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1.
Molecules ; 29(9)2024 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-38731625

RESUMEN

Upon a variety of environmental stresses, eukaryotic cells usually recruit translational stalled mRNAs and RNA-binding proteins to form cytoplasmic condensates known as stress granules (SGs), which minimize stress-induced damage and promote stress adaptation and cell survival. SGs are hijacked by cancer cells to promote cell survival and are consequently involved in the development of anticancer drug resistance. However, the design and application of chemical compounds targeting SGs to improve anticancer drug efficacy have rarely been studied. Here, we developed two types of SG inhibitory peptides (SIPs) derived from SG core proteins Caprin1 and USP10 and fused with cell-penetrating peptides to generate TAT-SIP-C1/2 and SIP-U1-Antp, respectively. We obtained 11 SG-inducing anticancer compounds from cell-based screens and explored the potential application of SIPs in overcoming resistance to the SG-inducing anticancer drug sorafenib. We found that SIPs increased the sensitivity of HeLa cells to sorafenib via the disruption of SGs. Therefore, anticancer drugs which are competent to induce SGs could be combined with SIPs to sensitize cancer cells, which might provide a novel therapeutic strategy to alleviate anticancer drug resistance.


Asunto(s)
Antineoplásicos , Sorafenib , Gránulos de Estrés , Humanos , Sorafenib/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , Gránulos de Estrés/metabolismo , Células HeLa , Resistencia a Antineoplásicos/efectos de los fármacos , Péptidos/farmacología , Péptidos/química , Supervivencia Celular/efectos de los fármacos , Ubiquitina Tiolesterasa/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Línea Celular Tumoral , Péptidos de Penetración Celular/farmacología , Péptidos de Penetración Celular/química
2.
J Colloid Interface Sci ; 665: 1065-1078, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38579389

RESUMEN

Reactive oxygen species (ROS)-centered chemodynamic therapy (CDT) holds significant potential for tumor-specific treatment. However, insufficient endogenous H2O2 and extra glutathione within tumor microenvironment (TME) severely deteriorate the CDT's effectiveness. Herein, rich-Zn-Co3O4/N-doped porous carbon (Zn-Co3O4/NC) was fabricated by two-step pyrolysis, and applied to build high-efficiency nano-platform for synergistic cancer therapy upon combination with glucose oxidase (GOx), labeled Zn-Co3O4/NC-GOx for clarity. Specifically, the multiple enzyme-like activities of the Zn-Co3O4/NC were scrutinously investigated, including peroxidase-like activity to convert H2O2 to O2∙-, catalase-like activity to decompose H2O2 into O2, and oxidase-like activity to transform O2 to O2∙-, which achieved the CDT through the catalytic cascade reaction. Simultaneously, GOx reacted with intracellular glucose to produce gluconic acid and H2O2, realizing starvation therapy. In the acidic TME, the Zn-Co3O4/NC-GOx rapidly caused intracellular Zn2+ pool overload and disrupted cellular homeostasis for ion-intervention therapy. Additionally, the Zn-Co3O4/NC exhibited glutathione peroxidase-like activity, which consumed glutathione in tumor cells and reduced the ROS consumption for ferroptosis. The tumor treatments offer some constructive insights into the nanozyme-mediated catalytic medicine, coupled by avoiding the TME limitations.


Asunto(s)
Cobalto , Peróxido de Hidrógeno , Neoplasias , Óxidos , Humanos , Porosidad , Especies Reactivas de Oxígeno , Glucosa Oxidasa , Imidazoles , Carbono , Glutatión , Zinc , Neoplasias/tratamiento farmacológico , Línea Celular Tumoral , Microambiente Tumoral
3.
FASEB J ; 37(12): e23269, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37889852

RESUMEN

Viruses deploy multiple strategies to suppress the host innate immune response to facilitate viral replication and pathogenesis. Typical G3BP1+ stress granules (SGs) are usually formed in host cells after virus infection to restrain viral translation and to stimulate innate immunity. Thus, viruses have evolved various mechanisms to inhibit SGs or to repurpose SG components such as G3BP1. Previous studies showed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection inhibited host immunity during the early stage of COVID-19. However, the precise mechanism is not yet well understood. Here we showed that the SARS-CoV-2 nucleocapsid (SARS2-N) protein suppressed the double-stranded RNA (dsRNA)-induced innate immune response, concomitant with inhibition of SGs and the induction of atypical SARS2-N+ /G3BP1+ foci (N+ foci). The SARS2-N protein-induced formation of N+ foci was dependent on the ability of its ITFG motif to hijack G3BP1, which contributed to suppress the innate immune response. Importantly, SARS2-N protein facilitated viral replication by inducing the formation of N+ foci. Viral mutations within SARS2-N protein that impair the formation of N+ foci are associated with the inability of the SARS2-N protein to suppress the immune response. Taken together, our study has revealed a novel mechanism by which SARS-CoV-2 suppresses the innate immune response via induction of atypical N+ foci. We think that this is a critical strategy for viral pathogenesis and has potential therapeutic implications.


Asunto(s)
COVID-19 , ADN Helicasas , Humanos , SARS-CoV-2/metabolismo , ARN Helicasas/metabolismo , Proteínas de Unión a Poli-ADP-Ribosa , Gránulos de Estrés , Proteínas con Motivos de Reconocimiento de ARN/metabolismo , Inmunidad Innata , Replicación Viral , Proteínas de la Nucleocápside/metabolismo
4.
J Med Virol ; 95(9): e29065, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37661566

RESUMEN

Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus that causes adult T-cell leukemia/lymphoma (ATL). HTLV-1 encodes Tax protein that activates transcription from viral long terminal repeats (LTR). Multiple cofactors are involved in the regulation of HTLV-1 transcription via association with Tax. Yes-associated protein (YAP), which is the key effector of Hippo pathway, is elevated and activated in ATL cells. In this study, we reported that YAP protein suppressed Tax activation of HTLV-1 5' LTR but not 3' LTR. The activation of the 5' LTR by Tax was potentiated when YAP was depleted. Moreover, overexpression of YAP repressed HTLV-1 plus-strand viral gene expression and virion production, whereas compromising YAP by RNA inference augmented the expression of HTLV-1 protein. As mechanisms of YAP-mediated viral transcription inhibition, we found that YAP interacted with Tax, and prevented the association between Tax and p300. It finally led to the inhibition of recruitment of Tax to the Tax-responsive element in the 5' LTR of HTLV-1. Taken together, our results demonstrate the negative regulatory function of YAP in Tax activation of HTLV-1 transcription. It may achieve sufficient transcriptional repression to maintain persistent infection and long-term latency of HTLV-1 in the host cells.


Asunto(s)
Virus Linfotrópico T Tipo 1 Humano , Leucemia de Células T , Adulto , Humanos , Virus Linfotrópico T Tipo 1 Humano/genética , Expresión Génica , Infección Persistente , ARN
5.
Am J Transl Res ; 15(8): 5425-5445, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37692951

RESUMEN

BACKGROUND: The prognostic assessment and therapeutic interventions of esophageal cancer (ESCA) require novel molecular targets. The prognostic value of necroptosis, a specific mode of programmed cell death strongly linked to cancer progression, remains largely unexplored in ESCA. The primary goal of this research is to develop a necroptosis-based prognostic signature, which will represent the microenvironmental characteristics and prognosis of individuals diagnosed with ESCA. METHODS: Transcriptome data of ESCA samples from The Cancer Genome Atlas were utilized to screen for necroptosis-related long non-coding RNAs (NR-lncRNAs) and genes (NRGs). The research employed the least absolute shrinkage and selection operator (LASSO) regression and univariate Cox regression analysis to identify prognostic candidates. Based on these analyses, a signature was developed in the training set and subsequently verified in the testing and entire sets. A clinicopathologic relevance assessment was carried out, after which a nomogram was established. The features of the immune microenvironment, functional pathways, mutational burden, checkpoint expression, and stemness of tumors were analyzed. Moreover, the sensitivity of individuals to immunotherapy and chemotherapy was compared for therapeutic guidance. RESULTS: A necroptosis-associated signature comprising two genes and eleven lncRNAs was constructed. High-risk patients showed worse prognosis and clinicopathologic features, with more tumor-infiltrating naïve B cells, CD4+ memory resting T cells, and regulatory T cells. Furthermore, stromal and ESTIMATE scores were decreased along with increased stemness scores and tumor mutational burden in high-risk individuals. For the quantitative prediction of the outcomes of individuals, a nomogram was established. High-risk individuals showed greater sensitivity to immunotherapy while low-risk individuals benefited more from conventional chemotherapeutic or targeted therapy. CONCLUSION: A necroptosis-related prognostic signature was developed to study the tumor microenvironment, mutational burden, clinical features, and the treatment response of ESCA patients. This may contribute to precision medicine for ESCA.

6.
Biomater Adv ; 154: 213618, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37725871

RESUMEN

Recently, nanozymes show increasing biological applications and promising possibilities for therapeutic intervention, while their mediated therapeutic outcomes are severely compromised due to their insufficient catalytic activity and specificity. Herein, ternary FeCoMn single atoms were incorporated into N-doped hollow mesoporous carbon nanospheres by in situ confinement pyrolysis at 800 °C as high-efficiency nanozyme. The confinement strategy endows the as-prepared nanozyme with the enhanced catalase- and oxidase-like activities. Specifically, the FeCoMn TSAs/N-HCSs nanozyme can decompose intracellular H2O2 to generate O2 and subsequently convert O2 to cytotoxic superoxide radicals (O2∙-), which can initiate cascade enzymatic reactions in tumor microenvironment (TME) for chemodynamic therapy (CDT). Moreover, the cancer therapy was largely enhanced by loading with doxorubicin (DOX). Impressively, the FeCoMn TSAs/N-HCSs nanozyme-mediated CDT and the DOX-induced chemotherapy endow the DOX@FeCoMn TSAs/N-HCSs with effective tumor inhibition, showing the superior therapeutic efficacy.


Asunto(s)
Nanosferas , Neoplasias , Peróxido de Hidrógeno , Benzopiranos , Carbono , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Neoplasias/tratamiento farmacológico
7.
Front Hum Neurosci ; 17: 1197613, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37457501

RESUMEN

Introduction: Major Depressive Disorder (MDD) is a leading cause of worldwide disability, and standard clinical treatments have limitations due to the absence of neurological evidence. Electroencephalography (EEG) monitoring is an effective method for recording neural activities and can provide electroneurophysiological evidence of MDD. Methods: In this work, we proposed a probabilistic graphical model for neural dynamics decoding on MDD patients and healthy controls (HC), utilizing the Hidden Markov Model with Multivariate Autoregressive observation (HMM-MAR). We testified the model on the MODMA dataset, which contains resting-state and task-state EEG data from 53 participants, including 24 individuals with MDD and 29 HC. Results: The experimental results suggest that the state time courses generated by the proposed model could regress the Patient Health Questionnaire-9 (PHQ-9) score of the participants and reveal differences between the MDD and HC groups. Meanwhile, the Markov property was observed in the neuronal dynamics of participants presented with sad face stimuli. Coherence analysis and power spectrum estimation demonstrate consistent results with the previous studies on MDD. Discussion: In conclusion, the proposed HMM-MAR model has revealed its potential capability to capture the neuronal dynamics from EEG signals and interpret brain disease pathogenesis from the perspective of state transition. Compared with the previous machine-learning or deep-learning-based studies, which regarded the decoding model as a black box, this work has its superiority in the spatiotemporal pattern interpretability by utilizing the Hidden Markov Model.

8.
Zhongguo Gu Shang ; 36(7): 628-34, 2023 Jul 25.
Artículo en Chino | MEDLINE | ID: mdl-37475626

RESUMEN

OBJECTIVE: To investigate the effect of different postures on direct anterior approach(DAA) total hip arthroplasty. METHODS: Total of 94 patients who underwent DAA total hip arthroplasty from July 2016 to June 2020 were retrospectively analyzed. They were divided into two groups according to different positions during the operation, including 45 cases in lateral position and 49 cases in supine position (with the aid of stent). The general data such as gender, affected limb, body mass index(BMI), incision length, operation time, intraoperative bleeding volume, drainage volume 24 hours after operation, hemoglobin difference before and after operation, first landing time after operation, postoperative hospitalization time, postoperative complications, visual analogue scale(VAS) at 1 day, 1, 2 weeks, 1, 3 and 6 months after operation, Harris score at 1, 2 weeks, 1, 3 and 6 months after operation were observed and compared between the two groups. RESULTS: Patients in both groups were followed up for 6 to 12 months with an average of (8.31±2.22) months. There was no significant difference between two groups in gender, affected limb, age, height, weight, body mass index(BMI), preoperative VAS score and preoperative Harris score(P>0.05). The incision length, operation time, intraoperative bleeding volume, 24-hour drainage volume, hemoglobin difference before and after operation, first time to the ground and postoperative hospitalization time of patients in supine position (assisted by stent) group were all better than those in lateral position group(P<0.05);There was no significant difference in the number of blood transfusions during and after operation(P=0.550). There was no significant difference in anteversion angle and abduction angle in the supine position(with the aid of stent) group during and after operation (P=0.825, P=0.066);There was significant difference in anteversion angle and abduction angle in the lateral position group during and after operation(P<0.05). VAS of patients in supine position (assisted by stent) group were lower than those in lateral position group at 1 day, 1, 2 weeks and 1 month after operation(P<0.05), and there was no statistical difference between two groups at 3 and 6 months after operation(P>0.05). Harris scores of patients in supine position(assisted by stent) group were higher than those in lateral position group at 1 week, 1 month and 3 months after operation(P<0.05), and there was no significant difference between two groups at 6 months after operation(P>0.05). CONCLUSION: Compared with the lateral position, the supine position DAA total hip arthroplasty has the advantages of small incision, short operation time, less bleeding, early landing time, short hospitalization time, and small intraoperative acetabular cup position judgment error. It has the advantage of fast postoperative recovery, but the recovery of hip joint function is the same after 6 months.


Asunto(s)
Artroplastia de Reemplazo de Cadera , Humanos , Estudios Retrospectivos , Resultado del Tratamiento , Postura
9.
Biosens Bioelectron ; 236: 115405, 2023 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-37267689

RESUMEN

Nowadays, synthesis of novel organic photosensitizer is imperative but challenging for photoelectrochemical (PEC) assay in analytical and biomedical fields. In this work, the PEC responses enhanced about 4.3 folds after in situ electrostatic assembly of 1-butyl-3-methylimidazole tetrafluoroborate ([BIm][BF4]) on meso-tetra (4-carboxyphenyl) porphine (TP), which was first covalently linked with NH2 modified indium tin oxide electrode ([BIm]+--TP-NH2-ITO). Moreover, the [BIm]+--TP-NH2-ITO showed a much larger photocurrent in a water/dimethyl sulfoxide (DMSO) binary solvent with a water fraction (fw) of 90%, which displayed 6.7-fold increase over that in pure DMSO, coupled by discussing the PEC enhanced mechanism in detail. Then, the PEC signals were sharply quenched via a competitive reaction between magnetic bead linked dsDNA (i.e., initial hybridization of aptamer DNA with linking DNA) and HCT-116 cells (closely associated with CRC), where the liberated L-DNA stripped the [BIm]+ from [BIm]+--TP-NH2-ITO. The PEC detection strategy exhibited a wider linear range (30 ∼ 3 × 105 cells mL-1) and a lower limit of detection (6 cells mL-1), achieving single-cell bioanalysis even in diluted human serum sample. The in situ assembly strategy offers a valuable biosensing platform to amplify the PEC signals with advanced organic photosensitizer for early diagnosis of tumors.


Asunto(s)
Técnicas Biosensibles , Porfirinas , Humanos , Fármacos Fotosensibilizantes/farmacología , Electricidad Estática , Dimetilsulfóxido , Células HCT116 , ADN , Agua
10.
Molecules ; 28(7)2023 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-37049786

RESUMEN

3C proteases (3Cpros) of picornaviruses and 3C-like proteases (3CLpros) of coronaviruses and caliciviruses represent a group of structurally and functionally related viral proteases that play pleiotropic roles in supporting the viral life cycle and subverting host antiviral responses. The design and screening for 3C/3CLpro inhibitors may contribute to the development broad-spectrum antiviral therapeutics against viral diseases related to these three families. However, current screening strategies cannot simultaneously assess a compound's cytotoxicity and its impact on enzymatic activity and protease-mediated physiological processes. The viral induction of stress granules (SGs) in host cells acts as an important antiviral stress response by blocking viral translation and stimulating the host immune response. Most of these viruses have evolved 3C/3CLpro-mediated cleavage of SG core protein G3BP1 to counteract SG formation and disrupt the host defense. Yet, there are no SG-based strategies screening for 3C/3CLpro inhibitors. Here, we developed a fluorescence resonance energy transfer (FRET) and SG dual-based system to screen for 3C/3CLpro inhibitors in living cells. We took advantage of FRET to evaluate the protease activity of poliovirus (PV) 3Cpro and live-monitor cellular SG dynamics to cross-verify its effect on the host antiviral response. Our drug screen uncovered a novel role of Telaprevir and Trifluridine as inhibitors of PV 3Cpro. Moreover, Telaprevir and Trifluridine also modulated 3Cpro-mediated physiological processes, including the cleavage of host proteins, inhibition of the innate immune response, and consequent facilitation of viral replication. Taken together, the FRET and SG dual-based system exhibits a promising potential in the screening for inhibitors of viral proteases that cleave G3BP1.


Asunto(s)
Transferencia Resonante de Energía de Fluorescencia , Inhibidores de Proteasa Viral , Humanos , ADN Helicasas/metabolismo , Trifluridina , Gránulos de Estrés , Proteínas Virales/metabolismo , ARN Helicasas/metabolismo , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , Proteínas con Motivos de Reconocimiento de ARN/metabolismo , Antivirales/farmacología , Inhibidores de Proteasas/farmacología
11.
Bioelectrochemistry ; 152: 108442, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37060704

RESUMEN

Breast cancer is the most common malignant tumor in women, which seriously threatens the life and health of patients. Therefore, facile and sensitive detection of human breast cancer cells is crucial for cancer diagnosis. In this work, plum-branched CdS/Bi2S3 heterostructures (CdS/Bi2S3 HSs) were synthesized under hydrothermal condition, whose photoelectrochemical (PEC) property and biocompatibility were scrutinously investigated. In parallel, a signal amplification strategy was designed based on immune recognition between epidermal growth factor receptor (EGFR) overexpressed on membrane of breast cancer cells MDA-MB-231 and its aptamer. Integration of the above together, a highly sensitive PEC cytosensor was developed for analysis of target MDA-MB-231 cells, exhibiting a wider linear range of 1 × 102 âˆ¼ 3 × 105 cells mL-1 with a limit of detection (LOD) down to 6 cells mL-1 (S/N = 3). Further, the biosensor was explored for anticancer drug (e.g., dacomitinib) screening by monitoring the variations in the PEC signals of the expressed EGFR upon drug stimulation. The obtained CdS/Bi2S3 HSs are identified as promising and feasible photoactive material for determination of cancer cells and drug screening in clinic and related research.


Asunto(s)
Técnicas Biosensibles , Neoplasias de la Mama , Prunus domestica , Humanos , Femenino , Técnicas Electroquímicas , Detección Precoz del Cáncer , Neoplasias de la Mama/diagnóstico , Límite de Detección , Receptores ErbB
12.
Peptides ; 158: 170895, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36240981

RESUMEN

Hyperglycemia remission by metabolic surgery is implicated in the resolution of low-grade inflammation in type 2 diabetes mellitus (T2DM). However, whether this beneficial effect of metabolic surgery is related to improving monocyte inflammatory response remains undefined. This investigation is addressed to evaluate this relationship. For this purpose, T2DM rats were subjected to Roux-en-Y gastric bypass (RYGB) and/or monocyte depletion or splenic sympathetic denervation. Fasting blood glucose (FBG), plasma tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß) were measured, and monocyte inflammatory response was assessed in vitro. The data showed that RYGB significantly reduced lipopolysaccharide (LPS)-induced release of TNF-α and IL-1ß from peripheral monocytes while alleviating hyperglycemia and reducing plasma TNF-α and IL-1ß levels. Hyperglycemia resulting from monocyte depletion by injection of clodronate liposomes resolved one week earlier than vehicle control after RYGB. Splenic denervation abrogated the glucose-lowering effect and decreased LPS-stimulated TNF-α and IL-1ß release from monocytes following RYGB. Overall, our results reveal that a marked reduction of monocyte inflammatory response after RYGB contributes to hyperglycemia remission in T2DM rats. The beneficial effect of RYGB is mediated through vagal-spleen axis anti-inflammatory activity.


Asunto(s)
Diabetes Mellitus Tipo 2 , Derivación Gástrica , Hiperglucemia , Ratas , Animales , Derivación Gástrica/métodos , Diabetes Mellitus Tipo 2/metabolismo , Monocitos/metabolismo , Lipopolisacáridos , Factor de Necrosis Tumoral alfa , Glucemia/metabolismo
13.
J Am Chem Soc ; 144(38): 17457-17467, 2022 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-36102877

RESUMEN

Here, we report the synthesis of two-dimensional (2D) layered metal-organic framework (MOF) nanoparticle (NP) superstructures via an ice-templating strategy. MOF NP monolayers and bilayers can be obtained by regulating the concentration of colloidal MOF NPs without any external fields during self-assembly. Adjacent polyhedral MOF NPs are packed and aligned through crystalline facets, resulting in the formation of a quasi-ordered array superstructure. The morphology of the MOF layers is well preserved when subjected to pyrolysis, and the obtained carbon NPs have hollow interiors driven by the outward contraction of MOF precursors during pyrolysis. With the advantages of large surface areas, hierarchical porosity, high exposure of active sites, and fast electron transport of the 2D layered structure, the mono- and bilayered carbon NP superstructures show better oxygen reduction activity than isolated carbon particles in alkaline media. Our work demonstrates that ice-templating is a powerful strategy to fabricate superstructures of various MOFs and their derivatives.

14.
Transl Cancer Res ; 11(7): 2449-2456, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-35966317

RESUMEN

Background: Lymphangioleiomyomatosis (LAM) is a rare low-grade malignant tumor featured with diffuse cystic changes due to the destructive proliferation of LAM cells, closely related to angiomyolipoma (AML). Here, we reported a rare case of pulmonary LAM coexisting with AMLs in multiple sites of the lung, liver, kidney, and retroperitoneum. We aimed to contribute to the body of knowledge regarding the diagnosis, identification and treatment of such cases. Case Description: A 48-year-old female with no symptoms underwent a chest computed tomography (CT) scan that showed diffuse thin-walled cysts and multiple solid nodules in the lungs. She received a right nephrectomy due to right kidney AML 30 years previously. The pathological manifestations of the right lower lung mass removed by thoracoscopic surgery was a multifocal AML with mutations in the tuberous sclerosis complex gene. Abdominal magnetic resonance imaging (MRI) reveals a vast area of fat signal shadow behind the peritoneum and multiple scattered fatty signal nodules in the liver parenchyma. No other treatment was given due to personal factors of the patient, and there was no significant change at the 1-year follow-up. Conclusions: LAM and AML are two different but substantively related rare neoplastic diseases. When typical LAM imaging features are found on chest CT or in pathological specimens collected from patients diagnosed with AML, multisystem screening should be performed for the early detection and diagnosis of LAM.

15.
Nucleic Acids Res ; 50(15): 8441-8458, 2022 08 26.
Artículo en Inglés | MEDLINE | ID: mdl-35947648

RESUMEN

Defining the impact of missense mutations on the recognition of DNA motifs is highly dependent on bioinformatic tools that define DNA binding elements. However, classical motif analysis tools remain limited in their capacity to identify subtle changes in complex binding motifs between distinct conditions. To overcome this limitation, we developed a new tool, MoMotif, that facilitates a sensitive identification, at the single base-pair resolution, of complex, or subtle, alterations to core binding motifs, discerned from ChIP-seq data. We employed MoMotif to define the previously uncharacterized recognition motif of CTCF zinc-finger 1 (ZF1), and to further define the impact of CTCF ZF1 mutation on its association with chromatin. Mutations of CTCF ZF1 are exclusive to breast cancer and are associated with metastasis and therapeutic resistance, but the underlying mechanisms are unclear. Using MoMotif, we identified an extension of the CTCF core binding motif, necessitating a functional ZF1 to bind appropriately. Using a combination of ChIP-Seq and RNA-Seq, we discover that the inability to bind this extended motif drives an altered transcriptional program associated with the oncogenic phenotypes observed clinically. Our study demonstrates that MoMotif is a powerful new tool for comparative ChIP-seq analysis and characterising DNA-protein contacts.


Asunto(s)
Cromatina , Zinc , Factor de Unión a CCCTC/genética , Factor de Unión a CCCTC/metabolismo , Zinc/metabolismo , Cromatina/genética , ADN/química , Mutación , Sitios de Unión
16.
Proc Natl Acad Sci U S A ; 119(36): e2203452119, 2022 09 06.
Artículo en Inglés | MEDLINE | ID: mdl-36037342

RESUMEN

The contribution of deregulated chromatin architecture, including topologically associated domains (TADs), to cancer progression remains ambiguous. CCCTC-binding factor (CTCF) is a central regulator of higher-order chromatin structure that undergoes copy number loss in over half of all breast cancers, but the impact of this defect on epigenetic programming and chromatin architecture remains unclear. We find that under physiological conditions, CTCF organizes subTADs to limit the expression of oncogenic pathways, including phosphatidylinositol 3-kinase (PI3K) and cell adhesion networks. Loss of a single CTCF allele potentiates cell invasion through compromised chromatin insulation and a reorganization of chromatin architecture and histone programming that facilitates de novo promoter-enhancer contacts. However, this change in the higher-order chromatin landscape leads to a vulnerability to inhibitors of mTOR. These data support a model whereby subTAD reorganization drives both modification of histones at de novo enhancer-promoter contacts and transcriptional up-regulation of oncogenic transcriptional networks.


Asunto(s)
Ensamble y Desensamble de Cromatina , Regulación Neoplásica de la Expresión Génica , Invasividad Neoplásica , Factor de Unión a CCCTC/metabolismo , Carcinogénesis/genética , Cromatina/genética , Cromatina/metabolismo , Humanos , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Regiones Promotoras Genéticas
17.
Anal Chem ; 94(35): 12240-12247, 2022 09 06.
Artículo en Inglés | MEDLINE | ID: mdl-35994715

RESUMEN

Hepatocellular carcinoma is a life-threatening malignant tumor found around the world for its high morbidity and mortality. Therefore, it is of great importance for sensitive analysis of liver cancer cells (HepG2 cells) in clinical diagnosis and biomedical research. To fulfill this demand, hollow CdIn2S4/In2S3 heterostructured microspheres (termed CdIn2S4/In2S3 for clarity) were prepared by a two-step hydrothermal strategy and applied for building a novel photoelectrochemical (PEC) cytosensor for ultrasensitive and accurate detection of HepG2 cells through specific recognition of CD133 protein on the cell surface with the respective aptamer. The optical properties of CdIn2S4/In2S3 were investigated by UV-vis diffuse reflectance spectroscopy (DRS) and PEC technology. By virtue of their appealing PEC characteristics, the resultant PEC sensor exhibited a wider dynamic linear range from 1 × 102 to 2 × 105 cells mL-1 with a lower limit of detection (LOD, 23 cells mL-1), combined by evaluating the expression level of CD133 protein stimulated by metformin as a benchmarked inhibitor. This work opens a valuable and feasible avenue for sensitive detection of diverse tumor cells, holding great potential in early clinical diagnosis and treatment coupled by screening inhibitors.


Asunto(s)
Técnicas Biosensibles , Técnicas Electroquímicas , Técnicas Electroquímicas/métodos , Células Hep G2 , Humanos , Microesferas
18.
Sensors (Basel) ; 22(14)2022 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-35890834

RESUMEN

Photoplethysmography is a widely used technique to noninvasively assess heart rate, blood pressure, and oxygen saturation. This technique has considerable potential for further applications-for example, in the field of physiological and mental health monitoring. However, advanced applications of photoplethysmography have been hampered by the lack of accurate and reliable methods to analyze the characteristics of the complex nonlinear dynamics of photoplethysmograms. Methods of nonlinear time series analysis may be used to estimate the dynamical characteristics of the photoplethysmogram, but they are highly influenced by the length of the time series, which is often limited in practical photoplethysmography applications. The aim of this study was to evaluate the error in the estimation of the dynamical characteristics of the photoplethysmogram associated with the limited length of the time series. The dynamical properties were evaluated using recurrence quantification analysis, and the estimation error was computed as a function of the length of the time series. Results demonstrated that properties such as determinism and entropy can be estimated with an error lower than 1% even for short photoplethysmogram recordings. Additionally, the lower limit for the time series length to estimate the average prediction time was computed.


Asunto(s)
Fotopletismografía , Procesamiento de Señales Asistido por Computador , Algoritmos , Presión Sanguínea/fisiología , Frecuencia Cardíaca/fisiología , Fotopletismografía/métodos
19.
Sci Rep ; 12(1): 9820, 2022 06 14.
Artículo en Inglés | MEDLINE | ID: mdl-35701500

RESUMEN

Detecting changes is an important issue for ophthalmology to compare longitudinal fundus images at different stages and obtain change regions. Illumination variations bring distractions on the change regions by the pixel-by-pixel comparison. In this paper, a new unsupervised change detection method based on sparse representation classification (SRC) is proposed for the fundus image pair. First, the local neighborhood patches are extracted from the reference image to build a dictionary of the local background. Then the current image patch is represented sparsely and its background is reconstructed by the obtained dictionary. Finally, change regions are given through background subtracting. The SRC method can correct automatically illumination variations through the representation coefficients and filter local contrast and global intensity effectively. In experiments of this paper, the AUC and mAP values of SRC method are 0.9858 and 0.8647 respectively for the image pair with small lesions; the AUC and mAP values of the fusion method of IRHSF and SRC are 0.9892 and 0.9692 separately for the image pair with the big change region. Experiments show that the proposed method in this paper is more robust than RPCA for the illumination variations and can detect change regions more effectively than pixel-wised image differencing.


Asunto(s)
Algoritmos , Interpretación de Imagen Asistida por Computador , Interpretación de Imagen Asistida por Computador/métodos
20.
Eur Surg Res ; 63(4): 294-301, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35605582

RESUMEN

Esophagogastric anastomosis stricture is one of the most common postoperative complications after esophagectomy; yet, its pathogenesis is still not fully understood, and the treatment and prevention of anastomotic stricture are limited due to the lack of a proper animal model. The insufficient blood supply in the gastric tube is considered a risk factor for postoperative anastomotic strictures. In this study, we used thermal imaging to develop a stable rodent model with esophagogastric anastomotic stricture caused by ischemia. Briefly, 30 male Sprague-Dawley rats have been divided into the control group and the ischemia group. The esophagogastric ischemia anastomosis was performed with the help of intraoperative thermal imaging to identify the poor perfusion area. An unpaired t test with Welch's correction was used to analyze the difference between the two groups. On postoperative day 84, in the control group, no anastomosis stricture was observed, while in the ischemia group, 12 out of 15 animals (80%) developed obvious anastomosis stricture which could not let a 2.7-mm endoscope pass through. The diameter of the anastomosis in the control group and the ischemia group were 2.80 ± 0.15 mm and 1.73 ± 0.44 mm (p < 0.01), respectively (evaluated by endoscopy examination and barium radiography). H&E stain and Masson's trichrome showed that the anastomosis in the ischemia group had more connective tissue hyperplasia and collagen deposition than control group. Thus, this new rat model can be used as a platform to further investigate the potential interventions for prevention of esophagogastric anastomotic stricture.


Asunto(s)
Neoplasias Esofágicas , Masculino , Ratas , Animales , Constricción Patológica/complicaciones , Constricción Patológica/cirugía , Neoplasias Esofágicas/cirugía , Ratas Sprague-Dawley , Esofagectomía/efectos adversos , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/prevención & control , Anastomosis Quirúrgica/efectos adversos , Anastomosis Quirúrgica/métodos , Isquemia/etiología , Fuga Anastomótica/etiología , Fuga Anastomótica/prevención & control
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