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1.
J Fish Biol ; 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36600527

RESUMO

Eels have fascinated biologists for centuries, due to their amazing long-distance migrations between freshwater habitats and very distant ocean spawning areas. The migratory life histories of the Japanese eel, Anguilla japonica, in the waters of south China are not very clear, despite its ecological importance, and the need for fishery regulation and management. In this study, strontium (Sr) and calcium (Ca) microchemical profiles of the otoliths of sliver eels were measured by X-ray electron probe microanalysis (EPMA) based on data collected from different habitats (including freshwater and brackish habitats), in the large subtropical Pearl River. The corresponding habitat preference characteristics were further analyzed using redundancy analysis (RDA). A total of 195 Japanese eels were collected over six years. The collected individuals ranged from 180 to 771 mm in total length and from 8 to 612 g in body weight. Two-dimensional pictures of the Sr:Ca concentrations in otoliths revealed that the A. japonica in the Pearl River are almost entirely river eels, spending the majority of their lives in freshwater without exposure to salt water. While the catadromous migration time has delayed about one month in the Pearl River estuary in the past 20 years. RDA analysis further indicated that juveniles and adults preferred water with high salinity and high tide levels. Youth preferred habitats with high river fractals. Our findings contribute to a growing body of evidence, and showing that the eels extremely scarce currently and conservation measures against them are imminent, including the protection of brackish and freshwater areas where they live in south China.

2.
J Clin Med ; 12(2)2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36675362

RESUMO

BACKGROUND: Ischemia reperfusion injury (IRI) remains a major problem in patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). We have developed a novel reperfusion strategy for PCI and named it "volume-controlled reperfusion (VCR)". The aim of the current study was to assess the safety and feasibility of VCR in patients with STEMI. METHODS: Consecutive patients admitted to Beijing Chaoyang Hospital with STEMI were prospectively enrolled. The feasibility endpoint was procedural success. The safety endpoints included death from all causes, major vascular complications, and major adverse cardiac event (MACE), i.e., a composite of cardiac death, myocardial reinfarction, target vessel revascularization (TVR), and heart failure. RESULTS: A total of 30 patients were finally included. Procedural success was achieved in 28 (93.3%) patients. No patients died during the study and no major vascular complications or MACE occurred during hospitalization. With the exception of one patient (3.3%) who underwent TVR three months after discharge, no patient encountered death (0.0%), major vascular complications (0.0%), or and other MACEs (0.0%) during the median follow-up of 16 months. CONCLUSION: The findings of the pilot study suggest that VCR has favorable feasibility and safety in patients with STEMI. Further larger randomized trials are required to evaluate the effectiveness of VCR in STEMI patients.

3.
Nanoscale ; 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36688256

RESUMO

Effective power management on the outputs of triboelectric nanogenerators (TENGs) is critical for their practical applications due to the large impedance and unbalanced load matching. Recently proposed voltage multiplying circuits for external-charge excitation and self-charge excitation are usually unstable and require reversal for device restarting and common switched-capacitor-converters usually cause large switching losses. In this work, we fabricated a fractal structured charge-excitation circuit for TENGs using diodes and capacitors. The fractal switched-capacitor-converter coupled with voltage regulator diodes can greatly boost the output charge and current of the TENG without reverse starting. The managed output performance of the TENG can be controlled by the electronic component parameters and external operating frequency. Through the component and condition optimization, the fractal structured charge-excitation TENG (FSC-TENG) can achieve nearly 5.8 times charge boosting and almost 16.8 times power boosting in the pulsed mode. Furthermore, the FSC-TENG successfully drove a hygrothermograph and was integrated into a yoga mat for harvesting human-body motion energy to power an electronic watch and a pedometer. The FSC-TENG with good charge accumulation properties and stability is a promising candidate for practical self-powered applications.

4.
Cancer Res ; 2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36622331

RESUMO

Tumor-associated macrophages (TAMs) play a crucial role in immunosuppression. However, how TAMs are transformed into immunosuppressive phenotypes and influence the tumor microenvironment (TME) is not fully understood. Here, we utilized single-cell RNA sequencing and whole-exome sequencing data of glioblastoma (GBM) tissues and identified a subset of TAMs dually expressing macrophage and tumor signatures, which were termed double-positive TAMs. Double-positive TAMs tended to be bone marrow-derived macrophages (BMDMs) and were characterized by immunosuppressive phenotypes. Phagocytosis of glioma cells by BMDMs in vitro generated double-positive TAMs with similar immunosuppressive phenotypes to double-positive TAMs in the GBM TME of patients. The double-positive TAMs were transformed into M2-like macrophages and drove immunosuppression by expressing immune checkpoint proteins CD276, PD-L1, and PD-L2 and suppressing the proliferation of activated T cells. Together, glioma cell phagocytosis by BMDMs in the TME leads to the formation of double-positive TAMs with enhanced immunosuppressive phenotypes, shedding light on the processes driving TAM-mediated immunosuppression in GBM.

5.
ACS Biomater Sci Eng ; 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36598339

RESUMO

Malignant tumor tissues exhibit inter- and intratumoral heterogeneities, aberrant development, dynamic stromal composition, diverse tissue phenotypes, and cell populations growing within localized mechanical stresses in hypoxic conditions. Experimental tumor models employing engineered systems that isolate and study these complex variables using in vitro techniques are under development as complementary methods to preclinical in vivo models. Here, advances in extrusion bioprinting as an enabling technology to recreate the three-dimensional tumor milieu and its complex heterogeneous characteristics are reviewed. Extrusion bioprinting allows for the deposition of multiple materials, or selected cell types and concentrations, into models based upon physiological features of the tumor. This affords the creation of complex samples with representative extracellular or stromal compositions that replicate the biology of patient tissue. Biomaterial engineering of printable materials that replicate specific features of the tumor microenvironment offer experimental reproducibility, throughput, and physiological relevance compared to animal models. In this review, we describe the potential of extrusion-based bioprinting to recreate the tumor microenvironment within in vitro models.

6.
BMC Cancer ; 23(1): 42, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36631762

RESUMO

BACKGROUND: This study aimed to develop an integrated model for predicting the occurrence of postoperative seizures in patients with diffuse high-grade gliomas (DHGGs) using clinical and RNA-seq data. METHODS: Patients with DHGGs, who received prophylactic anti-epileptic drugs (AEDs) for three months following surgery, were enrolled into the study. The patients were assigned randomly into training (n = 166) and validation (n = 42) cohorts. Differentially expressed genes (DEGs) were identified based on preoperative glioma-related epilepsy (GRE) history. Least absolute shrinkage and selection operator (LASSO) logistic regression analysis was used to construct a predictive gene-signature for the occurrence of postoperative seizures. The final integrated prediction model was generated using the gene-signature and clinical data. Receiver operating characteristic analysis and calibration curve method were used to evaluate the accuracy of the gene-signature and prediction model using the training and validation cohorts. RESULTS: A seven-gene signature for predicting the occurrence of postoperative seizures was developed using LASSO logistic regression analysis of 623 DEGs. The gene-signature showed satisfactory predictive capacity in the training cohort [area under the curve (AUC) = 0.842] and validation cohort (AUC = 0.751). The final integrated prediction model included age, temporal lobe involvement, preoperative GRE history, and gene-signature-derived risk score. The AUCs of the integrated prediction model were 0.878 and 0.845 for the training and validation cohorts, respectively. CONCLUSION: We developed an integrated prediction model for the occurrence of postoperative seizures in patients with DHGG using clinical and RNA-Seq data. The findings of this study may contribute to the development of personalized management strategies for patients with DHGGs and improve our understanding of the mechanisms underlying GRE in these patients.


Assuntos
Epilepsia , Glioma , Humanos , Estudos Retrospectivos , Glioma/genética , Glioma/cirurgia , Curva ROC , Epilepsia/genética , Epilepsia/cirurgia , Convulsões/genética
7.
Front Med ; 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36645634

RESUMO

Detailed characterizations of genomic alterations have not identified subtype-specific vulnerabilities in adult gliomas. Mapping gliomas into developmental programs may uncover new vulnerabilities that are not strictly related to genomic alterations. After identifying conserved gene modules co-expressed with EGFR or PDGFRA (EM or PM), we recently proposed an EM/PM classification scheme for adult gliomas in a histological subtype- and grade-independent manner. By using cohorts of bulk samples, paired primary and recurrent samples, multi-region samples from the same glioma, single-cell RNA-seq samples, and clinical samples, we here demonstrate the temporal and spatial stability of the EM and PM subtypes. The EM and PM subtypes, which progress in a subtype-specific mode, are robustly maintained in paired longitudinal samples. Elevated activities of cell proliferation, genomic instability and microenvironment, rather than subtype switching, mark recurrent gliomas. Within individual gliomas, the EM/PM subtype was preserved across regions and single cells. Malignant cells in the EM and PM gliomas were correlated to neural stem cell and oligodendrocyte progenitor cell compartment, respectively. Thus, while genetic makeup may change during progression and/or within different tumor areas, adult gliomas evolve within a neurodevelopmental framework of the EM and PM molecular subtypes. The dysregulated developmental pathways embedded in these molecular subtypes may contain subtype-specific vulnerabilities.

8.
Anal Chem ; 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36654498

RESUMO

The flow cytometer has become a powerful and widely accepted measurement device in both biological studies and clinical diagnostics. The application of the flow cytometer in emerging point-of-care scenarios, such as instant detection in remote areas and emergency diagnosis, requires a significant reduction in physical dimension, cost, and power consumption. This requirement promotes studies to develop portable flow cytometers, mostly based on the utilization of polymer microfluidic chips. However, due to the relatively poor optical performance of polymer materials, existing microfluidic flow cytometers are incapable of accurate blood analysis, such as the four-part leukocyte differential count, which is necessary to monitor the immune system and to assess the risk of allergic inflammation or viral infection. To address this issue, an ultraportable flow cytometer based on an all-glass microfluidic chip (AG-UFCM) has been developed in this study. Compared with that of a typical commercial flow cytometer (BD FACSAria III), the volume of the AG-UFCM was reduced by 90 times (from 720 to 8 L). A two-step laser processing was employed to fabricate an all-glass microfluidic chip with a surface roughness of less than 1 nm, significantly improving the optical performance of on-chip micro-lens. The signal-to-noise ratio was enhanced by 3 dB, compared with that of polymer materials. For the first time, a four-part leukocyte differential count based on single fluorescence staining was realized using a miniaturized flow cytometer, laying a foundation for the point-of-care testing of miniaturized flow cytometers.

9.
Artigo em Inglês | MEDLINE | ID: mdl-36633015

RESUMO

BACKGROUND: Although Lesion size index (LSI) has been reported to highly predict radiofrequency lesion size in vitro, its accuracy in lesion size and steam pop estimation has not been well investigated for every possible scenario. METHODS: Initially, radiofrequency ablations were performed on porcine myocardial slabs at various power, CF, and time settings with blinded LSI. Subsequently, radiofrequency power at 20, 30, 40, 50, and 60 W was applied at CF values of 5, 10, 20, and 30 g to reach target LSIs of 4, 5, 6, and 7. Lesion size and steam pops were recorded for each ablation. RESULTS: Lesion size was positively correlated with LSI regardless of power settings (p< 0.001). The linear correlation coefficients of lesion size and LSI decreased at higher power settings. At high power combined with high CF settings (50 W/20 g), lesion depth and LSI showed an irrelevant correlation (p = 0.7855). High-power ablation shortened ablation time and increased the effect of resistive heating. LSI could predict the risk of steam pops at high-power settings with the optimal threshold of 5.65 (sensitivity, 94.1%; specificity, 46.1%). The ablation depth of the heavy heart was shallower than that of the light heart under similar ablation settings. CONCLUSIONS: LSI could predict radiofrequency lesion size and steam pops at high power settings in vitro, while synchronous high power and high CF should be avoided. Lighter hearts require relatively lower ablation settings to create appropriate ablation depth. This article is protected by copyright. All rights reserved.

10.
Oncol Rep ; 49(2)2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36633142

RESUMO

Following the publication of the above article, an interested reader drew to the authors' attention that Figs. 3C and E in the paper appeared to contain instances of duplicated data. The authors were able to consult their original data files, and realized that these figures had indeed been assembled incorrectly; subsequently, they requested that a corrigendum be published to take account of the errors that were made during the compilation of these figures. Having investigated this matter in the Editorial Office, however, additional panels of overlapping data were identified, comparing between Figs. 3 and 5; specifically, overlapping data panels were also identified in panels in Figs. 3C, E and F, and 5C and D. The Editor of Oncology Reports has considered the authors' request to publish a corrigendum, but has decided to decline this request on account of the large number of errors that have been identified; rather, the article is to be be retracted from the Journal on the basis of an overall lack of confidence in the presented data. The Editor apologizes to the readership of the Journal for any inconvenience caused. [Oncology Reports 40: 1533­1544, 2018; DOI: 10.3892/or.2018.6570].

11.
Waste Manag ; 157: 330-338, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36603447

RESUMO

E-waste is a valuable resource for the recovery of secondary metals. However, traditional methods only focused on the extraction of Cu and noble metals (Au, Ag, etc.), and significant tin (Sn) loss occurred during the smelting or the leached. In this paper, a novel chemical vapor transport (CVT) process was proposed to separate and recycle Sn from e-waste to prepare nano-SnO2. The effect of roasting parameters on Sn volatilization and characterization of nano-SnO2 were investigated using thermodynamic analysis, XRD, SEM, TEM, etc. The results indicated that Sn volatilization of 92.8 % was obtained under optimal roasting parameters under CO-CO2-N2 atmosphere. In addition, nano-SnO2 with a crystallinity of 99.9 %, an average grain size of 24.8 nm and a specific surface area of 97.9 m2/g was synthesized successfully.


Assuntos
Resíduo Eletrônico , Estanho , Metais
12.
Cells ; 12(1)2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36611988

RESUMO

The prevalence of diabetes-associated cognitive dysfunction (DACD) has increased to 13.5%. Dementia, as the most severe DACD, is the second leading cause of death in patients with diabetes mellitus. Hence, the potential mechanisms of DACD for slowing or halting its progression need to be urgently explored. Given that the sigma-1 receptor (Sig-1R), a chaperone protein located in the endoplasmic reticulum (ER)-mitochondrion contact membranes to regulate ER stress (ERS), is associated with cognitive outcomes in neurodegenerative diseases, this study aimed to investigate the role of astrocytic Sig-1R in DACD and its underlying mechanism. Here, we examined the levels of ERS and complement component 3/3a (C3/C3a) from primary astrocytes with different concentrations of glucose and treatment. Subsequently, HT22 neurons were cultured in different astrocyte-conditioned medium, and the expression of synaptic proteins was detected. We constructed type 1 diabetes mellitus (T1DM) model to evaluate the astrocytic Sig-1R mechanism on synapse and cognitive function changes. In vitro, high glucose concentration downregulated Sig-1R and aggravated ERS in astrocytes, resulting in synapse deficits. PRE-084, a high-affinity and selective Sig-1R agonist, inhibited astrocytic ERS and complement cascades and restored synaptic damage, while the Sig-1R antagonist displayed the opposite results. Moreover, C3a receptor antagonist (C3aRA) could mimic the effect of PRE-084 and exerted neuroprotective effects. In vivo, PRE-084 substantially reduced ER-mitochondrion contact, activation of ERS, and C3/C3a secretion in mice with T1DM. Additionally, the synaptic loss and neurobehavioral dysfunction of mice with T1DM were less pronounced in both the PRE-084 and C3aRA treatment groups. These findings demonstrated that Sig-1R activation reduced the astrocytic ER-mitochondrion contact, ERS activation, and complement-mediated synaptic damage in T1DM. This study suggested the mechanisms and potential therapeutic approaches for treating DACD.


Assuntos
Disfunção Cognitiva , Diabetes Mellitus Tipo 1 , Camundongos , Animais , Astrócitos/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Fatores de Proteção , Estresse do Retículo Endoplasmático , Retículo Endoplasmático/metabolismo , Mitocôndrias/metabolismo , Disfunção Cognitiva/metabolismo
13.
Nanoscale ; 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36625286

RESUMO

Low-temperature fuel cells have great application potential in electric vehicles and portable electronic devices, which need advanced electrocatalysts. Controlling the composition and morphology of electrocatalysts can effectively improve their catalytic performance. In this work, a Rh metallene (Rhlene)-supported Pt nanoparticle (Pt/Rhlene) electrocatalyst is successfully synthesized by a simple chemical reduction method, in which ultra-small Pt nanoparticles are uniformly attached to the Rhlene surface due to the high surface area of Rhlene. Pt/Rhlene reveals a 3.60-fold Pt-mass activity enhancement for the ethylene glycol oxidation reaction in alkaline solution compared with commercial Pt black, and maintains high stability and excellent poisoning-tolerance during electrocatalysis, owing to the specific physical/chemical properties of Rhlene. The superior electrocatalytic performance of Pt/Rhlene may open an avenue to synthesize other metallene-supported noble metal nanoparticle hybrids for various electrocatalytic applications.

14.
ISME J ; 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36658395

RESUMO

Ocean warming (OW) and acidification (OA) are recognized as two major climatic conditions influencing phytoplankton growth and nutritional or toxin content. However, there is limited knowledge on the responses of harmful algal bloom species that produce toxins. Here, the study provides quantitative and mechanistic understanding of the acclimation and adaptation responses of the domoic acid (DA) producing diatom Pseudo-nitzschia multiseries to rising temperature and pCO2 using both a one-year in situ bulk culture experiment, and an 800-day laboratory acclimation experiment. Ocean warming showed larger selective effects on growth and DA metabolism than ocean acidification. In a bulk culture experiment, increasing temperature +4 °C above ambient seawater temperature significantly increased DA concentration by up to 11-fold. In laboratory when the long-term warming acclimated samples were assayed under low temperatures, changes in growth rates and DA concentrations indicated that P. multiseries did not adapt to elevated temperature, but could instead rapidly and reversibly acclimate to temperature shifts. However, the warming-acclimated lines showed evidence of adaptation to elevated temperatures in the transcriptome data. Here the core gene expression was not reversed when warming-acclimated lines were moved back to the low temperature environment, which suggested that P. multiseries cells might adapt to rising temperature over longer timescales. The distinct strategies of phenotypic plasticity to rising temperature and pCO2 demonstrate a strong acclimation capacity for this bloom-forming toxic diatom in the future ocean.

15.
ACS Med Chem Lett ; 14(1): 83-91, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36655132

RESUMO

Mitogen-activated protein kinase-interacting protein kinases (MNKs) phosphorylate eukaryotic initiation factor 4E (eIF4E) and regulate the processes of cell proliferation, cell cycle, and migration and invasion of cancer cells. Selectively inhibiting the activity of MNKs could be effective in treating cancers. In this study, we report a series of novel MNK inhibitors with an imidazo[2,1-b][1,3,4]thiadiazol scaffold, from which, compound 18 inhibited the phosphorylation of eIF4E in various cancer cell lines potently. Compound 18 was more potent against MNK2 than MNK1, and decreased the levels of cyclin-B1, cyclin-D3, and MMP-3 in A549 and MDA-MB-231 cells, impaired cell growth and colony formation, arrested the cell cycle in the G0/G1 phase, and inhibited cell migration and the secretion of TNF-α, MCP-1, and IL-8 from A549 cells. It represents a starting compound to design further inhibitors that selectively target MNKs and apply in other diseases.

16.
Med Res Rev ; 2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36658745

RESUMO

Cardio-metabolic-diseases (cardio-metabolic-diseases) are leading causes of death and disability worldwide and impose a tremendous burden on whole society as well as individuals. As a new type of regulated cell death (RCD), ferroptosis is distinct from several classical types of RCDs such as apoptosis and necroptosis in cell morphology, biochemistry, and genetics. The main molecular mechanisms of ferroptosis involve iron metabolism dysregulation, mitochondrial malfunction, impaired antioxidant capacity, accumulation of lipid-related peroxides and membrane disruption. Within the past few years, mounting evidence has shown that ferroptosis contributes to the pathophysiological process in cardio-metabolic-diseases. However, the exact roles and underlying molecular mechanisms have not been fully elucidated. This review comprehensively summarizes the mechanism of ferroptosis in the development and progression of cardio-metabolic-diseases, so as to provide new insights for cardio-metabolic-diseases pathophysiology. Moreover, we highlight potential druggable molecules in ferroptosis signaling pathway, and discuss recent advances in management strategies by targeting ferroptosis for prevention and treatment of cardio-metabolic-diseases.

17.
J Affect Disord ; 325: 102-109, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36623569

RESUMO

BACKGROUND: Psychotic symptoms are common in patients with major depressive disorder (MDD). However, few studies have assessed the incidence of comorbid psychotic symptoms in first-episode drug naïve (FEDN) MDD patients. The present study aimed to evaluate the prevalence and risk factors of psychotic symptoms in a large sample of middle-aged Chinese patients with FEDN MDD. METHODS: 813 middle-aged (age range 35 to 65 years) outpatients with FEDN MDD were recruited. The 17-item Hamilton Rating Scale for Depression (HAMD), the 14-item Hamilton Anxiety Rating Scale (HAMA), and the positive subscales of the Positive and Negative Syndrome Scale (PANSS) were used to assess patient anxiety, depression and psychotic symptoms, respectively. RESULTS: The prevalence of psychotic symptoms in middle-aged patients with FEND MDD was 10.95 %. Multivariate logistic regression analysis showed that HAMA score, HAMD score, TSH, TC and BMI levels were significant predictors of psychotic symptoms in MDD middle-aged patients. The HAMA score and HAMD score predicted psychotic symptoms for both male and female middle-aged patients with MDD, while higher TSH, TC and BMI levels were correlated with psychotic symptoms only in female MDD patients. Furthermore, combining the HAMA score, HAMD score, and TSH could differentiate between psychotic major depression (PMD) and nonpsychotic major depression (NPMD) in middle-aged patients. CONCLUSIONS: Psychotic symptoms among middle-aged patients with MDD can be identified by integrating clinical and biological variables as early as possible during the first time see a doctor.

18.
BMC Neurol ; 23(1): 32, 2023 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-36670390

RESUMO

BACKGROUND: The carriers of damaging heterozygous variants in interferon regulatory factor 2 binding protein-like (IRF2BPL), encoding a member of the IRF2BP family of transcriptional regulators, may be affected by a variety of neurological symptoms, such as neurodevelopmental regression, language and motor developmental delay, seizures, progressive ataxia and a lack of coordination, and even dystonia. CASE PRESENTATION: We report a Chinese boy who presented with dystonia, dysarthria, and normal development due to nonsense IRF2BPL mutation, with intact imaging and EEG findings but without developmental delays or seizures. Whole-exome sequencing revealed a novel nonsense variant IRF2BPL (NM_024496) Exon C.562C > T (p.Arg188*). CONCLUSION: This case report presents a Chinese boy with a novel nonsense variant in IRF2BPL, displaying rapid progressive dystonia and dysarthria, without early developmental delay or epilepsy; expands the IRF2BPL phenotypes in the Chinese population; and raises awareness of patients with IRF2BPL.


Assuntos
Distonia , Distúrbios Distônicos , Humanos , Distonia/genética , Disartria , Mutação , Convulsões/genética , Idioma , Proteínas de Transporte/genética , Proteínas Nucleares/genética
19.
J Immunother Cancer ; 11(1)2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36609487

RESUMO

BACKGROUND: Poly (ADP-ribose) polymerase (PARP) inhibition (PARPi) has demonstrated potent therapeutic efficacy in patients with BRCA-mutant ovarian cancer. However, acquired resistance to PARPi remains a major challenge in the clinic. METHODS: PARPi-resistant ovarian cancer mouse models were generated by long-term treatment of olaparib in syngeneic Brca1-deficient ovarian tumors. Signal transducer and activator of transcription 3 (STAT3)-mediated immunosuppression was investigated in vitro by co-culture experiments and in vivo by analysis of immune cells in the tumor microenvironment (TME) of human and mouse PARPi-resistant tumors. Whole genome transcriptome analysis was performed to assess the antitumor immunomodulatory effect of STING (stimulator of interferon genes) agonists on myeloid cells in the TME of PARPi-resistant ovarian tumors. A STING agonist was used to overcome STAT3-mediated immunosuppression and acquired PARPi resistance in syngeneic and patient-derived xenografts models of ovarian cancer. RESULTS: In this study, we uncover an adaptive resistance mechanism to PARP inhibition mediated by tumor-associated macrophages (TAMs) in the TME. Markedly increased populations of protumor macrophages are found in BRCA-deficient ovarian tumors that rendered resistance to PARPi in both murine models and patients. Mechanistically, PARP inhibition elevates the STAT3 signaling pathway in tumor cells, which in turn promotes protumor polarization of TAMs. STAT3 ablation in tumor cells mitigates polarization of protumor macrophages and increases tumor-infiltrating T cells on PARP inhibition. These findings are corroborated in patient-derived, PARPi-resistant BRCA1-mutant ovarian tumors. Importantly, STING agonists reshape the immunosuppressive TME by reprogramming myeloid cells and overcome the TME-dependent adaptive resistance to PARPi in ovarian cancer. This effect is further enhanced by addition of the programmed cell death protein-1 blockade. CONCLUSIONS: We elucidate an adaptive immunosuppression mechanism rendering resistance to PARPi in BRCA1-mutant ovarian tumors. This is mediated by enrichment of protumor TAMs propelled by PARPi-induced STAT3 activation in tumor cells. We also provide a new strategy to reshape the immunosuppressive TME with STING agonists and overcome PARPi resistance in ovarian cancer.


Assuntos
Neoplasias Ovarianas , Inibidores de Poli(ADP-Ribose) Polimerases , Animais , Feminino , Humanos , Camundongos , Linhagem Celular Tumoral , Terapia de Imunossupressão , Neoplasias Ovarianas/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Fator de Transcrição STAT3/metabolismo , Microambiente Tumoral
20.
Nanoscale ; 15(2): 461-469, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36533721

RESUMO

Bioorthogonal chemistry enables researchers to manipulate bioactive molecules in living systems. These highly selective and biocompatible reactions can be carried out in various complex environments. Over the past two decades, a considerable number of strides have been made to expand the capacities of bioorthogonal chemistry coupled with the aim to fine-tune present reactions for specific applications. The good points of bioorthogonal chemistry have pushed material chemists to integrate bioorthogonal chemistry with nanotechnologies to broaden the biological applications of nanomaterials. Notably, bioorthogonal nanotechnologies fundamentally rely on, more than half, according to our investigation, tetrazine bioorthogonal chemistry (TBC) to function as bioorthogonal handles to react with target agents owing to the extremely rapid kinetics and high selectivities of TBC. Its utilization in combination with nanotechnologies has led to developments in various areas of biomedicine, such as in situ drug activation and targeted delivery, bioimaging and biosensing, and the understanding of cell-biomolecule interactions. Given the fantastic past achievements and the rapid developments in tetrazine bioorthogonal technologies, the future is certainly very bright.


Assuntos
Química Click , Nanotecnologia
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