC for use in research and clinical practice are urgently needed. The last decade has seen increasingly rapid advances in sequencing and biotechnological methodologies. Consequently, multiple omics technologies, including genomic/transcriptomic sequencings and proteomic/metabolomic mass spectra, have been widely applied to analyze tissue- and liquid-derived samples from OC patients. The integration of multi-omics data has increased our knowledge of the disease and identified valuable OC biomarkers. In this review, we summarize the recent advances and perspectives in the use of multi-omics technologies in OC research and highlight potential applications of multi-omics for identifying novel biomarkers and improving clinical assessments.

Exploration of Leisure Constraints Perception in the Context of a Pandemic: An Empirical Study of the Macau Light Festival.

Individuals' capacity to participate in leisure activities is contingent upon their ability to overcome obstacles. It is worthwhile to investigate how individuals perceive constraints on their leisure activities participation during the COVID-19 pandemic. This study demonstrates that the connotation of leisure constraints during pandemic includes personal health concerns, shock on economic revenue, reduced freedom of travel, and inconvenience associated with epidemic prevention. Reduced travel freedom is the most influential factor on participation intentions, followed by personal health concerns. Significant differences in perceptions of constraints are observed between groups with different characteristics.

The Apoptotic Resistance of BRCA1-Deficient Ovarian Cancer Cells is Mediated by cAMP.

Breast cancer type 1 susceptibility protein (BRCA1) is essential for homologous recombination repair of DNA double-strand breaks. Loss of BRCA1 is lethal to embryos due to extreme genomic instability and the activation of p53-dependent apoptosis. However, the apoptosis is resisted in BRCA1-deficient cancer cells even though their p53 is proficient. In this study, by analysis of transcriptome data of ovarian cancer patients bearing BRCA1 defects in TCGA database, we found that cAMP signaling pathway was significantly activated. Experimentally, we found that BRCA1 deficiency caused an increased expression of ADRB1, a transmembrane receptor that can promote the generation of cAMP. The elevated cAMP not only inhibited DNA damage-induced apoptosis through abrogating p53 accumulation, but also suppressed the proliferation of cytotoxic T lymphocytes by enhancing the expression of immunosuppressive factors DKK1. Inhibition of ADRB1 effectively killed cancer cells by abolishing the apoptotic resistance. These findings uncover a novel mechanism of apoptotic resistance in BRCA1-deficient ovarian cancer cells and point to a potentially new strategy for treating BRCA1-mutated tumors.

A Research on Delayed Thermal Depolarization, Electric Properties, and Stress in (Bi0.5Na0.5)TiO3-Based Ceramic Composites.

Depolarization behavior is one of the main shortcomings of (Bi0.5Na0.5)TiO3-based ceramics. Considering the undesirable efficiency of traditional modification methods, in this paper a series of 0-3 type ceramic composites 0.85(Bi0.5Na0.5)TiO3-0.11(Bi0.5K0.5)TiO3-0.04BaTiO3-x mol% ZnO (BNKT-BT-xZnO)) were synthesized by introducing ZnO nanoparticles. The results of the X-ray diffraction pattern (XRD) and energy dispersive spectroscopy (EDS) demonstrate that the majority of ZnO nanoparticles grow together to form enrichment regions, and the other Zn2+ ions diffuse into the matrix after sintering. With ZnO incorporated, the ferroelectric-ergodic relaxor transition temperature, TF-R, and depolarization temperature, Td, increase to above 120 °C and 110 °C, respectively. The research on temperature-dependent P-E loops verifies an attenuated ergodic degree induced by ZnO incorporation. For this reason, piezoelectric properties can be well-maintained below 110 °C. The electron backscatter diffraction (EBSD) was employed to investigate the stress effect. Orientation maps reveal the random orientation of all grains, excluding the impact of texture on depolarization. The local misorientation image shows that more pronounced strain appears near the boundaries, implying stress is more concentrated there. This phenomenon supports the hypothesis that potential stress suppresses depolarization. These results demonstrate that the depolarization behavior is significantly improved by the introduction of ZnO. The composites BNKT-BT-xZnO are promising candidates of lead-free ceramics for practical application in the future.

Targeting LRRC15 Inhibits Metastatic Dissemination of Ovarian Cancer.

Dissemination of ovarian cancer cells can lead to inoperable metastatic lesions in the bowel and omentum that cause patient death. Here we show that LRRC15, a type-I 15-leucine-rich repeat-containing membrane protein, highly overexpressed in ovarian cancer bowel metastases compared with matched primary tumors and acts as a potent promoter of omental metastasis. Complementary models of ovarian cancer demonstrated that LRRC15 expression leads to inhibition of anoikis-induced cell death and promotes adhesion and invasion through matrices that mimic omentum. Mechanistically, LRRC15 interacted with ß1-integrin to stimulate activation of focal adhesion kinase (FAK) signaling. As a therapeutic proof of concept, targeting LRRC15 with the specific antibody-drug conjugate ABBV-085 in both early and late metastatic ovarian cancer cell line xenograft models prevented metastatic dissemination, and these results were corroborated in metastatic patient-derived ovarian cancer xenograft models. Furthermore, treatment of 3D-spheroid cultures of LRRC15-positive patient-derived ascites with ABBV-085 reduced cell viability. Overall, these data uncover a role for LRRC15 in promoting ovarian cancer metastasis and suggest a novel and promising therapy to target ovarian cancer metastases.Significance: This study identifies that LRRC15 activates ß1-integrin/FAK signaling to promote ovarian cancer metastasis and shows that the LRRC15-targeted antibody-drug conjugate ABBV-085 suppresses ovarian cancer metastasis in preclinical models.

Improved Non-Piezoelectric Electric Properties Based on La Modulated Ferroelectric-Ergodic Relaxor Transition in (Bi0.5Na0.5)TiO3-Ba(Ti, Zr)O3 Ceramics.

The characteristic transition from ferroelectric (FE) to ergodic relaxor (ER) state in (Bi0.5Na0.5)TiO3 (BNT) based lead-free ceramics provides an efficient approach to bring a highly ordered phase back to a disordered one. It would be rational to utilize this transition to improve relevant non-piezoelectric properties based on domain decomposition. In this work, different La contents were introduced to 0.93(Bi0.5Na0.5)TiO3-0.07Ba(Ti0.945Zr0.055)O3 ceramics (BNT-BZT-xLa) to induce evolution of ergodic degree. The results reveal that with increasing La content, both the FE-ER transition temperature TF-R and depolarization temperature Td shift towards room temperature, implying a deepened ergodic degree. By modulation of ergodic degree, thermally stimulated depolarization current experiment shows a higher current density peak, and corresponding pyroelectric coefficient increases from 2.46 to 2.81 µC/(cm2∙°C) at Td. For refrigeration, the indirect measurement demonstrates the ΔT maximum increases from 1.1 K to 1.4 K, indicating an enhanced electrocaloric effect. Moreover, the optimized energy storage effect is observed after La doping. With appearance of "slimmer" P-E loops, both calculated recoverable energy storage density Wrec and storage efficiency η increase to 0.23 J/cm3 and 22.8%, respectively. These results denote La doping conduces to the improvement of non-piezoelectric properties of BNT-based ceramics in a certain range. Therefore, La doping should be an adopted modification strategy for lead-free ceramics used in areas like refrigerator and pulse capacitors.

Distinct Characteristics of COVID-19 Infection in Children.

SARS-CoV-2, a member of the family coronaviridae, has triggered a lethal pandemic termed coronavirus disease 2019 (COVID-19). Pediatric patients, mainly from families with a cluster of infection or a history of exposure to epidemic areas, get infected via direct contacts or air-borne droplets. Children (aged below 18 years) are susceptible to COVID-19, with an average incubation period of about 6.5 days. Most cases present asymptomatic or common cold symptoms such as fever, cough, and myalgia or fatigue, which is milder than adult patients. Besides, most abnormal laboratory and radiologic findings in children with COVID-19 are non-specific. Since no specific chemotherapeutic agents have been approved for children, timely preventive methods could effectively forestall the transmission of SARS-CoV-2. To date, mostly studied cases have been adults with COVID-19, whereas data on pediatrics patients remain poorly defined. We herein conducted a literature review for papers published in PubMed and medRxiv (preprints) between December 2019 and December 2020 that reported on pediatrics patients (aged below 18 years) with a confirmed COVID-19 diagnosis. In this review, we summarized and discussed the pathogenesis, epidemiology, and clinical management of COVID-19 in pediatrics patients to improve our understanding of this new disease in children.

Effect of Interface Pretreatment of Al Alloy on Bonding Strength of the Laser Joined Al/CFRTP Butt Joint.

In the present research, the carbon fiber reinforced thermoplastic (CFRTP) was laser joined with the Al alloy whose joining interface was pretreated by laser micro-texturing, anodizing, and hybrid of laser micro-texturing and anodizing. The surface morphology of the pretreated Al joining interface and bonding strength of the corresponding Al/CFRTP butt joint were investigated. The results show that the laser micro-texturing has fabricated the micro-pit or micro-furrow in the Al joining interface. With the increasing of laser scanning times, the size of the micro-pit or micro-furrow decreases, when the laser scanning distance is constant. The bonding strength of the Al/CFRTP butt joint with Al joining interface pretreated by micro-texturing fluctuates with the increasing of laser scanning distance and times, reaching the maximum value of 20 MPa at laser scanning distance of 0.1 mm and 1 time. The anodizing pretreatment has formed the Al2O3 oxide layer on the Al joining interface. The Al/CFRTP butt joint with Al joining interface pretreated by anodizing obtains the maximum bonding strength of 11 MPa at anodizing time of 10 min. The hybrid pretreatment of micro-texturing and subsequent anodizing fabricates the regular grid structure with smooth micro-furrow and micro-pit, while the hybrid pretreatment of anodizing and subsequent micro-texturing fabricates the Al joining interface with explosive micro-pit and micro-furrow. The bonding strength of the Al/CFRTP butt joint with hybrid-pretreated Al joining interface is relative better than that of the Al/CFRTP butt joint with anodizing-pretreated Al joining interface but almost lower than that of the Al/CFRTP butt joint with micro-texturing pretreated Al joining interface. Such results should be attributed to the surface morphology of the Al joining interface.

Clinical benefit of neoadjuvant anti-PD-1/PD-L1 utilization among different tumors.

PD-1/PD-L1 (programmed cell death-1 and programmed death-ligand 1) inhibitors utilization in neoadjuvant therapy has been assessed in tumors. This study focused on the clinical benefits of neoadjuvant anti-PD-1/PD-L1 therapy. A comprehensive search was conducted in electronic databases to identify eligible studies. Major response rate (MRR) and complete response rate (CRR) were pooled in this analysis to assess the efficacy of neoadjuvant anti-PD-1/PD-L1 utilization, all grades and high-grade adverse events (AEs) were pooled to evaluate its safety. Twenty studies were included in this meta-analysis, with 828 patients suffering from different tumors. The pooled CRR of triple-negative breast cancer was 0.569 (95% CI 0.514, 0.624, I 2 = 0%) and the pooled MRR of lung cancer was 0.471 (95% CI 0.267, 0.575, I 2 = 0%). The most frequent adverse event was fatigue (0.272 95% CI 0.171, 0.402, I 2 = 87%), and the most common high-grade adverse event was febrile neutropenia (0.084 95% CI 0.063, 0.112, I 2 = 85%). In conclusion, neoadjuvant anti-PD-1/PD-L1 therapy received satisfactory clinical results in these tumors included.

Application of CT-Based Radiomics in Discriminating Pancreatic Cystadenomas From Pancreatic Neuroendocrine Tumors Using Machine Learning Methods.

OBJECTIVES: The purpose of this study aimed at investigating the reliability of radiomics features extracted from contrast-enhanced CT in differentiating pancreatic cystadenomas from pancreatic neuroendocrine tumors (PNETs) using machine-learning methods. METHODS: In this study, a total number of 120 patients, including 66 pancreatic cystadenomas patients and 54 PNETs patients were enrolled. Forty-eight radiomic features were extracted from contrast-enhanced CT images using LIFEx software. Five feature selection methods were adopted to determine the appropriate features for classifiers. Then, nine machine learning classifiers were employed to build predictive models. The performance of the forty-five models was evaluated with area under the curve (AUC), accuracy, sensitivity, specificity, and F1 score in the testing group. RESULTS: The predictive models exhibited reliable ability of differentiating pancreatic cystadenomas from PNETs when combined with suitable selection methods. A combination of DC as the selection method and RF as the classifier, as well as Xgboost+RF, demonstrated the best discriminative ability, with the highest AUC of 0.997 in the testing group. CONCLUSIONS: Radiomics-based machine learning methods might be a noninvasive tool to assist in differentiating pancreatic cystadenomas and PNETs.

Multifunctional, Robust, and Porous PHBV-GO/MXene Composite Membranes with Good Hydrophilicity, Antibacterial Activity, and Platelet Adsorption Performance.

The limitations of hydrophilicity, strength, antibacterial activity adsorption performance of the biobased and biocompatible polymer materials, such as polyhydroxyalkanoates (PHAs), significantly restrict their wider applications especially in medical areas. In this paper, a novel composite membrane with high antibacterial activity and platelet adsorption performance was prepared based on graphene oxide (GO), MXene and 3-hydroxybutyrate-co-hydroxyvalerate (PHBV), which are medium-chain-length-copolymers of PHA. The GO/MXene nanosheets can uniformly inset on the surface of PHBV fibre and give the PHBV-GO/MXene composite membranes superior hydrophilicity due to the presence of hydroxyl groups and terminal oxygen on the surface of nanosheets, which further provides the functional site for the free radical polymerization of ester bonds between GO/MXene and PHBV. As a result, the tensile strength, platelet adsorption, and blood coagulation time of the PHBV-GO/MXene composite membranes were remarkably increased compared with those of the pure PHBV membranes. The antibacterial rate of the PHBV-GO/MXene composite membranes against gram-positive and gram-negative bacteria can reach 97% due to the antibacterial nature of MXene. The improved strength, hydrophilicity, antibacterial activity and platelet adsorption performance suggest that PHBV-GO/MXene composite membranes might be ideal candidates for multifunctional materials for haemostatic applications.

Quinacrine-Induced Autophagy in Ovarian Cancer Triggers Cathepsin-L Mediated Lysosomal/Mitochondrial Membrane Permeabilization and Cell Death.

We previously reported that the antimalarial compound quinacrine (QC) induces autophagy in ovarian cancer cells. In the current study, we uncovered that QC significantly upregulates cathepsin L (CTSL) but not cathepsin B and D levels, implicating the specific role of CTSL in promoting QC-induced autophagic flux and apoptotic cell death in OC cells. Using a Magic Red® cathepsin L activity assay and LysoTracker red, we discerned that QC-induced CTSL activation promotes lysosomal membrane permeability (LMP) resulting in the release of active CTSL into the cytosol to promote apoptotic cell death. We found that QC-induced LMP and CTSL activation promotes Bid cleavage, mitochondrial outer membrane permeabilization (MOMP), and mitochondrial cytochrome-c release. Genetic (shRNA) and pharmacological (Z-FY(tBU)-DMK) inhibition of CTSL markedly reduces QC-induced autophagy, LMP, MOMP, apoptosis, and cell death; whereas induced overexpression of CTSL in ovarian cancer cell lines has an opposite effect. Using recombinant CTSL, we identified p62/SQSTM1 as a novel substrate of CTSL, suggesting that CTSL promotes QC-induced autophagic flux. CTSL activation is specific to QC-induced autophagy since no CTSL activation is seen in ATG5 knockout cells or with the anti-malarial autophagy-inhibiting drug chloroquine. Importantly, we showed that upregulation of CTSL in QC-treated HeyA8MDR xenografts corresponds with attenuation of p62, upregulation of LC3BII, cytochrome-c, tBid, cleaved PARP, and caspase3. Taken together, the data suggest that QC-induced autophagy and CTSL upregulation promote a positive feedback loop leading to excessive autophagic flux, LMP, and MOMP to promote QC-induced cell death in ovarian cancer cells.

Inhibition of PFKFB3 induces cell death and synergistically enhances chemosensitivity in endometrial cancer.

The advanced or recurrent endometrial cancer (EC) has a poor prognosis because of chemoresistance. 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a glycolytic enzyme, is overexpressed in a variety of human cancers and plays important roles in promoting tumor cell growth. Here, we showed that high expression of PFKFB3 in EC cell lines is associated with chemoresistance. Pharmacological inhibition of PFKFB3 with PFK158 and or genetic downregulation of PFKFB3 dramatically suppressed cell proliferation and enhanced the sensitivity of EC cells to carboplatin (CBPt) and cisplatin (Cis). Moreover, PFKFB3 inhibition resulted in reduced glucose uptake, ATP production, and lactate release. Notably, we found that PFK158 with CBPt or Cis exerted strong synergistic antitumor activity in chemoresistant EC cell lines, HEC-1B and ARK-2 cells. We also found that the combination of PFK158 and CBPt/Cis induced apoptosis- and autophagy-mediated cell death through inhibition of the Akt/mTOR signaling pathway. Mechanistically, we found that PFK158 downregulated the CBPt/Cis-induced upregulation of RAD51 expression and enhanced CBPt/Cis-induced DNA damage as demonstrated by an increase in γ-H2AX levels in HEC-1B and ARK-2 cells, potentially revealing a means to enhance PFK158-induced chemosensitivity. More importantly, PFK158 treatment, either as monotherapy or in combination with CBPt, led to a marked reduction in tumor growth in two chemoresistant EC mouse xenograft models. These data suggest that PFKFB3 inhibition alone or in combination with standard chemotherapy may be used as a novel therapeutic strategy for improved therapeutic efficacy and outcomes of advanced and recurrent EC patients.