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Exosome metabolite-based liquid biopsy is a promising strategy for large-scale application in practical clinics toward precise medicine. Given the current challenges in successive isolation and analysis of exosomes and their metabolites in this field, we established a low-cost, high-throughput, and rapid platform for serological exosome metabolic biopsy of hepatocellular carcinoma (HCC) via designed core-shell nanoparticles. It starts with the efficient extraction of high-quality serum exosomes and exosome metabolic features, based on which significantly obvious sample clusters are observed by unsupervised cluster analysis. The following integration of feature selection and supervised machine learning enables the identification of six key metabolites and achieves high-performance prediction between HCC, liver cirrhosis, and healthy controls. Specifically, both sensitivity and accuracy achieve 100% among any pairwise intergroup discrimination in a blind test. The quality and reliability of six key metabolites are further evaluated and validated by using different machine learning algorithms and pathway exploration. Our platform contributes to the future growth of new liquid biopsy technologies for precision diagnosis and real-time monitoring of HCC, among other conditions.
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Immune checkpoint inhibitors (ICIs) offer promise in breaking through the treatment and survival dilemma of triple-negative breast cancer (TNBC), yet only immunomodulatory subtype and ≈5% TNBC patients respond as monotherapy due to lack of effector immune cells (internal problem) and physical barrier (external limitation) formed by cancer-associated fibroblasts (CAFs). A hydrogel drug-delivery platform, ALG@TBP-2/Pt(0)/nintedanib (ALG@TPN), is designed to induce strong immune functions and the dual elimination of the internal and external tumor microenvironment (TME). Activated by white light, through type I and II photodynamic therapy (PDT), TBP-2 generates large amounts of reactive oxygen species (ROS) intracellularly, oxidizing mitochondrial DNA (mtDNA). The unique catalase activity of Pt(0) converts endogenous H2O2 to O2, reducing the anoxia-limiting PDT and enhancing ROS generation efficacy. Abundant ROS can oxidize Pt(0) to cytotoxic Pt(II), damaging the nuclear DNA (nDNA). Dual damage to mtDNA and nDNA might bi-directionally activate the cGAS/STING pathway and enhance the immune cell response. Besides, nintedanib demonstrates a significant inhibitory effect on CAFs, weakening the immune barrier and deepening immune cell infiltration. Overall, the study provides a self-oxygenating hydrogel with the "PDT/chemotherapy/anti-CAFs" effect, triggering the cGAS/STING pathway to reshape the TME. Both internal and external interventions increase anti-TNBC immune responses.
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In brief: Progenitor cells with ovulation-related tissue repair activity were identified with defined markers (LGR5, EPCR, LY6A, and PDGFRA), but their potentials to form steroidogenic cells were not known. This study shows that the cells can generate progenies with different steroidogenic activities. Abstract: Adult mammalian ovaries contain stem/progenitor cells necessary for folliculogenesis and ovulation-related tissue rupture repair. Theca cells are recruited and developed from progenitors during the folliculogenesis. Theca cell progenitors were not well defined. The aim of current study is to compare the potentials of four ovarian progenitors with defined markers (LY6A, EPCR, LGR5, and PDGFRA) to form steroidogenic theca cells in vitro. The location of the progenitors with defined makers was determined by immunohistochemistry and immunofluorescence staining of ovarian sections of adult mice. Different progenitor populations were purified by magnetic-activated cell sorting (MACS) and/or fluorescence-activated cell sorting (FACS) techniques from ovarian cell preparation and were tested for their abilities to generate steroidogenic theca cells in vitro. The cells were differentiated with a medium containing LH, ITS, and DHH agonist for 12 days. The results showed that EPCR+ and LGR5+ cells primarily distributed along the ovarian surface epithelium (OSE), while LY6A+ cells distributed in both the OSE and parenchyma. However, PDGFRA+ cells were exclusively located in interstitial compartment. When the progenitors were purified by these markers and differentiated in vitro, LY6A+ and PDGFRA+ cells formed steroidogenic cells expressing both CYP11A1 and CYP17A1 and primarily producing androgens, showing characteristics of theca-like cells, while LGR5+ cells generated steroidogenic cells devoid of CYP17A1 expression and androgen production, showing a characteristic of progesterone-producing cells (granulosa- or lutea-like cells). In conclusion, progenitors from both OSE and parenchyma of adult mice are capable of generating steroidogenic cells with different steroidogenic capacities, showing a possible lineage preference.
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Diferenciação Celular , Receptores Acoplados a Proteínas G , Células-Tronco , Células Tecais , Animais , Feminino , Células Tecais/metabolismo , Células Tecais/citologia , Camundongos , Células-Tronco/metabolismo , Células-Tronco/citologia , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Antígenos Ly/metabolismo , Células Cultivadas , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Ovário/citologia , Ovário/metabolismo , Camundongos Endogâmicos C57BL , Biomarcadores/metabolismoRESUMO
PURPOSE: To investigate the relationship between blood lead levels (BLLs) and IVF clinical outcomes in infertile females and to further explore the possible involvement of granulosa cell (GC) endoplasmic reticulum (ER) stress in the process. METHODS: One hundred twenty-three infertile women undergoing IVF cycles were included in the current study. All participants were divided into three (low, medium, and high) groups determined by BLL tertiles. Gonadotropin releasing hormone (GnRH) agonist regimen for ovarian stimulation was used for all patients, with follicular fluids being collected on the day of oocyte retrieval. Lactate dehydrogenase (LDH) levels in follicular fluid and the endoplasmic reticulum stress-signaling pathway of granulosa cells (GCs) were examined. RESULTS: The oocyte maturation rate and high-quality embryo rate on cleaved stage decreased significantly as BLL increased. For lead levels from low to high, live birth rate (68.29%, 56.10%, 39.02%; P=0.028) showed negative correlations with BLLs. Also, follicular fluid Pb level and LDH level was significantly higher in the high lead group versus the low group. Binomial regression analysis revealed significant negative correlation between BLLs and live birth rate (adjusted OR, 0.38; 95% CI, 0.15-0.95, P=0.038). Further analysis of the endoplasmic reticulum stress (ER stress) signaling pathway of GCs found that expressions of GRP78, total JNK, phosphorylated JNK, and CHOP increased and BCL-2 decreased with increasing BLLs. CONCLUSIONS: BLLs are negatively associated with final clinical outcomes in IVF patients that may be related to increased ER stress response and GC apoptosis. Thus, reducing Pb exposure before IVF procedures may improve final success rates.
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Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático , Fertilização in vitro , Líquido Folicular , Células da Granulosa , Infertilidade Feminina , Chumbo , Indução da Ovulação , Humanos , Feminino , Células da Granulosa/metabolismo , Adulto , Infertilidade Feminina/terapia , Infertilidade Feminina/sangue , Infertilidade Feminina/patologia , Chumbo/sangue , Chumbo/toxicidade , Gravidez , Líquido Folicular/metabolismo , Indução da Ovulação/métodos , Taxa de Gravidez , Recuperação de Oócitos , Nascido Vivo/genética , Oócitos/crescimento & desenvolvimento , Coeficiente de NatalidadeRESUMO
Metal-organic framework-based metal ion therapy has attracted increasing attention to promote the cascade wound-healing process. However, multimetal ion synergistic administration and accurately controlled ion release are still the challenges. Herein, an aptamer-functionalized silver@cupriferous Prussian blue (ACPA) is established as a metal-based theranostic nanoagent for a chronic nonhealing diabetic wound treatment. Prussian blue offers a programmable nanoplatform to formulate metal ion prescriptions, achieving cooperative wound healing. Silver, copper, and iron ions are released from ACPA controlled by the near-infrared-triggered mild hyperthermia and then synergistically participate in antipathogen, cell migration, and revascularization. ACPA also demonstrates a unique core-satellite nanostructure which enables it with improved surface-enhanced Raman scattering (SERS) capability as potent bacteria-targeted Raman-silent nanoprobe to monitor the residual bacteria during wound healing with nearly zero background. The theranostic feature of ACPA allows high-performance SERS imaging-guided chronic wound healing in infectious diabetic skin and keratitis.
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The activation of dinitrogen (N2) and direct incorporation of its N atom into C-H bonds to create aliphatic C-N compounds remains unresolved. Incompatible conditions between dinitrogen reduction and C-H functionalization make this process extremely challenging. Herein, we report the first example of dinitrogen insertion into an aliphatic Csp3-H bond on the ligand scaffold of a 1,3-propane-bridged [N2N]2--type dititanium complex. Mechanistic investigations on the behaviors of dinuclear and mononuclear Ti complexes indicated the intramolecular synergistic effect of two Ti centers at a C-N bond-forming step. Computational studies revealed the critical isomerization between the inactive side-on N2 complex and the active nitridyl complex, which is responsible for the Csp3-H amination. This strategy maps an efficient route toward the future synthesis of aliphatic amines directly from N2.
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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease which leads to the formation of immune complex deposits in multiple organs and has heterogeneous clinical manifestations. Currently, exosomes for liquid biopsy have been applied in diagnosis and monitoring of diseases, whereas SLE discrimination based on exosomes at the metabolic level is rarely reported. Herein, we constructed a protocol for metabolomic study of urinary exosomes from SLE patients and healthy controls (HCs) with high efficiency and throughput. Exosomes were first obtained by high-performance liquid size-exclusion chromatography (HPL-SEC), and then metabolic fingerprints of urinary exosomes were extracted by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) with high throughput and high efficency. With the statistical analysis by orthogonal partial least-squares discriminant analysis (OPLS-DA) model, SLE patients were efficiently distinguished from HCs, the area under the curve (AUC) of the receiver characteristic curve (ROC) was 1.00, and the accuracy of the unsupervised clustering heatmap was 90.32%. In addition, potential biomarkers and related metabolic pathways were analyzed. This method, with the characteristics of high throughput, high efficiency, and high accuracy, will provide the broad prospect of exosome-driven precision medicine and large-scale screening in clinical applications.
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Epidemic studies showed that lead exposures are associated with various female reproductive dysfunctions, including infertility, miscarriage, preterm delivery, and early menopause. However, the mechanism involved is still unclear. In the current study, SD rats were exposed to lead at doses of 0, 5, 25, 50 or 250 mg/L through drinking water from postnatal day 21-56. Lead exposures did not affect the body weight or ovary weight. However, the puberty initiation (ages by which vagina opens and estrous cycle occurs) was significantly delayed by as many as 5.8 and 6.8 days respectively (P < 0.05). Also, lead exposures disrupted the estrous cycles, reduced the numbers of primordial and primary follicles and increased the number of atretic follicles by adult. Furthermore, for the highest does group, serum levels of progesterone and testosterone decreased by 80.2% (P < 0.01) and 49.9% (P < 0.05) respectively, while estradiol level increased by 69.8% (P < 0.01). Western blot analyses indicated that lead exposures specifically down-regulated the expressions of steroidogenic protein STAR, CYP17A1, and HSD3B1, while up-regulated FSHR and CYP19A1. Also, the exposure stimulated the endoplasmic reticulum stress (ERS)-related IRE1α-JNK signaling pathway members. Such activation may also result in apoptosis since the death-signaling molecules CHOP and cleaved-CASP3 were up-regulated while BCL2 was down-regulated. In conclusion, lead exposure during juvenile and puberty significantly affected ovary development and functions. The effects may relate to ERS response since the 6 members related to the pathway were all consistently activated.
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Ovário , Proteínas Serina-Treonina Quinases , Ratos , Animais , Feminino , Proteínas Serina-Treonina Quinases/metabolismo , Sistema de Sinalização das MAP Quinases , Endorribonucleases/metabolismo , Ratos Sprague-Dawley , Chumbo/metabolismoRESUMO
Photothermal therapy (PTT) in the second near-infrared (NIR-II) window has emerged as a better candidate for deep-tissue tumor elimination. More interestingly, the photothermal ablated tumor cells also manifest somewhat immunostimulation potency to elicit antitumor immunity, although most dying cells are undergoing apoptosis that is commonly considered as immunologically silent. Here, a NIR-II responsive nanosystem is established for tumor photoimmunotherapy using molybdenum dioxide (MoO2) nanodumbbells as the nanoconverter. Meanwhile, an apoptosis-blocking strategy is proposed to regulate the cell death pattern under NIR-II laser irradiation in order to improve the immunogenic cell death. The nanoformulation can efficiently block caspase 8-dependent apoptotic pathway in photothermal ablated tumor cells and transform into more immunogenic death patterns, thereby activating systemic immunity to inhibit tumor growth and metastasis. In addition, this strategy also helps enhance the body's responses to α-PD-1 immune checkpoint inhibitor, which implies a potential optimal combination for cancer immunotherapy.
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Nanopartículas , Neoplasias , Linhagem Celular Tumoral , Humanos , Imunoterapia , Molibdênio , Nanopartículas/uso terapêutico , Neoplasias/terapia , Óxidos , FototerapiaRESUMO
Molecular diagnosing, typing, and staging have been considered to be the ideal alternatives of imaging-based detection methods in clinics. Designer matrix-based analytical tools, with high speed, throughout, efficiency and low/noninvasiveness, have attracted much attention recently for in vitro metabolite detection. Herein, we develop an advanced metabolic analysis tool based on highly porous metal oxides derived from available metal-organic frameworks (MOFs), which elaborately inherit the morphology and porosity of MOFs and newly incorporate laser adsorption capacity of metal oxides. Through optimized conditions, direct high-quality fingerprinting spectra in 0.5 µL of urine are acquired. Using these fingerprinting spectra, we can discriminate the renal cell carcinoma (RCC) from healthy controls with higher than 0.99 of area under the curve (AUC) values (R2Y(cum) = 0.744, Q2 (cum) = 0.880), as well, from patients with other tumors (R2Y(cum) = 0.748, Q2(cum) = 0.871). We also realize the typing of three RCC subtypes, including clear cell RCC, chromophobe RCC (R2Y(cum) = 0.620, Q2(cum) = 0.656), and the staging of RCC (R2Y(cum) = 0.755, Q2(cum) = 0.857). Moreover, the tumor sizes (threshold value is 3 cm) can be remarkably recognized by this advanced metabolic analysis tool (R2Y(cum) = 0.710, Q2(cum) = 0.787). Our work brings a bright prospect for designer matrix-based analytical tools in disease diagnosis, typing and staging.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/metabolismo , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/metabolismo , Diagnóstico Diferencial , Urinálise , Óxidos , Estadiamento de NeoplasiasRESUMO
OBJECTIVES: Develop and evaluate a deep learning-based automatic meningioma segmentation method for preoperative meningioma differentiation using radiomic features. METHODS: A retrospective multicentre inclusion of MR examinations (T1/T2-weighted and contrast-enhanced T1-weighted imaging) was conducted. Data from centre 1 were allocated to training (n = 307, age = 50.94 ± 11.51) and internal testing (n = 238, age = 50.70 ± 12.72) cohorts, and data from centre 2 external testing cohort (n = 64, age = 48.45 ± 13.59). A modified attention U-Net was trained for meningioma segmentation. Segmentation accuracy was evaluated by five quantitative metrics. The agreement between radiomic features from manual and automatic segmentations was assessed using intra class correlation coefficient (ICC). After univariate and minimum-redundancy-maximum-relevance feature selection, L1-regularized logistic regression models for differentiating between low-grade (I) and high-grade (II and III) meningiomas were separately constructed using manual and automatic segmentations; their performances were evaluated using ROC analysis. RESULTS: Dice of meningioma segmentation for the internal testing cohort were 0.94 ± 0.04 and 0.91 ± 0.05 for tumour volumes in contrast-enhanced T1-weighted and T2-weighted images, respectively; those for the external testing cohort were 0.90 ± 0.07 and 0.88 ± 0.07. Features extracted using manual and automatic segmentations agreed well, for both the internal (ICC = 0.94, interquartile range: 0.88-0.97) and external (ICC = 0.90, interquartile range: 0.78-70.96) testing cohorts. AUC of radiomic model with automatic segmentation was comparable with that of the model with manual segmentation for both the internal (0.95 vs. 0.93, p = 0.176) and external (0.88 vs. 0.91, p = 0.419) testing cohorts. CONCLUSIONS: The developed deep learning-based segmentation method enables automatic and accurate extraction of meningioma from multiparametric MR images and can help deploy radiomics for preoperative meningioma differentiation in clinical practice. KEY POINTS: ⢠A deep learning-based method was developed for automatic segmentation of meningioma from multiparametric MR images. ⢠The automatic segmentation method enabled accurate extraction of meningiomas and yielded radiomic features that were highly consistent with those that were obtained using manual segmentation. ⢠High-grade meningiomas were preoperatively differentiated from low-grade meningiomas using a radiomic model constructed on features from automatic segmentation.
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Aprendizado Profundo , Neoplasias Meníngeas , Meningioma , Imageamento por Ressonância Magnética Multiparamétrica , Adulto , Humanos , Imageamento por Ressonância Magnética/métodos , Neoplasias Meníngeas/diagnóstico por imagem , Meningioma/diagnóstico por imagem , Meningioma/cirurgia , Pessoa de Meia-Idade , Curva ROC , Estudos RetrospectivosRESUMO
The flexible surface-enhanced Raman scattering (SERS) platform has ceaselessly propelled the development of point-of-care testing (POCT) in diverse fields. Herein, we report a facile strategy for the SERS-chemometric analysis of four ß-blockers (bisoprolol, metoprolol, acebutolol and esmolol) based on a super-sticky mussel-inspired hydrogel SERS tape. The surface morphology and mechanical properties of the hydrogel tape can be easily controlled by adjusting the compositional ratio. The optimized tape with excellent toughness and adhesiveness allows efficient collection of analytes through a simple "paste and peel off" approach, further by spraying with silver nanoparticles using a household sprayer to instantly assemble a flexible SERS substrate, the analytes can then detected by a portable Raman spectrometer. This POCT strategy enables the identification and discrimination of four similar ß-blockers with high sensitivity and accuracy in combination with the statistical algorithms. The developed SERS tape is finally utilized for the recognition of ß-blockers in simulated urine solution, which realizes a limit of detection of 1.0 ng mL-1, revealing a promising potential of this SERS-based POCT for the clinical detection of doping abuse.
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Nanopartículas Metálicas , Prata , Hidrogéis , Nanopartículas Metálicas/química , Testes Imediatos , Prata/química , Análise Espectral RamanRESUMO
Priapism, a prolonged penile erection in the absence of sexual arousal, is common among patients with sickle cell disease (SCD). Hypogonadism is also common in patients with SCD. While the administration of exogenous testosterone reverses hypogonadism, it is contraceptive. We hypothesized that the stimulation of endogenous testosterone production decreases priapism by normalizing molecular signaling involved in penile erection without decreasing intratesticular testosterone production, which would affect fertility. Treatment of SCD mice with FGIN-1-27, a ligand for translocator protein (TSPO) that mobilizes cholesterol to the inner mitochondrial membrane, resulted in eugonadal levels of serum testosterone without decreasing intratesticular testosterone production. Normalized testosterone levels, in turn, decreased priapism. At the molecular level, TSPO restored phosphodiesterase 5 activity and decreased NADPH oxidase-mediated oxidative stress in the penis, which are major molecular signaling molecules involved in penile erection and are dysregulated in SCD. These results indicate that pharmacologic activation of TSPO could be a novel, targetable pathway for treating hypogonadal men, particularly patients with SCD, without adverse effects on fertility.
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Anemia Falciforme/complicações , Ácidos Indolacéticos/farmacologia , Priapismo/complicações , Receptores de GABA/metabolismo , Testosterona/biossíntese , Anemia Falciforme/sangue , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Humanos , Hormônio Luteinizante/sangue , Masculino , Camundongos Transgênicos , NADPH Oxidases/metabolismo , Óxido Nítrico/metabolismo , Pênis/efeitos dos fármacos , Pênis/patologia , Fosforilação/efeitos dos fármacos , Priapismo/sangue , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia , Testosterona/sangue , Testosterona/deficiência , Tirosina/análogos & derivados , Tirosina/metabolismoRESUMO
Previous studies reported that, with aging, Leydig cell intracellular antioxidants are reduced in concentration and intracellular ROS levels increase, suggesting that oxidant/antioxidant imbalance may contribute to the reduced testosterone production that characterizes the aging cells. As yet, little is known about how the Leydig cell oxidant/antioxidant environment is regulated. Sirt1, an enzyme that deacetylates transcription factors, and the transcription factor Nrf2, have been shown to be associated with cellular response to oxidative stress. We hypothesized that Sirt1 and/or Nrf2 might be involved in regulating the oxidant/antioxidant environment of Leydig cells, and therefore, the testosterone production. We found that Sirt1 and Nrf2 are present in the Leydig cells of Brown Norway rats, though reduced in aged cells. In MA-10 cells in which Sirt1 or Nrf2 were suppressed by nicotinamide (NAM) or ML385, respectively, or in which siRNAs were used for knockdown of Sirt1 or Nrf2, increased ROS levels and decreased progesterone production occurred. In rat Leydig cells, inhibition of Sirt1 by culturing the cells with NAM resulted in increased ROS and reduced testosterone production, and subsequent removal of NAM from the culture medium resulted in increased testosterone production. Activation of rat Leydig cells Sirt1 with honokiol or of Nrf2 with sulforaphane resulted in the maintenance of testosterone production despite the exposure of the cells to oxidizing agent. These results, taken together, suggest that Sirt1 and Nrf2 are involved in maintaining the Leydig cell oxidant/antioxidant environment, and thus in maintaining steroid production.
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Antioxidantes , Células Intersticiais do Testículo , Fator 2 Relacionado a NF-E2 , Oxidantes , Sirtuína 1 , Testosterona , Animais , Masculino , Ratos , Antioxidantes/metabolismo , Células Intersticiais do Testículo/metabolismo , Oxidantes/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Testosterona/biossíntese , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismoRESUMO
Perfluoroundecanoic acid (PFUnA) is one of long-chain perfluoroalkyl carboxylic acids. However, the effect of PFUnA on pubertal development of Leydig cells remains unclear. The goal of this study was to investigate the effect of PFUnA on Leydig cell development in pubertal male rats. We orally dosed male Sprague-Dawley rats (age 35 days) with PFUnA at doses of 0, 1, 5, and 10 mg/kg/day from postnatal day (PND) 35 to PND 56. Serum testosterone and luteinizing hormone levels were remarkably reduced by PFUnA at ≥1 mg/kg while serum follicle-stimulating hormone levels were lowered at 5 and 10 mg/kg. PFUnA down-regulated the expression of Lhcgr, Scarb1, Star, Cyp11a1, Hsd3b1, Cyp17a1, Hsd17b3, Hsd11b1, Insl3, Nr5a1, Fshr, Dhh, Sod1, and Sod2 and their proteins in the testis and the expression of Lhb and Fshb in the pituitary. PFUnA reduced Leydig cell number at 5 and 10 mg/kg. PFUnA induced oxidative stress and increased autophagy. These may result from the inhibition of phosphorylation of mTOR, AKT1, AKT2, and ERK1/2 in the testis. In conclusion, PFUnA exhibits inhibitory effects on pubertal Leydig cell development possibly via inducing oxidative stress and increasing autophagy.
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Autofagia/efeitos dos fármacos , Ácidos Graxos/toxicidade , Fluorocarbonos/toxicidade , Células Intersticiais do Testículo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fatores Etários , Animais , Proteínas Relacionadas à Autofagia/metabolismo , Hormônio Foliculoestimulante/sangue , Regulação Enzimológica da Expressão Gênica , Células Intersticiais do Testículo/metabolismo , Células Intersticiais do Testículo/patologia , Hormônio Luteinizante/sangue , Masculino , Hipófise/efeitos dos fármacos , Hipófise/metabolismo , Ratos Sprague-Dawley , Desenvolvimento Sexual , Transdução de Sinais , Contagem de Espermatozoides , Espermatozoides/efeitos dos fármacos , Espermatozoides/patologia , Testosterona/sangueRESUMO
The Leydig cells of the mammalian testis produce testosterone (T) in response to luteinizing hormone (LH). In rats and men with reduced serum T levels, T replacement therapy (TRT) will raise T levels, but typically with suppressive effects on sperm formation. The rate-determining step in T formation is the translocation of cholesterol to the inner mitochondrial membrane, mediated by protein-protein interactions of cytosolic and outer mitochondrial membrane proteins. Among the involved proteins is cholesterol-binding translocator protein (TSPO) (18 kDa TSPO). We hypothesized that in contrast to TRT, the administration of the TSPO agonist N,N-dihexyl-2-(4-fluorophenyl)indole-3-acetamide (FGIN-1-27), by stimulating the ability of the Leydig cells to produce T, would result in the elevation of serum T levels while maintaining intratesticular T concentration and therefore without suppression of spermatogenesis. Age-related reductions in both serum and intratesticular T levels were seen in old Brown Norway rats. Both exogenous T and FGIN-1-27 increased serum T levels. With exogenous T, serum LH and Leydig cell T formation were suppressed, and intratesticular T was reduced to below the concentration required to maintain spermatogenesis quantitatively. In contrast, FGIN-1-27 stimulated Leydig cell T formation, resulting in increased serum T without reductions in intratesticular T concentrations or in testicular sperm numbers. FGIN-1-27 also significantly increased serum and intratesticular T levels in rats made LH-deficient by treatment with the gonadotropin-releasing hormone antagonist cetrorelix. These results point to a possible approach to increasing serum T without negative effects on spermatogenesis, based upon stimulating T production by the Leydig cells themselves rather than administering T exogenously.
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Células Intersticiais do Testículo/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Testículo/efeitos dos fármacos , Testosterona/metabolismo , Envelhecimento/metabolismo , Animais , Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/farmacologia , Antagonistas de Hormônios/farmacologia , Ácidos Indolacéticos/farmacologia , Células Intersticiais do Testículo/metabolismo , Hormônio Luteinizante/sangue , Masculino , Ratos , Contagem de Espermatozoides , Testículo/metabolismo , Testosterona/sangueRESUMO
BACKGROUND: It is difficult to prospectively differentiate between benign (World Health Organization [WHO] I) and nonbenign (WHO II and III) meningiomas. PURPOSE: To evaluate the feasibility of preoperative differentiation between benign and nonbenign meningiomas by using texture analysis from multiparametric MR data. STUDY TYPE: Retrospective. SUBJECTS: In all, 184 patients with meningioma (139 benign and 45 nonbenign) were included as the training cohort and 79 patients with meningioma (60 benign and 19 nonbenign) were included as the external validation cohort. FIELD STRENGTH/SEQUENCE: T1 -weighted, T2 -weighted, and contrast-enhanced T1 -weighted imaging were performed on 1.5 or 3.0T MR systems from two centers. ASSESSMENT: Tumor segmentation and radiological characteristic (RC) evaluation were performed by experienced radiologists. The texture features were extracted from preprocessed images and combined with RCs, and then the combined features were reduced by using a two-step feature selection. Three single-sequence models and a multiparametric MRI (the combination of single sequences) model were constructed and then evaluated with the external validation cohort. STATISTICAL TESTS: Area under receiver operating characteristic curve (AUC), accuracy (Acc), f1-score (F1), sensitivity (Sen), and specificity (Spec), were calculated to quantify the performance of the models. RESULTS: Among the four texture models, the multiparametric MRI model demonstrated the best performance for differentiating between benign and nonbenign meningiomas in both the training and external validation cohorts (AUC 0.91, Acc 89%, F1 0.88, Sen 0.93, and Spec 0.87 in the training cohort; AUC 0.83, Acc 80%, F1 0.77, Sen 0.84, and Spec 0.78 in the validation cohort). DATA CONCLUSION: Nonbenign meningiomas might be preoperatively differentiated from benign meningiomas by using texture analysis from multiparametric MR data. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:1810-1820.
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Neoplasias Meníngeas , Meningioma , Imageamento por Ressonância Magnética Multiparamétrica , Humanos , Meningioma/diagnóstico por imagem , Curva ROC , Estudos RetrospectivosRESUMO
We are developing a social mobile robot that has a name calling function using a face memorization system. It is said that it is an important function for a social robot to call to a person by her/his name, and the name calling can make a friendly impression of the robot on her/him. Our face memorization system has the following features: (1) When the robot detects a stranger, it stores her/his face images and name after getting her/his permission. (2) The robot can call to a person whose face it has memorized by her/his name. (3) The robot system has a sleep-wake function, and a face classifier is re-trained in a REM sleep state, or execution frequencies of information processes are reduced when it has nothing to do, for example, when there is no person around the robot. In this paper, we confirmed the performance of these functions and conducted an experiment to evaluate the impression of the name calling function with research participants. The experimental results revealed the validity and effectiveness of the proposed face memorization system.
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We reported that FGIN-1-27 (N,N-dihexyl-2-(4-fluorophenyl)indole-3-acetamide, FGIN), a synthetic ligand for translocator protein (TSPO, 18 kDa), increased serum testosterone levels in young and aged Brown Norway rats after its administration daily for 10 days. It is not known, however, how soon after treatment with FGIN serum testosterone rises, how long levels remain elevated after cessation of treatment, or whether the drug acts solely through TSPO. Adult Sprague-Dawley male rats received a single ip dose of FGIN (1 mg/kg BW). Serial blood samples were collected, and serum testosterone and luteinizing hormone (LH) were assessed hourly throughout 24 h. Testosterone concentration was maximal by 3 h, remained significantly higher than the controls at 10 h, and returned to the control level by 24 h. Consistent with the in vivo study, culturing isolated Leydig cells with either FGIN (40 µM) or LH (0.1 ng/ml) resulted in significantly increased testosterone production by 30 min, and the stimulatory effects persisted through 48 h. At a very early (15 min) treatment time, however, FGIN significantly increased testosterone production but LH had not yet done so. Surprisingly, in vivo treatment with FGIN not only increased serum testosterone but also serum LH concentration, raising the possibility that FGIN may increase serum testosterone concentration by dual mechanisms.
Assuntos
Ácidos Indolacéticos/farmacologia , Células Intersticiais do Testículo/efeitos dos fármacos , Hormônio Luteinizante/sangue , Testosterona/sangue , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Células Intersticiais do Testículo/metabolismo , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVES: To develop and validate an MRI-based radiomics strategy for the preoperative estimation of pathological grade in bladder cancer (BCa) tumors. METHODS: A primary cohort of 70 patients (31 high-grade BCa and 39 low-grade BCa) with BCa were retrospectively enrolled. Three sets of radiomics features were separately extracted from tumor volumes on T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), and apparent diffusion coefficient (ADC) maps. Two sets of multimodal features were separately generated by the maxout and concatenation of the above mentioned single-modality features. Each feature set was subjected to a two-sample t test and the least absolute shrinkage and selection operator (LASSO) algorithm for feature selection. Multivariable logistic regression (LR) analysis was used to obtain five corresponding radiomics models. The diagnostic abilities of the radiomics models were evaluated using receiver operating characteristic (ROC) curve analysis and compared using the DeLong test. Validation was performed on a time-independent cohort containing 30 consecutive patients. RESULTS: The areas under the ROC curves (AUCs) of single-modality T2WI, DWI, and ADC models in the training cohort were 0.7933 (95% confidence interval [CI] 0.7471-0.8396), 0.8083 (95% CI 0.7565-0.8601), and 0.8350 (95% CI 0.7924-0.8776), respectively. Both multimodality models achieved higher AUCs (maxout 0.9233, 95% CI 0.9001-0.9466; concatenation 0.9233, 95% CI 0.9001-0.9466) than single-modality models. The AUCs of the maxout and concatenation models in the validation cohort were 0.9186 and 0.9276, respectively. CONCLUSIONS: The MRI-based multiparametric radiomics approach has the potential to be used as a noninvasive imaging tool for preoperative grading of BCa tumors. Multicenter validation is needed to acquire high-level evidence for its clinical application. KEY POINTS: ⢠Multiparametric MRI may help in the preoperative grading of BCa tumors. ⢠The Joint_Model established from T2WI, DWI, and ADC feature subsets demonstrated a high diagnostic accuracy for preoperative prediction of pathological grade in BCa tumors. ⢠The radiomics approach has the potential to preoperatively assess tumor grades in BCa and avoid subjectivity.