RESUMEN
Pancreatic lipase (PL) is a well-known key target for the prevention and treatment of obesity. Human carboxylesterase 1A (hCES1A) has become an important target for the treatment of hyperlipidaemia. Thus, the discovery of potent dual-target inhibitors based on PL and hCES1A hold great potential for the development of remedies for treating related metabolic diseases. In this study, a series of natural triterpenoids were collected and the inhibitory effects of these triterpenoids on PL and hCES1A were determined using fluorescence-based biochemical assays. It was found that oleanolic acid (OA) and ursolic acid (UA) have the excellent inhibitory effects against PL and hCES1A, and highly selectivity over hCES2A. Subsequently, a number of compounds based on the OA and UA skeletons were synthesised and evaluated. Structure-activity relationship (SAR) analysis of these compounds revealed that the acetyl group at the C-3 site of UA (compound 41) was very essential for both PL and hCES1A inhibition, with IC50 of 0.75 µM and 0.014 µM, respectively. In addition, compound 39 with 2-enol and 3-ketal moiety of OA also has strong inhibitory effects against both PL and hCES1A, with IC50 of 2.13 µM and 0.055 µM, respectively. Furthermore, compound 39 and 41 exhibited good selectivity over other human serine hydrolases including hCES2A, butyrylcholinesterase (BChE) and dipeptidyl peptidase IV (DPP-IV). Inhibitory kinetics and molecular docking studies demonstrated that both compounds 39 and 41 were effective mixed inhibitors of PL, while competitive inhibitors of hCES1A. Further investigations demonstrated that both compounds 39 and 41 could inhibit adipocyte adipogenesis induced by mouse preadipocytes. Collectively, we found two triterpenoid derivatives with strong inhibitory ability on both PL and hCES1A, which can be served as promising lead compounds for the development of more potent dual-target inhibitors targeting on PL and hCES1A.
Asunto(s)
Hidrolasas de Éster Carboxílico/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Lipasa/antagonistas & inhibidores , Páncreas/enzimología , Triterpenos/farmacología , Hidrolasas de Éster Carboxílico/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Lipasa/metabolismo , Estructura Molecular , Relación Estructura-Actividad , Triterpenos/síntesis química , Triterpenos/químicaRESUMEN
BACKGROUND: 0.17-2% of mature cystic teratoma of the ovary (MCTO) undergo malignant transformation, of which 80% are squamous cell carcinoma (SCC) transformation in MCTO. We aim to investigate the clinical characteristics and treatment of SCC transformation in MCTO METHODS: We systematically searched PubMed database and individual patient data about SCC transformation in MCTO were extracted. The published cases were combined with 6 cases of SCC transformation in MCTO from Qilu Hospital, Shandong University. RESULTS: The incidence of SCC transformation in MCTO was 0.3%. A total of 435 cases of SCC transformation in MCTO were enrolled in the analysis. The mean age of diagnosis was 53.5 (range 19-87) years old. The most common clinical manifestations were abdominal pain (47.3%) and abdominal mass (26.0%). StageI,II, III and IV accounted for 50.0, 18.8, 26.8 and 4.4% of all cases, respectively. Patients with stage I had significantly better prognosis than stage II, III and IV patients (P < 0.01). Hysterectomy can improve overall survival (P < 0.01). For patients younger than 45 years old with stageIA orIC, there was no difference in mortality between fertility-sparing and radical surgery (P = 1.00). Adjuvant chemotherapy can improve survival in patients with advanced stage (P = 0.02), and chemotherapy with platinum was related to better prognosis (P = 0.02). CONCLUSION: SCC transformation in MCTO is a rare malignancy mainly occurs in older age. FIGO stage is an independent prognostic factor. Hysterectomy and platinum-based chemotherapy are associated with better survival. Fertility-sparing surgery is feasible for young patients with early stage.
Asunto(s)
Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/cirugía , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/cirugía , Teratoma/diagnóstico , Teratoma/cirugía , Adulto , Anciano , Femenino , Humanos , Persona de Mediana EdadRESUMEN
OBJECTIVES: To screen the phylogenetically-nearest members of Cellulosimicrobium cellulans for the production of cellulosome-like multienzyme complexes and extracellular ß-xylosidase activity against 7-xylosyltaxanes and to get corresponding molecular insights. RESULTS: Cellulosimicrobium (family Promicromonosporaceae) and all genera of the family Cellulomonadeceaec produced both cellulosome-like multienzyme complexes and extracellular ß-xylosidase activity, while the other genera of the family Promicromonosporaceae did not. Multiple sequence alignments further indicated that hypothetic protein M768_06655 might be a possible key subunit. CONCLUSION: This is the first report that many actinobacteria species can produce cellulosome-like multienzyme complexes. The production of cellulosome-like complexes and the extracellular ß-xylosidase activity against 7-xylosyltaxanes might be used to differentiate the genus Cellulosimicrobium from other genera of the family Promicromonosporaceae.
Asunto(s)
Actinobacteria/enzimología , Celulosomas/enzimología , Complejos Multienzimáticos/metabolismo , Actinobacteria/metabolismo , Biotecnología , Celulosomas/metabolismo , Paclitaxel/análogos & derivados , Paclitaxel/metabolismo , Xilosidasas/metabolismoRESUMEN
OBJECTIVE: The cell of origin of ovarian low-grade serous carcinoma (LGSC) remains unclarified. Our recent morphologic and immunophenotypic study suggests that most LGSCs may be derived from the fallopian tube. The purpose of the current study was to gain further insight into the origin of LGSC at the molecular level. METHODS: RNA-seq analysis was performed on a total of 31 tissue samples including LGSC (n=6), serous borderline tumors (SBT, n=6), fallopian tube epithelia (FTE, n=5), ovarian surface epithelia (OSE, n=4), and human peritoneal mesothelia (HPM, n=4). HGSC cases (n=6) served as a positive control. Gene expression profiles were compared and analyzed. To validate the findings from the gene expression array study, we selected the highly differentially expressed genes (PAX8, CDH1, FOXA2, and ARX) as well as those corresponding proteins and examined their expression levels in tissue samples of ovarian serous tumors, fallopian tube, ovarian surface epithelia, and peritoneal mesothelia. RESULTS: Dendrograms revealed that OSE samples clustered with HPM, while ovarian serous tumors, including LGSC, SBT and high-grade serous carcinoma (HGSC), clustered with FTE. Furthermore, LGSC showed a significantly closer relationship with FTE than with OSE and HPM samples. PAX8, CDH1, and FOXA2 were highly and specifically expressed in serous tumors and FTE samples but not in OSE samples. In contrast, ARX was mainly expressed in OSE samples but not in FTE and serous tumors. CONCLUSIONS: The findings of the current study provide further evidence at a molecular level that the fallopian tube is likely the cellular source of LGSC. This finding may enable new prevention strategies, improve early detection, and allow novel therapies to be tested.
Asunto(s)
Cistadenocarcinoma Seroso/genética , Neoplasias de las Trompas Uterinas/genética , Neoplasias Ováricas/genética , Cistadenocarcinoma Seroso/patología , Neoplasias de las Trompas Uterinas/patología , Femenino , Secciones por Congelación , Humanos , Clasificación del Tumor , Neoplasias Ováricas/patología , ARN Neoplásico/genética , TranscriptomaRESUMEN
PARPi is currently the most important breakthrough in the treatment of ovarian cancer in decades, and it has been integrated into the initial maintenance therapy for ovarian cancer. However, the mechanism leading to PARPi resistance remains unelucidated. Our study aims to screen novel targets to better predict and reverse resistance to PARPi and explore the potential mechanism. Here, we conducted a comparative analysis of differentially expressed genes between platinum-sensitive and platinum-resistant groups within the TCGA ovarian cancer cohort. The analysis indicated that lncRNA PART1 was significantly highly expressed in platinum-sensitive patients compared to platinum-resistant individuals in TCGA-OV cohort and further validated in the GEO dataset and Qilu hospital cohort. Moreover, the upregulation of PART1 was positively correlated with a favorable prognosis in ovarian cancer. Furthermore, in vitro and in vivo experiments showed that inhibition of PART1 confers resistance to both cisplatin and PARP inhibitor and promotes cellular senescence. Senescent cells are more resistant to chemotherapeutics. RNA antisense purification and RNA immunoprecipitation assays revealed an interaction between PART1 and PHB2, a crucial mitophagy receptor. Knockdown of PART1 could promote the degradation of PHB2, impairing mitophagy and leading to cellular senescence. Rescue assays indicated that overexpression of PHB2 remarkably diminished the resistance to PARPi and cellular senescence caused by PART1 knockdown. PDX models were utilized to further confirm the findings. Altogether, our study demonstrated that lncRNA PART1 has the potential to serves as a novel promising target to reverse resistance to PARPi and improve prognosis in ovarian cancer.
RESUMEN
DPP-IV inhibitors, which are close to the natural hypoglycemic pathway of human physiology and have few side effects, have been extensively employed in the management of type 2 diabetes mellitus (T2DM). However, there are currently no specific blood indicators that can indicate or predict a patient's suitability for DPP-IV inhibitors. In this study, based on the self-developed high-specificity fluorescent substrate glycyl-prolyl-N-butyl-4-amino-1, 8-naphthimide (GP-BAN), a detection method of human serum DPP-IV activity was established and optimized. The method demonstrates a favorable lower limit of detection (LOD) at 0.32â¯ng/mL and a satisfactory lower limit of quantification (LOQ) of 1.12â¯ng/mL, and can be used for the detection of DPP-IV activity in trace serum (2⯵L). In addition, Vitalliptin and Sitagliptin showed similar IC50 values when human recombinant DPP-IV and human serum were used as enzyme sources, and the intra-day and inter-day precision obtained by the microplate analyzer were less than 15â¯%. These results indicate that the microplate reader based detection technique has good accuracy, repeatability and reproducibility. A total of 700 volunteers were recruited, and 646 serum samples were tested for DPP-IV activity. The results showed that serum DPP-IV activity was higher in patients with T2DM than in controls (P < 0.01). However, the statistical data of family history of diabetes, gender and age of diabetic patients showed no statistical significance, and there was no contrast difference. The DPP-IV activity of serum in T2DM patients ranged from 2.4 µmol/min/L to 78.6 µmol/min/L, with a huge difference of up to 32-fold. These results suggest that it is necessary to test DPP-IV activity in patients with T2DM when taking DPP-IV inhibitors to determine the applicability of DPP-IV inhibitors in T2DM patients. These results suggest that it is necessary to detect the activity of DPP-IV in blood before taking DPP-IV inhibitors in patients with T2DM to judge the applicability of DPP-IV inhibitors in patients with T2DM.
Asunto(s)
Diabetes Mellitus Tipo 2 , Dipeptidil Peptidasa 4 , Inhibidores de la Dipeptidil-Peptidasa IV , Límite de Detección , Fosfato de Sitagliptina , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Dipeptidil Peptidasa 4/sangre , Reproducibilidad de los Resultados , Masculino , Persona de Mediana Edad , Femenino , Espectrometría de Fluorescencia/métodos , Fluorescencia , Anciano , Adulto , Hipoglucemiantes/sangre , Hipoglucemiantes/uso terapéuticoRESUMEN
Immune checkpoint blockade (ICB) therapies display clinical efficacy in microsatellite instable (MSI) endometrial cancer (EC) treatment, the key mechanism of which is reversing T cell exhaustion and restoration of anti-tumor immunity. Here, we demonstrate that transcription factor 19 (TCF19), one of the most significantly differentially expressed genes between MSI and microsatellite stable (MSS) patients in The Cancer Genome Atlas (TCGA)-EC cohort, is associated with poor prognosis and immune exhaustion signature. Specifically, TCF19 is significantly elevated in MSI EC, which in turn promotes tripartite motif-containing 14 (TRIM14) transcription and correlates with hyperactive signaling of the TANK-binding kinase 1 (TBK1)-interferon regulatory factor 3 (IRF3)-interferon ß (IFN-ß) pathway. The TCF19-TRIM14 axis promotes tumorigenicity under non-immunological background, and the enhanced downstream secretion of IFN-ß facilitates CD8+ T cell exhaustion through cell differentiation reprogramming. Finally, using humanized models, we show that a combination of TCF19 inhibition and ICB therapy demonstrates more effective anti-tumor responses. Together, our study indicates that targeting TCF19 is a potent strategy for alleviating CD8+ T cell exhaustion and synergizing with ICB in tumor treatment.
RESUMEN
Conversion of waste plastic to carbon materials has been considered as a potential approach for plastic recycling. In this study, polyvinyl chloride (PVC) plastic, one of the most widely used polymers, was used as a single precursor to prepare porous carbons via chemical activation process. The results showed that KOH activation followed by acid washing was an effective strategy to recover all calcium- and up to 92% of titanium-based compounds, the main metal additives in PVC, in the form of soluble salt. Those metal additives in PVC acted as a type of hard template, which benefit the development of microporosity and carbon dioxide (CO2) adsorption. Textural characterization demonstrated that the prepared carbons possessed high surface area and pore volume of up to 2507 m2/g and 1.11 cm3/g, respectively. At 0 °C and 100 kPa, the PVC-derived carbon, PH_73, which has highest ultra-micropore volume among all samples, exhibited excellent CO2 adsorption capacity of 6.90 mmol/g and high CO2/N2 selectivity. Converting the non-degradable PVC into high-quality porous carbon materials could be considered as a potential strategy for plastic waste recycling.
Asunto(s)
Carbón Orgánico , Cloruro de Polivinilo , Adsorción , Dióxido de Carbono/química , Carbón Orgánico/química , Cloruro de Polivinilo/química , PorosidadRESUMEN
Absorption is an eminent technology for volatile organic compounds (VOCs) elimination with the merits of high efficiency and low cost. Absorbent plays a critical role in the absorption process, and the thermal stability, saturation capacity, and regeneration performance should be concerned. As a kind of green and eco-friendly solvent, ionic liquid (IL) is expected to be a substitute for the conventional VOCs absorbent. In this study, 1-butyl-3-methylimidazolium hexafluorophosphate ([Bmim][PF6]) is employed to absorb the modeling VOCs (toluene and acetone). Moreover, the used [Bmim][PF6] is recovered by thermal distillation and the reusability is then conducted by consecutive batch experiments. Based on that, the thermal stability of [Bmim][PF6] is comprehensively examined, in which the kinetic and thermodynamic parameters are also calculated. Results reveal that [Bmim][PF6] owned promising toluene absorption performance with inlet concentration of 3000 mg/m3 and flow rate of 300 mL/min at 20 °C, it possesses the saturated adsorption capacity of 5.16 mg/g. [Bmim][PF6] also shows satisfying thermal stability up to 610 K. In addition, thermal distillation is proved to be a reliable regeneration route on account of the recovered [Bmim][PF6] remained satisfying capacity even after five cycles.
Asunto(s)
Líquidos Iónicos , Acetona , Solventes , Termodinámica , ToluenoRESUMEN
In light of the promising merits of large surface area, uniform pore size, and tunable functional groups, metal-organic frameworks (MOFs) have great potential to be utilized for adsorbing volatile organic compounds (VOCs). In this study, three Fe-based MOFs, MIL-100(Fe), MIL-101(Fe), and MIL-53(Fe), were synthesized systematically and used to adsorb a typical VOC, toluene. Static adsorption, dynamic breakthrough curves, and adsorption kinetics were conducted to assess the adsorption performance. Additionally, the surface functional groups, pore structure, and morphology were systematically characterized by means of XRD, SEM, XPS, FTIR and N2 adsorption-desorption analyses to reveal the cause of the difference in adsorption of these Fe-based MOFs. The results revealed that the maximum equilibrium adsorption capacity of 663 mg/g was achieved by MIL-100(Fe) with the highest specific surface area and pore volume. The dynamic adsorption of toluene on MIL-100(Fe) was in accordance with the pseudo-first order kinetic model and the Langmuir isothermal model. The formed π-π stacking interaction between organic ligands and the benzene ring in the MIL-100(Fe) cluster is the primary adsorption mechanism based on XPS analysis. Moreover, MIL-100(Fe) was easily regenerated via microwave irradiation with a negligible adsorption capacity decrease after three cycles. This work highlights the feasibility of hierarchical porous Fe-based MOFs as toluene adsorbents and promotes the application of MOFs in the field of pollution control.
Asunto(s)
Estructuras Metalorgánicas , Adsorción , Cinética , Porosidad , ToluenoRESUMEN
Tumor immunotherapy has attracted more and more attention nowadays, and multiple clinical trials have confirmed its effect in a variety of solid tumors. Immune checkpoint inhibitors (ICIs), cancer vaccines, adoptive cell transfer (ACT), and lymphocyte-promoting cytokines are the main immunotherapy methods. Endometrial cancer (EC) is one of the most frequent tumors in women and the prognosis of recurrent or metastatic EC is poor. Since molecular classification has been applied to EC, immunotherapy for different EC subtypes (especially POLE and MSI-H) has gradually attracted attention. In this review, we focus on the expression and molecular basis of the main biomarkers in the immunotherapy of EC firstly, as well as their clinical application significance and limitations. Blocking tumor immune checkpoints is one of the most effective strategies for cancer treatment in recent years, and has now become the focus in the field of tumor research and treatment. We summarized clinical date of planned and ongoing clinical trials and introduced other common immunotherapy methods in EC, such as cancer vaccine and ACT. Hormone aberrations, metabolic syndrome (MetS) and p53 mutant and that affect the immunotherapy of endometrial cancer will also be discussed in this review.
RESUMEN
BACKGROUND: Serous ovarian cancer (SOC) is a highly lethal gynecological malignancy with poor prognosis. Given the importance of the immune-related tumor microenvironment (TME) in ovarian cancer, investigating tumor-immune interactions and identifying novel prognostic and therapeutic targets in SOC is a promising avenue of research. ALOX5AP (Arachidonate 5-Lipoxygenase Activating Protein) is a key enzyme in converting arachidonic acid to leukotriene: a crucial immune-modulating lipid mediator. However, the role of ALOX5AP in SOC has yet to be studied. METHODS: ALOX5AP expression patterns across ovarian cancer and their normal tissue counterparts were cross-checked using public microarray and RNA-seq analyses and then validated in clinical samples by qRT-PCR. Kaplan-Meier survival analysis was performed in multiple independent SOC patient cohorts. Univariate and multivariate Cox regression analysis were then employed to identify clinical risk parameters associated with survival, and a genomic-clinicopathologic nomogram was built. Gene enrichment, immune infiltration, and immunosuppressor correlation analyses were then evaluated. RESULTS: ALOX5AP mRNA levels in SOC tissues were significantly upregulated compared to normal tissues. Elevated ALOX5AP was markedly associated with poor overall survival and progression-free survival in multiple SOC patient cohorts as well as with adverse clinicopathological features, including lymphatic invasion, unsatisfactory cytoreductive surgery, rapid relapse after primary treatment, and platinum non-responsiveness. A predictive nomogram, which integrated ALOX5AP expression and two independent prognosis factors (primary therapy outcome and tumor residual), was conducted to predict the 3-year and 5-year survival rate of SOC patients. Mechanistically, functional and pathway enrichment analyses revealed that ALOX5AP was primarily involved in immune response and regulation. Further exploration demonstrated that ALOX5AP was highly expressed in the immunoreactive subtype of ovarian cancer and closely related to immunocyte infiltration, especially M2 macrophage polarization. Additionally, ALOX5AP was enriched in the C4 (lymphocyte depleted) immune subtype of SOC and associated with crucial immune-repressive receptors in the tumor microenvironment at the genomic level. CONCLUSIONS: ALOX5AP expression indicates a worse survival outcome and has the potential to be utilized as a prognostic predictor for SOC patients. Given the availability of well-studied ALOX5AP inhibitors, this study has immediate clinical implications for the exploitation of ALOX5AP as an immunotherapeutic target in SOC.
RESUMEN
Multi-walled carbon nanotubes (MWCNTs) modified nickel foams (MWCNTs-NF) were developed with an electrophoretic deposition methodology for microwave (MW) assisted catalysis and processing enhancement. A nickel foam (NF) was selected to serve the dual purpose both as the MW absorbing catalytic materials and the matrix for MWCNTs loading in order to maximize the recyclability of the catalysts. The effects of electrophoretic voltage and concentration of electrophoretic fluid on the morphology and deposition characteristics of MWCNTs on the NF matrix were investigated. It was found that the MWCNTs-NF composite material resulted in strong enhancement of MW absorptivity with synergistic heat-generating effects that were not observed when MWCNTs or NF was exposed to MW alone. The combination of NF and MWCNTs brought a catalytic total organic carbon removal efficiency of 97% in wastewater treatment, while that using bare MWCNTs and NF were only 65.2% and 79.3%, respectively. The coupling of NF with MWCNTs led to the formation of additional MW-absorbing channels and focal sites with strong MW absorptivity, which in turn gave rise to the synergistic MW heating effects. This research highlights the great prospect of the MW-assisted reaction enhancement using the MWCNTs-NF composite material as the catalyst in wastewater treatment and other similar engineering applications.
RESUMEN
Ovarian cancer is a type of gynecological cancer with the highest mortality rate worldwide. Due to a lack of effective screening methods, most cases are diagnosed at later stages where the survival rates are poor. Thus, it is termed a 'silent killer' and is the most lethal of all the malignancies in women. IQ motif containing GTPase Activating Protein 3 (IQGAP3) is a member of the Rho family of GTPases, and plays a crucial role in the development and progression of several types of cancer. The aim of the present study was to investigate the oncogenic functions and mechanisms of IQGAP3 on the proliferation and metastasis of high-grade serous ovarian cancer (HGSOC). Therefore, the expression levels of IQGAP3 in HGSOC and normal tissue samples were compared, and IQGAP3 knockdown was performed to examine its functional role using various in vitro and in vivo experiments. It was demonstrated that the expression of IQGAP3 was upregulated in HGSOC tissues compared with the healthy tissues; this differential expression was also observed in the ovarian cancer cell lines. Functional experimental results suggested that IQGAP3 silencing significantly reduced proliferation, migration and invasion in ovarian cancer cell lines. Moreover, in vivo experimental findings validated the in vitro results, where the tumorigenic and metastatic capacities of IQGAP3-silenced cells were significantly lower in the nude mice compared with the mice implanted with the control cells. Furthermore, knockdown of IQGAP3 resulted in increased apoptosis, and the effects of IQGAP3 expression on various epithelial-mesenchymal transition markers were identified, suggesting a possible mechanism associated with the role of IQGAP3 in metastasis. The effect of IQGAP3 silencing on chemosensitivity towards olaparib was also assessed. Collectively, the present results indicated that IQGAP3 is a potential diagnostic and prognostic marker, and a putative therapeutic target of HGSOC.
RESUMEN
The original article [1] contains errors in Fig. 3C, Results and Discussion.
RESUMEN
Uterine leiomyosarcoma (ULMS) is the most lethal gynecologic malignancy with few therapeutic options. Chemoresistance prevails as a major hurdle in treating this malignancy, yet the mechanism of chemoresistance remains largely unclear. In this study, we certified MELK as a poor prognostic marker through bioinformatic analysis of the GEO database. Cellular experiments in vitro revealed that MELK played an essential role in ULMS cells' chemoresistance and that a high expression of MELK could lead to doxorubicin resistance. mRNA profiling uncovered the pathways that MELK was involved in which led to doxorubicin resistance. MELK was found to affect ULMS cells' chemoresistance through an anti-apoptotic mechanism via the JAK2/STAT3 pathway. miRNA profiling also revealed that upregulated MELK could induce the decrease of miRNA-34a (regulated by JAK2/STAT3 pathway). We detected that MELK overexpression could induce M2 macrophage polarization via the miR-34a/JAK2/STAT3 pathway, contributing to doxorubicin chemoresistance in the tumor microenvironment. OTSSP167, a MELK inhibitor, may increase ULMS sensitivity to doxorubicin. Our investigation could propose novel targets for early diagnosis and precision therapy in ULMS patients.
RESUMEN
BACKGROUND: PARP inhibitors have been the most promising target drugs with widely proven benefits among ovarian cancer patients. Although platinum-response, HR-related genes, or HRD genomic scar detection are acceptably used in assessment of Olaparib response, there are still evident limitations in the present approaches. Therefore, we aim to investigate more accurate approaches to predict Olaparib sensitivity and effective synergistic treatment strategies. METHODS: We probed two databases (TCGA and Qilu Hospital) in order to quest novel miRNAs associated with platinum-sensitivity or HR-related genes. Cellular experiments in vitro or in vivo and PDX models were utilized to validate their role in tumor suppression and Olaparib sensitizing. Furthermore, HR gene mutation was analyzed through WES to explore the relation between HR gene mutation and Olaparib response. RESULTS: High miR-509-3 expression indicated better response to platinum and longer progression-free and overall survival in two independent ovarian cancer patient cohorts (high vs. low miR-509-3 expression; PFS: TCGA P < 0.05, Qilu P < 0.05; OS: TCGA P < 0.05, Qilu P < 0.01). MiR-509-3 could impair the proliferation, migration, and invasion ability but enhance the sensitivity to Olaparib of ovarian cancer cell in vitro and in vivo by directly targeting HMGA2 and RAD51. In two PDX cases (PDX1 and PDX9), miR-509-3 could significantly increase the sensitivity to Olaparib along with the decrease of RAD51 positive rate (mean tumor weight NC + Olaparib vs. miR-509 + Olaparib; PDX1 P < 0.05, PDX9 P < 0.05). Additionally, in PDX8, miR-509-3 treatment dramatically reversed the Olaparib insensitivity (P < 0.05) by downregulating RAD51 expression. RAD51 functional detection revealed that all Olaparib sensitive cases exhibited low RAD51 positive rate (lesser than 50%) in treated groups. Furthermore, among the four HR gene mutation patients, three harbored HR core gene mutation and were sensitive to Olaparib while the remaining one with non-HR core gene mutation did not respond well to Olaparib. CONCLUSIONS: MiR-509-3 can sensitize ovarian cancer cells to Olaparib by impeding HR, which makes it a potential target in PARPi synergistic treatment. HR core gene analysis and RAD51 functional detection are prospectively feasible in prediction of PARPi response.
Asunto(s)
Antineoplásicos/uso terapéutico , MicroARNs/genética , Neoplasias Ováricas/tratamiento farmacológico , Ftalazinas/uso terapéutico , Piperazinas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Reparación del ADN por Recombinación/efectos de los fármacos , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Femenino , Humanos , Ratones Desnudos , Neoplasias Ováricas/genética , Ftalazinas/farmacología , Piperazinas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Recombinasa Rad51/genética , Mutaciones Letales Sintéticas/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Microfluidic systems have advanced beyond natural and life science applications and lab-on-a-chip uses. A growing trend of employing microfluidic technologies for environmental detection has emerged thanks to the precision, time-effectiveness, and cost-effectiveness of advanced microfluidic systems. This paper reviews state-of-the-art microfluidic technologies for environmental applications, such as on-site environmental monitoring and detection. Microdevices are extensively used in collecting environmental samples as a means to facilitate detection and quantification of targeted components with minimal quantities of samples. Likewise, microfluidic-inspired approaches for separation and treatment of contaminated water and air, such as the removal of heavy metals and waterborne pathogens from wastewater and carbon capture are also investigated.
RESUMEN
Ovarian cancer is the most lethal gynaecologic malignancy. Although there are various subtypes of ovarian cancer, high-grade serous ovarian cancer (HGSOC) accounts for 70% of ovarian cancer deaths. Chemoresistance is the primary reason for the unfavourable prognosis of HGSOC. Kallistatin (KAL), also known as SERPINA4, is part of the serpin family. Kallistatin has been discovered to exert multiple effects on angiogenesis, inflammation and tumour progression. However, the roles and clinical significance of kallistatin in HGSOC remain unclear. Here, we showed that kallistatin was significantly downregulated in HGSOC compared to normal fallopian tube (FT) tissues. Low expression of kallistatin was associated with unfavourable prognosis and platinum resistance in HGSOC. Overexpression of kallistatin significantly inhibited proliferation and metastasis, and enhanced platinum sensitivity and apoptosis in ovarian cancer cells. Collectively, these findings demonstrate that kallistatin serves as a prognostic predictor and provide a potential therapeutic target for HGSOC.
Asunto(s)
Neoplasias Ováricas/metabolismo , Serpinas/metabolismo , Animales , Antineoplásicos/uso terapéutico , Biomarcadores/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Cisplatino/uso terapéutico , Progresión de la Enfermedad , Regulación hacia Abajo , Resistencia a Antineoplásicos/genética , Trompas Uterinas/metabolismo , Femenino , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Pronóstico , Serpinas/genéticaRESUMEN
BACKGROUND: With the advent of minimally invasive surgery, the limits of surgery have been stretched by questioning the more usual, established 2-stage approach for choledocholithiasis with an initial endoscopic retrograde cholangiography and endoscopic biliary sphincterotomy followed by laparoscopic cholecystectomy in favor of the single-stage laparoscopic common bile duct exploration with laparoscopic cholecystectomy. The aim of this study was to compare the related benefits, difficulties, and outcomes of these 2 methods at a single institution. METHODS: A retrospective analysis of 128 patients satisfying the inclusion criteria was divided into 2 groups (nâ¯=â¯68 for the group with laparoscopic common bile duct exploration with laparoscopic cholecystectomy and nâ¯=â¯60 for the group with endoscopic retrograde cholangiography/laparoscopic cholecystectomy) between 2014 and 2017. Patient data including age, sex, duration of the operation, intraoperative and postoperative complications, and duration of hospital stay were reviewed. RESULTS: The group with laparoscopic common bile duct exploration with laparoscopic cholecystectomy had 24 men and 44 women (mean age 52 years), and the group with endoscopic retrograde cholangiography/laparoscopic cholecystectomy had 16 men and 44 women (mean age 47 years). Statistically significant results were found in the clearance range (100% in the group with laparoscopic common bile duct exploration with laparoscopic cholecystectomy versus 75% in the group with endoscopic retrograde cholangiography/laparoscopic cholecystectomy), a shorter total duration of hospitalization for the group with laparoscopic common bile duct exploration with laparoscopic cholecystectomy (4.1 days vs 8.4 days) (P < .05), but a great incidence of biliary leakage in the group with laparoscopic common bile duct exploration with laparoscopic cholecystectomy. Duration of surgery was not different between the 2 groups. CONCLUSION: Laparoscopic common bile duct exploration with laparoscopic cholecystectomy is a single-stage procedure that has many advantages over endoscopic retrograde cholangiography/laparoscopic cholecystectomy if appropriate experience and when expertise is available.