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1.
Am J Hum Genet ; 111(7): 1370-1382, 2024 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-38917801

RESUMEN

Extra-axial cavernous hemangiomas (ECHs) are complex vascular lesions mainly found in the spine and cavernous sinus. Their removal poses significant risk due to their vascularity and diffuse nature, and their genetic underpinnings remain incompletely understood. Our approach involved genetic analyses on 31 tissue samples of ECHs employing whole-exome sequencing and targeted deep sequencing. We explored downstream signaling pathways, gene expression changes, and resultant phenotypic shifts induced by these mutations, both in vitro and in vivo. In our cohort, 77.4% of samples had somatic missense variants in GNA14, GNAQ, or GJA4. Transcriptomic analysis highlighted significant pathway upregulation, with the GNAQ c.626A>G (p.Gln209Arg) mutation elevating PI3K-AKT-mTOR and angiogenesis-related pathways, while GNA14 c.614A>T (p.Gln205Leu) mutation led to MAPK and angiogenesis-related pathway upregulation. Using a mouse xenograft model, we observed enlarged vessels from these mutations. Additionally, we initiated rapamycin treatment in a 14-year-old individual harboring the GNAQ c.626A>G (p.Gln209Arg) variant, resulting in gradual regression of cutaneous cavernous hemangiomas and improved motor strength, with minimal side effects. Understanding these mutations and their pathways provides a foundation for developing therapies for ECHs resistant to current therapies. Indeed, the administration of rapamycin in an individual within this study highlights the promise of targeted treatments in treating these complex lesions.


Asunto(s)
Subunidades alfa de la Proteína de Unión al GTP Gq-G11 , Subunidades alfa de la Proteína de Unión al GTP , Humanos , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/genética , Animales , Ratones , Femenino , Masculino , Subunidades alfa de la Proteína de Unión al GTP/genética , Mutación , Adulto , Persona de Mediana Edad , Transducción de Señal , Hemangioma Cavernoso/genética , Hemangioma Cavernoso/patología , Adolescente , Secuenciación del Exoma , Sirolimus/farmacología , Sirolimus/uso terapéutico , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/genética
2.
Int J Biol Markers ; : 3936155241261390, 2024 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-38881381

RESUMEN

PURPOSE: Gastric cancer is the most common malignancy worldwide and is the third leading cause of cancer-related deaths, urgently requiring an early and non-invasive diagnosis. Circulating extracellular vesicles may emerge as promising biomarkers for the rapid diagnosis in a non-invasive manner. METHODS: Using high-throughput small RNA sequencing, we profiled the small RNA population of serum-derived extracellular vesicles from healthy controls and gastric cancer patients. Differentially expressed microRNAs (miRNAs) were randomly selected and validated by reverse transcription-quantitative real-time polymerase chain reaction. Receiver operating characteristic curves were employed to assess the predictive value of miRNAs for gastric cancer. RESULTS: In this study, 193 differentially expressed miRNAs were identified, of which 152 were upregulated and 41 were significantly downregulated. Among the differently expressed miRNA, the expression levels of miR-21-5p, miR-26a-5p, and miR-27a-3p were significantly elevated in serum-derived extracellular vesicles of gastric cancer patients. The miR-21-5p and miR-27a-3p were closely correlated with the tumor size. Moreover, the expression levels of serum miR-21-5p and miR-26a-5p were significantly decreased in gastric cancer patients after surgery. CONCLUSIONS: The present study discovered the potential of serum miR-21-5p and miR-26a-5p as promising candidates for the diagnostic and prognostic markers of gastric cancer.

3.
Angew Chem Int Ed Engl ; : e202407752, 2024 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-38844430

RESUMEN

Inherently chiral calix[4]arenes are an excellent structural scaffold for enantioselective synthesis, chiral recognition, sensing, and circularly polarized luminescence. However, their catalytic enantioselective synthesis remains challenging. Herein, we report an efficient synthesis of inherently chiral calix[4]arene derivatives via cascade enantioselective cyclization and oxidation reactions. The three-component reaction features a broad substrate scope (33 examples), high efficiency (up to 90 % yield), and excellent enantioselectivity (>95 % ee on average). The potential applications of calix[4]arene derivatives are highlighted by their synthetic transformation and a detailed investigation of their photophysical and chiroptical properties.

4.
Angiogenesis ; 2024 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-38700584

RESUMEN

Current treatments of brain arteriovenous malformation (BAVM) are associated with considerable risks and at times incomplete efficacy. Therefore, a clinically consistent animal model of BAVM is urgently needed to investigate its underlying biological mechanisms and develop innovative treatment strategies. Notably, existing mouse models have limited utility due to heterogenous and untypical phenotypes of AVM lesions. Here we developed a novel mouse model of sporadic BAVM that is consistent with clinical manifestations in humans. Mice with BrafV600E mutations in brain ECs developed BAVM closely resembled that of human lesions. This strategy successfully induced BAVMs in mice across different age groups and within various brain regions. Pathological features of BAVM were primarily dilated blood vessels with reduced vascular wall stability, accompanied by spontaneous hemorrhage and neuroinflammation. Single-cell sequencing revealed differentially expressed genes that were related to the cytoskeleton, cell motility, and intercellular junctions. Early administration of Dabrafenib was found to be effective in slowing the progression of BAVMs; however, its efficacy in treating established BAVM lesions remained uncertain. Taken together, our proposed approach successfully induced BAVM that closely resembled human BAVM lesions in mice, rendering the model suitable for investigating the pathogenesis of BAVM and assessing potential therapeutic strategies.

5.
Micromachines (Basel) ; 15(5)2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38793192

RESUMEN

Separating plasma or serum from blood is essential for precise testing. However, extracting precise plasma quantities outside the laboratory poses challenges. A recent study has introduced a capillary force-driven membrane filtration technique to accurately separate small plasma volumes. This method efficiently isolates 100-200 µL of pure human whole blood with a 48% hematocrit, resulting in 5-30 µL of plasma with less than a 10% margin of error. The entire process is completed within 20 min, offering a simple and cost-effective approach to blood separation. This study has successfully addressed the bottleneck in self-service POCT, ensuring testing accuracy. This innovative method shows promise for clinical diagnostics and point-of-care testing.

6.
Nat Commun ; 15(1): 4407, 2024 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-38782885

RESUMEN

Topological flat bands - where the kinetic energy of electrons is quenched - provide a platform for investigating the topological properties of correlated systems. Here, we report the observation of a topological flat band formed by polar-distortion-assisted Rashba splitting in the three-dimensional Dirac material ZrTe5. The polar distortion and resulting Rashba splitting on the band are directly detected by torque magnetometry and the anomalous Hall effect, respectively. The local symmetry breaking further flattens the band, on which we observe resistance oscillations beyond the quantum limit. These oscillations follow the temperature dependence of the Lifshitz-Kosevich formula but are evenly distributed in B instead of 1/B at high magnetic fields. Furthermore, the cyclotron mass gets anomalously enhanced about 102 times at fields ~ 20 T. Our results provide an intrinsic platform without invoking moiré or order-stacking engineering, which opens the door for studying topologically correlated phenomena beyond two dimensions.

7.
Anal Methods ; 16(21): 3392-3412, 2024 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-38752456

RESUMEN

Cocculus orbiculatus (L.) DC. (C. orbiculatus) is a medicinal herb valued for its dried roots with anti-inflammatory, analgesic, diuretic, and other therapeutic properties. Despite its traditional applications, chemical investigations into C. orbiculatus remain limited, focusing predominantly on alkaloids and flavonoids. Furthermore, the therapeutic use of C. orbiculatus predominantly focuses on the roots, leaving the stems, a significant portion of the plant, underutilized. This study employed ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS/MS) with in-house and online databases for comprehensive identification of components in various plant parts. Subsequently, untargeted metabolomics was employed to analyze differences in components across different harvest periods and plant sections of C. orbiculatus, aiming to screen for distinct components in different parts of the plant. Finally, metabolomic analysis of the roots and stems, which contribute significantly to the plant's weight, was conducted using chemometrics, including principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), orthogonal partial least squares discriminant analysis (OPLS-DA), and heatmaps. A total of 113 components, including alkaloids, flavonoids, and organic acids, were annotated across the root, stem, leaf, flower, and fruit, along with numerous previously unreported compounds. Metabolomic analyses revealed substantial differences in components between the root and stem compared to the leaf, flower, and fruit during the same harvest period. PLS-DA and OPLS-DA annotated 10 differentiating components (VIP > 1.5, P < 0.05, FC > 2 or FC < 0.67), with 5 unique to the root and stem, exhibiting lower mass spectrometric responses. This study provided the first characterization of 113 chemical constituents in different parts of C. orbiculatus, laying the groundwork for pharmacological research and advocating for the enhanced utilization of its stem.


Asunto(s)
Metabolómica , Raíces de Plantas , Espectrometría de Masas en Tándem , Cromatografía Líquida de Alta Presión/métodos , Espectrometría de Masas en Tándem/métodos , Metabolómica/métodos , Raíces de Plantas/química , Flavonoides/análisis , Alcaloides/análisis , Alcaloides/química , Tallos de la Planta/química , Extractos Vegetales/química , Análisis de Componente Principal
8.
World J Gastrointest Oncol ; 16(5): 1796-1807, 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38764818

RESUMEN

BACKGROUND: Rectal carcinoma (RC), one of the most common malignancies globally, presents an increasing incidence and mortality year by year, especially among young people, which seriously affects the prognosis and quality of life of patients. At present, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters and serum carbohydrate antigen 19-9 (CA19-9) and CA125 Levels have been used in clinical practice to evaluate the T stage and differentiation of RC. However, the accuracy of these evaluation modalities still needs further research. This study explores the application and value of these methods in evaluating the T stage and differentiation degree of RC. AIM: To analyze the diagnostic performance of DCE-MRI parameters combined with serum tumor markers (TMs) in assessing pathological processes and prognosis of RC patients. METHODS: A retrospective analysis was performed on 104 RC patients treated at Yantai Yuhuangding Hospital from May 2018 to January 2022. Patients were categorized into stages T1, T2, T3, and T4, depending on their T stage and differentiation degree. In addition, they were assigned to low (L group) and moderate-high differentiation (M + H group) groups based on their differentiation degree. The levels of DCE-MRI parameters and serum CA19-9 and CA125 in different groups of patients were compared. In addition, the value of DCE-MRI parameters [volume transfer constant (Ktrans), rate constant (Kep), and extravascular extracellular volume fraction (Ve) in assessing the differentiation and T staging of RC patients was discussed. Furthermore, the usefulness of DCE-MRI parameters combined with serum CA19-9 and CA125 Levels in the evaluation of RC differentiation and T staging was analyzed. RESULTS: Ktrans, Ve, CA19-9 and CA125 were higher in the high-stage group and L group than in the low-stage group and M + H Group, respectively (P < 0.05). The areas under the curve (AUCs) of the Ktran and Ve parameters were 0.638 and 0.694 in the diagnosis of high and low stages, respectively, and 0.672 and 0.725 in diagnosing moderate-high and low differentiation, respectively. The AUC of DCE-MRI parameters (Ktrans + Ve) in the diagnosis of high and low stages was 0.742, and the AUC in diagnosing moderate-high and low differentiation was 0.769. The AUCs of CA19-9 and CA-125 were 0.773 and 0.802 in the diagnosis of high and low stages, respectively, and 0.834 and 0.796 in diagnosing moderate-high and low differentiation, respectively. Then, we combined DCE-MRI (Ktrans + Ve) parameters with CA19-9 and CA-125 and found that the AUC of DCE-MRI parameters plus serum TMs was 0.836 in the diagnosis of high and low stages and 0.946 in the diagnosis of moderate-high and low differentiation. According to the Delong test, the AUC of DCE-MRI parameters plus serum TMs increased significantly compared with serum TMs alone in the diagnosis of T stage and differentiation degree (P < 0.001). CONCLUSION: The levels of the DCE-MRI parameters Ktrans and Ve and the serum TMs CA19-9 and CA125 all increase with increasing T stage and decreasing differentiation degree of RC and can be used as indices to evaluate the differentiation degree of RC in clinical practice. Moreover, the combined evaluation of the above indices has a better effect and more obvious clinical value, providing important guiding importance for clinical condition judgment and treatment selection.

9.
Sci Bull (Beijing) ; 69(12): 1936-1953, 2024 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-38734583

RESUMEN

Molecular glues are typically small chemical molecules that act at the interface between a target protein and degradation machinery to trigger ternary complex formation. Identifying molecular glues is challenging. There is a scarcity of target-specific upregulating molecular glues, which are highly anticipated for numerous targets, including P53. P53 is degraded in proteasomes through polyubiquitination by specific E3 ligases, whereas deubiquitinases (DUBs) remove polyubiquitination conjugates to counteract these E3 ligases. Thus, small-molecular glues that enhance P53 anchoring to DUBs may stabilize P53 through deubiquitination. Here, using small-molecule microarray-based technology and unbiased screening, we identified three potential molecular glues that may tether P53 to the DUB, USP7, and elevate the P53 level. Among the molecular glues, bromocriptine (BC) is an FDA-approved drug with the most robust effects. BC was further verified to increase P53 stability via the predicted molecular glue mechanism engaging USP7. Consistent with P53 upregulation in cancer cells, BC was shown to inhibit the proliferation of cancer cells in vitro and suppress tumor growth in a xenograft model. In summary, we established a potential screening platform and identified potential molecular glues upregulating P53. Similar strategies could be applied to the identification of other types of molecular glues that may benefit drug discovery and chemical biology studies.


Asunto(s)
Proteína p53 Supresora de Tumor , Peptidasa Específica de Ubiquitina 7 , Regulación hacia Arriba , Peptidasa Específica de Ubiquitina 7/metabolismo , Peptidasa Específica de Ubiquitina 7/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Humanos , Animales , Regulación hacia Arriba/efectos de los fármacos , Ratones , Línea Celular Tumoral , Ubiquitinación/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Desnudos
10.
Acad Radiol ; 2024 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-38641451

RESUMEN

RATIONALE AND OBJECTIVES: To develop and validate a nomogram that combines contrast-enhanced spectral mammography (CESM) deep learning with clinical-pathological features to predict neoadjuvant chemotherapy (NAC) response (either low Miller Payne (MP-L) grades 1-2 or high MP (MP-H) grades 3-5) in patients with ER-positive/HER2-negative breast cancer. MATERIALS AND METHODS: In this retrospective study, 265 breast cancer patients were randomly allocated into training and test sets (used for models training and testing, respectively) at a 4:1 ratio. Deep learning models, based on the pre-trained ResNet34 model and initially fine-tuned for identifying breast cancer, were trained using low-energy and subtracted CESM images. The predicted results served as deep learning features for the deep learning-based model. Clinical-pathological features, including age, progesterone receptor (PR) status, estrogen receptor (ER) status, Ki67 expression levels, and neutrophil-to-lymphocyte ratio, were used for the clinical model. All these features contributed to the nomogram. Feature selection was performed through univariate analysis. Logistic regression models were developed and chosen using a stepwise selection method. The deep learning-based and clinical models, along with the nomogram, were evaluated using precision-recall curves, receiver operating characteristic (ROC) curves, specificity, recall, accuracy, negative predictive value, positive predictive value (PPV), balanced accuracy, F1-score, and decision curve analysis (DCA). RESULTS: The nomogram demonstrated considerable predictive ability, with higher area under the ROC curve (0.95, P < 0.05), accuracy (0.94), specificity (0.98), PPV (0.89), and precision (0.89) compared to the deep learning-based and clinical models. In DCA, the nomogram showed substantial clinical value in assisting breast cancer treatment decisions, exhibiting a higher net benefit than the other models. CONCLUSION: The nomogram, integrating CESM deep learning with clinical-pathological features, proved valuable for predicting NAC response in patients with ER-positive/HER2-negative breast cancer. Nomogram outperformed deep learning-based and clinical models.

11.
Am J Transl Res ; 16(3): 925-932, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38586096

RESUMEN

OBJECTIVE: To investigate the efficacy and safety of tranexamic acid (TXA) in preventing upper gastrointestinal (GI) bleeding in patients with gastric cancer. METHODS: The clinical data of patients with gastric cancer complicated with acute non-operative GI bleeding treated in the Fourth Hospital of Hebei Medical University from 2020 to 2022 were collected and retrospectively analyzed. The survival status of the patients was followed up by telephone. The dataset of 168 patients was divided into a control group (n=85) and a TXA group (n=83), at a 1:1 ratio. The patients in the control group were treated with esomeprazole, and the patients in the TXA group received additional TXA. The hemostatic effect, rebleeding rate, and mortality of patients were compared between the two groups. The Cox proportional hazard model was used to evaluate the overall survival of patients as well as the related risk factors. RESULTS: The success rate of hemostasis and the normal blood coagulation rate in the TXA group were significantly higher than those in the control group (P=0.003 and P=0.016). The secondary bleeding rate, thrombus formation rate and digestive tract perforation rate in the TXA group were significantly lower than those in the control group (P=0.002, P=0.003 and P=0.035). The improvement of all indicators in the TXA group was better than that in the control group (all P<0.05). For patients with gastric cancer complicated with acute GI bleeding treated with TXA, the Cox proportional hazard model identified III~IV stage, time of TXA treatment, surgical treatment after hemorrhage, and an increase of D-dimer as independent risk factors for upper GI bleeding (all P<0.05). CONCLUSION: TXA can be an effective treatment for patients with gastric cancer complicated by GI bleeding.

12.
Anal Sci ; 40(7): 1239-1248, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38598051

RESUMEN

Alpha-fetoprotein (AFP), commonly employed for early diagnosis of liver cancer, serves as a biomarker for cancer screening and diagnosis. Combining the high sensitivity and specificity of fluorescence immunoassay (FIA), developing a low-cost and efficient immunoassay system for AFP detection holds significant importance in disease diagnosis. In this work, we developed a miniaturized oblique laser-induced fluorescence (LIF) immunoassay system, coupled with a microfluidic PMMA/paper hybrid chip, for rapid detection of AFP. The system employed an avalanche photodiode (APD) as the detector, and implemented multi-level filtering in the excitation light channel using the dichroic mirror and optical trap. At first, we employed the Savitzky-Golay filter and baseline off-set elimination methods to denoise and normalize the original data. Then the cutoff frequency of the low-pass filter and the reverse voltage of the APD were optimized to enhance the detection sensitivity of the system. Furthermore, the effect of laser power on the fluorescence excitation efficiency was investigated, and the sampling time during the scanning process was optimized. Finally, a four-parameter logistic (4PL) model was utilized to establish the concentration-response equation for AFP. The system was capable of detecting concentrations of AFP standard solution within the range of 1-500 ng/mL, with a detection limit of 0.8 ng/mL. The entire immunoassay process could be completed within 15 min. It has an excellent potential for applications in low-cost portable diagnostic instruments for the rapid detection of biomarkers.


Asunto(s)
Rayos Láser , alfa-Fetoproteínas , alfa-Fetoproteínas/análisis , Técnicas Analíticas Microfluídicas/instrumentación , Humanos , Inmunoensayo/métodos , Factores de Tiempo , Fluorescencia
13.
Front Endocrinol (Lausanne) ; 15: 1291389, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38298378

RESUMEN

The increasing life expectancy observed in recent years has resulted in a higher prevalence of late-onset hypogonadism (LOH) in older men. LOH is characterized by the decline in testosterone levels and can have significant impacts on physical and mental health. While the underlying causes of LOH are not fully understood, there is a growing interest in exploring the role of inflammaging in its development. Inflammaging is a concept that describes the chronic, low-grade, systemic inflammation that occurs as a result of aging. This inflammatory state has been implicated in the development of various age-related diseases. Several cellular and molecular mechanisms have been identified as contributors to inflammaging, including immune senescence, cellular senescence, autophagy defects, and mitochondrial dysfunction. Despite the extensive research on inflammaging, its relationship with LOH has not yet been thoroughly reviewed in the literature. To address this gap, we aim to review the latest findings related to inflammaging and its impact on the development of LOH. Additionally, we will explore interventions that target inflammaging as potential treatments for LOH.


Asunto(s)
Hipogonadismo , Masculino , Humanos , Anciano , Envejecimiento , Senescencia Celular , Inflamación , Esperanza de Vida
14.
J Chromatogr A ; 1717: 464659, 2024 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-38271771

RESUMEN

The removal of zinc ions (Zn(II)) in water and the separation of zinc isotopes were fully investigated in this study. Imidodiacetic acid (IDA) type adsorbent (named PSGI) based on polystyrene spheres (PS) was synthesized by simultaneous irradiation grafting. By adsorption method, the removal of Zn(II) from water by the chelating adsorbent was studied in batch experiments. Under optimized condition, PSGI showed the removal efficiency of more than 98 % for Zn(II) and the adsorption capacity of 70.1 mg/g. Langmuir isothermal and pseudo-second-order kinetic model fitted the experimental results better, indicating that the adsorption is dominated by chemical adsorption. The spent adsorbent (PSGI-Zn) was used for further zinc isotope separation by displacement chromatography using EDTA-NH4 solution as eluent. Due to the mass effect of isotopes, 70Zn was found to preferentially fractionated into the front-end effluents with the highest front enrichment values of 70Zn/64Zn. By extending the migration distance to 20 m, we obtained the best isotope enrichment with the front maximum enrichment values as 1.0949, 1.0739 and separation coefficient values as 1.977 × 10-3, 8.33 × 10-3 corresponding to the isotope pairs 66Zn/64Zn, 68Zn/64Zn.


Asunto(s)
Contaminantes Químicos del Agua , Isótopos de Zinc , Isótopos de Zinc/análisis , Adsorción , Zinc/química , Quelantes/análisis , Agua/química , Contaminantes Químicos del Agua/análisis , Cinética , Concentración de Iones de Hidrógeno
15.
Angew Chem Int Ed Engl ; 63(4): e202315061, 2024 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-37966368

RESUMEN

The development of multimode photopatterning systems based on supramolecular coordination complexes (SCCs) is considerably attractive in supramolecular chemistry and materials science, because SCCs can serve as promising platforms for the incorporation of multiple functional building blocks. Herein, we report a light-responsive liquid-crystalline metallacycle that is constructed by coordination-driven self-assembly. By exploiting its fascinating liquid crystal features, bright emission properties, and facile photocyclization capability, a unique system with spatially-controlled fluorescence-resonance energy transfer (FRET) is built through the introduction of a photochromic spiropyran derivative, which led to the realization of the first example of a liquid-crystalline metallacycle for orthogonal photopatterning in three-modes, namely holography, fluorescence, and photochromism.

16.
Oncogene ; 43(1): 35-46, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38007537

RESUMEN

Homologous recombination (HR) is a major DNA double-strand break (DSB) repair pathway of clinical interest because of treatment with poly(ADP-ribose) polymerase inhibitors (PARPi). Cooperation between RAD51 and BRCA2 is pivotal for DNA DSB repair, and its dysfunction induces HR deficiency and sensitizes cancer cells to PARPi. The depletion of the DEAD-box protein DDX11 was found to suppress HR in hepatocellular carcinoma (HCC) cells. The HR ability of HCC cells is not always dependent on the DDX11 level because of natural DDX11 mutations. In Huh7 cells, natural DDX11 mutations were detected, increasing the susceptibility of Huh7 cells to olaparib in vitro and in vivo. The HR deficiency of Huh7 cells was restored when CRISPR/Cas9-mediated knock-in genomic editing was used to revert the DDX11 Q238H mutation to wild type. The DDX11 Q238H mutation impeded the phosphorylation of DDX11 by ATM at serine 237, preventing the recruitment of RAD51 to damaged DNA sites by disrupting the interaction between RAD51 and BRCA2. Clinically, a high level of DDX11 correlated with advanced clinical characteristics and a poor prognosis and served as an independent risk factor for overall and disease-free survival in patients with HCC. We propose that HCC with a high level of wild-type DDX11 tends to be more resistant to PARPi because of enhanced recombination repair, and the key mutation of DDX11 (Q238H) is potentially exploitable.


Asunto(s)
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Línea Celular Tumoral , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Antineoplásicos/farmacología , Recombinación Homóloga/genética , ADN , Recombinasa Rad51/genética , Recombinasa Rad51/metabolismo , ADN Helicasas/genética , ARN Helicasas DEAD-box/genética , Proteína BRCA2/genética
17.
Arch Gerontol Geriatr ; 117: 105274, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-37995648

RESUMEN

BACKGROUND: The aging inflammatory microenvironment surrounding Leydig cells is linked to reduced testosterone levels in males. Tumor necrosis factor alpha-induced protein 3 (TNFAIP3) acts as a critical anti-inflammatory factor in various aging-related diseases. This study aims to investigate the protective effect of TNFAIP3 on testosterone production in Leydig cells under an aging inflammatory microenvironment. METHODS: Bioinformatics analysis examined TNFAIP3 expression differences in aging rat testes and validated the findings in aging mouse testes. In vitro models of inflammation were established using two Leydig cell lines, with tumor necrosis factor alpha (TNF-α) as the inflammatory factor. Lentiviral transduction was utilized to manipulate TNFAIP3 expression in these cell lines. Transcriptomic sequencing identified differentially expressed genes in TNFAIP3-overexpressing cells. RESULTS: Bioinformatics analysis and validation experiments revealed increased inflammatory signaling and elevated TNFAIP3 expression in aging rat and mouse testes. TNFAIP3 knockdown worsened testosterone synthesis inhibition and apoptosis in cells, while TNFAIP3 overexpression reversed these effects. Transcriptome analysis identified alterations in the P38MAPK pathway following TNFAIP3 overexpression. TNFAIP3 knockdown enhanced TNF-induced P38MAPK signaling, whereas its overexpression attenuated this effect. TNFAIP3 was found to regulate testosterone synthesis by upregulating CEBPB expression. CONCLUSIONS: TNFAIP3 exhibits inhibitory effects on apoptosis and promotes testosterone production in Leydig cells. The protective influence of TNFAIP3 on Leydig cells within an inflammatory microenvironment is likely mediated through by inhibiting the P38MAPK pathway and upregulating CEBPB expression.


Asunto(s)
Células Intersticiales del Testículo , Testosterona , Animales , Humanos , Masculino , Ratones , Ratas , Envejecimiento/fisiología , Células Intersticiales del Testículo/metabolismo , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genética , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/metabolismo , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/farmacología
18.
BMC Plant Biol ; 23(1): 662, 2023 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-38124037

RESUMEN

BACKGROUND: Phosphorus (P) and salt stress are common abiotic stressors that limit crop growth and development, but the response mechanism of soybean to low phosphorus (LP) and salt (S) combined stress remains unclear. RESULTS: In this study, two soybean germplasms with similar salt tolerance but contrasting P-efficiency, A74 (salt-tolerant and P-efficient) and A6 (salt-tolerant and P-inefficient), were selected as materials. By combining physiochemical and transcriptional analysis, we aimed to elucidate the mechanism by which soybean maintains high P-efficiency under salt stress. In total, 14,075 differentially expressed genes were identified through pairwise comparison. PageMan analysis subsequently revealed several significantly enriched categories in the LP vs. control (CK) or low phosphorus + salt (LPS) vs. S comparative combination when compared to A6, in the case of A74. These categories included genes involved in mitochondrial electron transport, secondary metabolism, stress, misc, transcription factors and transport. Additionally, weighted correlation network analysis identified two modules that were highly correlated with acid phosphatase and antioxidant enzyme activity. Citrate synthase gene (CS), acyl-coenzyme A oxidase4 gene (ACX), cytokinin dehydrogenase 7 gene (CKXs), and two-component response regulator ARR2 gene (ARR2) were identified as the most central hub genes in these two modules. CONCLUSION: In summary, we have pinpointed the gene categories responsible for the LP response variations between the two salt-tolerant germplasms, which are mainly related to antioxidant, and P uptake process. Further, the discovery of the hub genes layed the foundation for further exploration of the molecular mechanism of salt-tolerant and P-efficient in soybean.


Asunto(s)
Antioxidantes , Glycine max , Glycine max/genética , Fósforo/metabolismo , Perfilación de la Expresión Génica , Factores de Transcripción/genética , Estrés Fisiológico/genética , Regulación de la Expresión Génica de las Plantas
19.
World J Gastrointest Surg ; 15(10): 2331-2342, 2023 Oct 27.
Artículo en Inglés | MEDLINE | ID: mdl-37969715

RESUMEN

BACKGROUND: Colorectal cancer ranks third in global cancer prevalence and stands as the second leading cause of cancer-related mortalities. With obesity recognized as a pivotal risk factor for colorectal cancer, the potential protective role of bariatric surgery, especially laparoscopic Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy, has garnered attention. AIM: To investigate the Roux-en-Y gastric bypass (RYGB) vs sleeve gastrectomy (SG) effect on colorectal cancer incidence in obese individuals. METHODS: A systematic review and meta-analysis of the literature was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Seventeen studies with a total of 12497322 patients were included. The primary outcome was the relative risk (RR) of developing colorectal cancer in obese patients who underwent weight loss surgery compared to those who did not. Secondary outcomes included determining the RR for colon and rectal cancer separately and subgroup analyses by gender and type of weight loss surgery. RESULTS: The meta-analysis revealed a 54% reduction in colorectal cancer risk in morbidly obese patients who underwent bariatric surgery compared to those who did not. A significant 46% reduction in colorectal cancer risk was observed among female patients. However, no significant differences were found in the meta-analysis for various types of bariatric surgery, such as SG and RYGB. CONCLUSION: This meta-analysis reveals weight loss surgery, regardless of type, reduces colorectal cancer risk, especially in women, as indicated by RR and hazard ratio assessments. Further validation is essential.

20.
BMC Pulm Med ; 23(1): 446, 2023 Nov 17.
Artículo en Inglés | MEDLINE | ID: mdl-37978491

RESUMEN

BACKGROUND: The risk factors for mucus plug in children with adenovirus (ADV) pneumonia. METHODS AND MATERIALS: A retrospective analysis was conducted of children diagnosed ADV pneumonia and underwent fiberoptic bronchoscopy admitted to the Xiamen Children's Hospital from September 2018 to September 2021.The patients were divided into a mucus plug group (39 cases) and a non-mucus plug group (53 cases). The children's data including sex, age, clinical presentation, laboratory test parameters, imaging and bronchoscopic data were collected. The risk factors for the development of airway mucus plug were analysed by multifactorial logistic regression. RESULTS: There were no statistically significant differences in sex, age, fever, hospitalization days, mixed infection, white blood cells (WBC) count, percentage of neutrophils (NE%), C-reactive protein(CRP), and D-dimer (all P > 0.05); Thermal range, procalcitonin (PCT), lactate dehydrogenase (LDH), Pleural effusion and associated decreased breath sounds was significantly higher in mucus plug group than in non-mucus plug group, and the differences were statistically significant (all P < 0.05); multifactorial logistic regression analysis showed that the duration of fever, PCT, and LDH were independent risk factors for the formation of mucus plugs. The critical values of ROC curves were pyroprocedure ≥ 6.5 d, PCT ≥ 0.705 ng/ml and LDH ≥ 478.5 U/L. CONCLUSION: Duration of fever, PCT and LDH levels were the independent risk factors for the formation of an airway mucus plug in children with ADV pneumonia.


Asunto(s)
Neumonía por Mycoplasma , Neumonía Viral , Humanos , Niño , Estudios Retrospectivos , Factores de Riesgo , Moco
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