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1.
Heliyon ; 10(17): e37345, 2024 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-39296227

RESUMEN

Background: CD276 is a promising immune checkpoint molecule with significant therapeutic potential. Several clinical trials are currently investigating CD276-targeted therapies. Purpose: This study aims to assess the prognostic significance of CD276 expression levels and to predict its expression using a radiomic approach in breast cancer (BC). Methods: A cohort of 840 patients diagnosed with BC from The Cancer Genome Atlas was included in this study. The Cancer Imaging Archive provided 98 magnetic resonance imaging (MRI) scans, which were randomly allocated to training and validation datasets in a 7:3 ratio. The association between CD276 expression and patient survival was assessed using Cox regression analysis. Feature selection was performed using the maximum relevance minimum redundancy algorithm and recursive feature elimination. Subsequently, support vector machine (SVM) and logistic regression (LR) models were constructed to predict CD276 expression. Results: The expression of CD276 was found to be elevated in BC. It was an independent risk factor for overall survival (hazard ratio = 1.579, 95 % CI: 1.054-2.366). There were eight radiomic features selected in total. In both the training and validation subsets, the SVM and LR models demonstrated favorable predictive abilities with AUC values of 0.744 and 0.740 for the SVM model and 0.742 and 0.735 for the LR model. These results indicate that the radiomic models efficiently differentiate the CD276 expression status. Conclusions: CD276 expression levels can have an impact on cancer prognosis. The MRI-based radiomic signature described in this study can discriminate the CD276 expression status.

2.
Int J Ophthalmol ; 17(9): 1675-1680, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39296571

RESUMEN

AIM: To evaluate the clinical effect of a new surgery technique (covering corneal stromal lenticule, CSL) for macular hole (MH) in pathological myopia. METHODS: This was a prospective non-randomized series case study. Fourteen eyes of 14 patients whose axial length were more than 29 mm and suffered from MH and macular hole retinal detachment (MHRD) were included in this study. All cases were treated with 25-gauge pars plana vitrectomy (PPV) with internal limiting membrane (ILM) peeling, covering CSL and C3F8 gas tamponade. These cases were followed for 6mo, and the best-corrected visual acuity (BCVA), healing status of MH, the reattached rate of retinal detachment (RD), and reoperation rate were analyzed. RESULTS: All cases were successfully performed the surgery and the postoperative follow-up was completed. After surgery, MHs were healed in all 14 eyes (100%, 14/14) after assessed by optical coherence tomography. The reattachment of retina was achieved in all 6 eyes (100%, 6/6) with MHRD. BCVA was improved in 12 eyes (85.71%, 12/14), and had no significant change in 2 eyes (14.29%, 2/14). The overall mean BCVA was improved from 1.80±0.77 to 0.82±0.46 logMAR (F=10.46, P<0.01). No serious complications occurred in all cases. CONCLUSION: The new surgery technique (covering CSL) has high reattached rate of RD and high healing rate of MH in pathological myopia in the preliminary study. And it can effectively improve the visual function of patients. This new technique offers meaningful new ideas for treating refractory MH in pathological myopia.

3.
J Asian Nat Prod Res ; : 1-9, 2024 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-39279056

RESUMEN

A new sterol, aspersterol E (1), a newly discovered alkaloid, asperginine A (2), and five known compounds (3-7) were obtained from the endophytic fungus Aspergillus sp. S3 of Hibiscus tiliaceus Linn. The compounds were extracted from their fermentation products using silica gel, ODS C18, and semi-preparative HPLC. The structure of each compound was determined through spectroscopic analysis. All the obtained compounds (1-7) were evaluated for their cytotoxic activity against the mouse pre-gastric cancer cell line MFC by using the MTT assay. The IC50 values of compounds 1, 2, 3, and 5 were found to be 153.43 µM, 61.25 µM, 73.19 µM, and 181.69 µM respectively.

4.
World J Clin Cases ; 12(25): 5775-5783, 2024 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-39247741

RESUMEN

BACKGROUND: During the Coronavirus disease 2019 (COVID-19) pandemic, a notable increase in acute macular neuroretinopathy (AMN) cases was observed. This study aimed to investigate the potential association between AMN and COVID-19 by examining 3 cases in China. CASE SUMMARY: The first case involved a 30-year-old man who presented with progressive vision loss following a COVID-19 infection. Optical coherence tomography (OCT) and near-infrared imaging identified hallmark AMN lesions, hyperreflective disruptions within the outer plexiform layer, and hyporeflective anomalies in the ellipsoid zone, leading to an AMN diagnosis. Despite partial visual recovery, OCT angiography (OCTA) revealed persistent microvascular changes, specifically a decreased vascular density in the deep capillary plexus. The second case was a 24-year-old woman who experienced blurred vision and exhibited bilateral cotton-wool spots on fundus examination post-COVID-19. Imaging confirmed the presence of AMN along with paracentral acute middle maculopathy (PAMM). Follow-up OCTA found a progressive reduction in vascular density, indicating ongoing microvascular compromise. The third case was a 28-year-old woman who reported sensations of occlusion in her right eye following a COVID-19 infection. Imaging confirmed both AMN and PAMM, revealing similar decreases of microvascular density on OCTA despite a significant improvement in visual acuity. We noted that all 3 patients had received the COVID-19 vaccine prior to the appearance of symptoms. CONCLUSION: The findings highlight the diagnostic utility of advanced ocular imaging in detecting AMN in COVID-19 patients and the importance of comprehensive eye examinations.

5.
World J Clin Cases ; 12(25): 5729-5738, 2024 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-39247748

RESUMEN

BACKGROUND: Previous epidemiologic investigations have consistently demonstrated a strong association between the ratio of cholesterol to total lipids in medium very-low-density lipoprotein (VLDL) and the occurrence of peptic ulcers (PU). However, the precise causal relationship between these factors remains ambiguous. Consequently, this study aims to elucidate the potential correlation between the ratio of cholesterol to total lipids in medium VLDL and the incidence of peptic ulcer. AIM: To investigate the ratio of cholesterol to total lipids in medium very-low-density lipoprotein (VLDL) association with PU via genetic methods, guiding future clinical research. METHODS: Genome-wide association study (GWAS) datasets for the ratio of cholesterol to total lipids in intermediate VLDL and peptic ulcer were retrieved from the IEU OpenGWAS project (https://gwas.mrcieu.ac.uk). For the forward Mendelian randomization (MR) analysis, 72 single nucleotide polymorphisms (SNPs) were identified as instrumental variables. These SNPs were selected based on their association with the ratio of cholesterol to total lipids in intermediate VLDL, with peptic ulcer as the outcome variable. Conversely, for the inverse MR analysis, no SNPs were identified with peptic ulcer as the exposure variable and the ratio of cholesterol to total lipids in intermediate VLDL as the outcome. All MR analyses utilized inverse variance weighted (IVW) as the primary analytical method. Additionally, weighted median and MR-Egger methods were employed as supplementary analytical approaches to assess causal effects. Egger regression was used as a supplementary method to evaluate potential directional pleiotropy. Heterogeneity and multiplicity tests were conducted using the leave-one-out method to evaluate result stability and mitigate biases associated with multiple testing. RESULTS: The genetically predicted ratio of cholesterol to total lipids in medium VLDL was significantly associated with an elevated risk of peptic ulcer (IVW: OR = 2.557, 95%CI = 1.274-5.132, P = 0.008). However, no causal association of peptic ulcer with the ratio of cholesterol to total lipids in medium VLDL was observed in the inverse Mendelian randomization analysis. CONCLUSION: In conclusion, our study reveals a significant association between the ratio of cholesterol to total lipids in medium VLDL and an elevated risk of peptic ulcers. However, further validation through laboratory investigations and larger-scale studies is warranted to strengthen the evidence and confirm the causal relationship between these factors.

6.
J Cardiovasc Pharmacol ; 84(3): 331-339, 2024 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-39240728

RESUMEN

ABSTRACT: In this study, we investigated the safety and efficacy of fondaparinux sodium in postpercutaneous coronary intervention (PCI) anticoagulation therapy for patients with ST-segment elevation myocardial infarction. There are a total of 200 patients with ST segment elevation myocardial infarction underwent PCI and anticoagulation therapy. They were randomly split into experimental (n = 108) and control groups (n = 92). The experimental group received postoperative fondaparinux sodium (2.5 mg q.d), while the control group received enoxaparin (4000 IU q12 h). We did not use a loading dose for enoxaparin. Bleeding incidence and major adverse cardiovascular/cerebrovascular events were monitored during hospitalization, and at 1, 3, and 6 months postsurgery. The primary end points, including bleeding, mortality, and myocardial infarction during hospitalization, were not significantly different between the 2 groups. For secondary end points, the incidence of combined end point events at 1 month, 3 months, and 6 months after surgery in the experimental group was lower than in the control group (P < 0.05). According to Cox regression analysis, the risk of bleeding in the experimental group was significantly lower than that in the control group [hazard ratios: 0.506, 95% confidence interval (CI): 0.284-0.900] (P = 0.020). The risk of mortality in the experimental group was significantly lower than in the control group (hazard ratio: 0.188, 95% CI: 0.040-0.889) (P = 0.035). In summary, perioperative use of fondaparinux sodium during PCI in patients with STEMI in this study was associated with a lower risk of bleeding and death compared with enoxaparin use in the absence of loading dose.


Asunto(s)
Enoxaparina , Fondaparinux , Hemorragia , Intervención Coronaria Percutánea , Infarto del Miocardio con Elevación del ST , Humanos , Fondaparinux/uso terapéutico , Fondaparinux/efectos adversos , Fondaparinux/administración & dosificación , Intervención Coronaria Percutánea/efectos adversos , Intervención Coronaria Percutánea/mortalidad , Masculino , Femenino , Persona de Mediana Edad , Anciano , Infarto del Miocardio con Elevación del ST/terapia , Infarto del Miocardio con Elevación del ST/mortalidad , Infarto del Miocardio con Elevación del ST/diagnóstico , China/epidemiología , Resultado del Tratamiento , Hemorragia/inducido químicamente , Enoxaparina/efectos adversos , Enoxaparina/administración & dosificación , Enoxaparina/uso terapéutico , Factores de Riesgo , Factores de Tiempo , Anticoagulantes/efectos adversos , Anticoagulantes/administración & dosificación , Anticoagulantes/uso terapéutico , Inhibidores del Factor Xa/efectos adversos , Inhibidores del Factor Xa/administración & dosificación , Inhibidores del Factor Xa/uso terapéutico , Estudios Prospectivos
7.
Zhonghua Nan Ke Xue ; 30(6): 547-563, 2024 Jun.
Artículo en Chino | MEDLINE | ID: mdl-39212365

RESUMEN

OBJECTIVE: To evaluate the efficacy and safety of traditional Chinese medicine (TCM) in the treatment of male immune infertility (MII) by meta-analysis. METHODS: We retrieved randomized controlled trial (RCT) on the treatment of male immune infertility with traditional Chinese medicine from the databases of WanFang, Chinese Biomedical Literature, Cochrane Library, Weipu, PubMed and CNKI, and performed methodological quality assessment of the RCTs identified and statistical analysis and evaluation of the publication bias using the RevMan5.4 software. RESULTS: Totally, 25 RCTs (2 563 cases) were included in this study. Compared with Western medicine alone in the treatment of MII, TCM achieved a significantly higher total effectiveness rate (OR = 6.35, 95% CI: 4.96-8.13, P<0.000 01), negative conversion rate of seminal plasma anti-sperm antibodies (OR = 4.52, 95% CI: 2.72 - 7.51, P<0.000 01), negative rate of serum anti-sperm antibodies (OR = 2.98, 95% CI: 2.23-3.96, P<0.000 01), sperm concentration (MD = 15.56, 95% CI: 11.32-19.79, P<0.000 01), grade a sperm motility (MD = 3.85, 95% CI: 1.91-5.79, P=0.000 01), grade a+b sperm motility (MD = 13.77, 95% CI: 7.06-20.48, P<0.000 1), sperm viability (MD = 10.32, 95% CI: 6.78-13.86, P<0.000 01) and pregnancy rate (OR = 3.53, 95% CI: 2.68-4.63, P<0.000 01), but a lower rate of adverse reactions (OR = 0.06, 95% CI: 0.01-0.23, P<0.000 01). There was no statistically significant difference in the percentage of morphologically abnormal sperm between TCM and Western medicine alone in the treatment of MII (MD = -7.53, 95% CI: -15.50-0.44, P = 0.06). CONCLUSION: TCM has a definite effectiveness and high safe in the treatment of male immune infertility.


Asunto(s)
Medicamentos Herbarios Chinos , Infertilidad Masculina , Humanos , Masculino , Medicamentos Herbarios Chinos/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Medicina Tradicional China/métodos , Fitoterapia
8.
PLoS One ; 19(8): e0307132, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39173013

RESUMEN

PURPOSE: We evaluated the IOP-lowering efficacy and safety of latanoprostene bunod (LBN) ophthalmic solution 0.024% (Vyzulta®), the first topical nitric oxide-donating prostaglandin analog (PGA), in clinical practice. MATERIALS AND METHODS: A retrospective medical chart review from July 2021 to July 2023 of patients with open-angle glaucoma receiving LBN with at least 1 year follow-up was conducted. All included patients received LBN 0.024% as a replacement for a PGA, with examinations at 1-, 3-, 6-and 12-months follow-up. Main outcome measures were IOP, retinal nerve fiber layer thickness, visual fields before/after LBN use and adverse effects. Subgroup analysis with glaucoma types and PGA use were performed for additional IOP reduction after LBN use. RESULTS: Among 78 included patients, 47 patients (81 eyes), 60% with open-angle glaucoma (OAG) remained on LBN throughout 12-month follow-up. Baseline IOP was 18.2±4.2 mm Hg, and Prostaglandin analog (PGA)-IOP was 14.4 ± 3.0 mm Hg (21% mean IOP reduction). After switched to LBN, mean additional IOP reduction was 1.0 mm Hg at month 1, and the greatest reduction was 1.6 mm Hg (8.8% additional mean IOP reduction) at month 12 (P<0.0001). Subgroup analysis (NTG, 73%) showed that mean additional IOP reduction at month 12 was 1.3±2.0 mm Hg in NTG group and 2.1±3.2 mm Hg in POAG group (7.7% vs. 8.7% additional IOP reduction rates, P = 0.23). Subgroup analysis of PGA use at month 12 was 1.8±2.3 mm Hg in tafluoprost group and 0.5±1.7 mm Hg in travoprost group (9.5% vs.2.6% additional IOP reduction rates, P = 0.02). Tolerable ocular adverse effects included irritation (n = 16, 19.8%), mild conjunctival hyperemia (n = 11, 13.6%), dark circles (n = 4, 4.9%) and blurred vision (n = 2, 2.5%). There were no significant visual field and retinal nerve fiber layer thickness changes after 12 months of treatment with LBN 0.024%. CONCLUSIONS: Although high intolerable adverse effects including conjunctival hyperemia and eye irritation happened in the first month, remaining sixty percent of patients exhibited statistically significant additional IOP reductions in the replacement of other PGAs during 12 months of clinical use of LBN 0.024%.


Asunto(s)
Glaucoma de Ángulo Abierto , Presión Intraocular , Soluciones Oftálmicas , Prostaglandinas F Sintéticas , Humanos , Femenino , Masculino , Estudios Retrospectivos , Anciano , Presión Intraocular/efectos de los fármacos , Glaucoma de Ángulo Abierto/tratamiento farmacológico , Persona de Mediana Edad , Prostaglandinas F Sintéticas/uso terapéutico , Prostaglandinas F Sintéticas/administración & dosificación , Prostaglandinas F Sintéticas/efectos adversos , Antihipertensivos/uso terapéutico , Antihipertensivos/efectos adversos , Antihipertensivos/administración & dosificación , Anciano de 80 o más Años , Resultado del Tratamiento , Estudios de Seguimiento
9.
Org Lett ; 26(32): 6859-6865, 2024 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-39092611

RESUMEN

Despite the widespread utilizable value of 3-oxazolines, mild and efficient access to such a class of unique structures still remains, to date, a challenge. Herein, we present a [3 + 2] annulation strategy, guided by the retrosynthetic principle of [CO + CCN], that utilizes vinyl azides as the CCN module and aldehydes as the CO module. This approach enables the efficient construction of the 3-oxazoline framework with remarkable features, including operational simplicity, environmental friendliness, and high efficiency. Notably, it solely requires the addition of inexpensive and readily available N-hydroxyphthalimide (NHPI) and air oxygen to obtain the desired product. It also provides a new way to generate the hydroxyl radical, which is produced by the homolysis of peroxycarboxylic acid. In addition, control experiments, X-ray crystallographic analysis, high-resolution mass spectrometry (HRMS), and density functional theory (DFT) calculations afford evidence for the key intermediates (hydroxyl radical, carboxyl radical, imine radical, hydroxyl substituted amide derivatives), further confirming the path for realization of 3-oxazolines.

10.
Molecules ; 29(16)2024 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-39202911

RESUMEN

In this work, we report the synthesis of a new thiosemicarbazone-based drug of N'-(di(pyridin-2-yl)methylene)-4-(thiazol-2-yl)piperazine-1-carbothiohydrazide (HL) featuring a thiazole spectator for efficient coordination with Cu(II) to give [CuCl(L)]2 (1) and [Cu(NO3)(L)]2 (2). Both 1 and 2 exhibit dimeric structures ascribed to the presence of di-2-pyridylketone moieties that demonstrate dual functions of chelation and intermolecular bridging. HL, 1, and 2 are highly toxic against hepatocellular carcinoma cell lines Hep-G2, PLC/PRF/5, and HuH-7 with half maximal inhibitory concentration (IC50) values as low as 3.26 nmol/mL (HL), 2.18 nmol/mL (1), and 2.54 × 10-5 nmol/mL (2) for PLC/PRF/5. While the free ligand HL may elicit its anticancer effect via the sequestration of bio-relevant metal ions (i.e., Fe3+ and Cu2+), 1 and 2 are also capable of generating cytotoxic reactive oxygen species (ROS) to inhibit cancer cell proliferation. Our preliminary pharmacokinetic studies revealed that oral administration (per os, PO) of HL has a significantly longer half-life t1/2 of 21.61 ± 9.4 h, nearly doubled as compared with that of the intravenous (i.v.) administration of 11.88 ± 1.66 h, certifying HL as an effective chemotherapeutic drug via PO administration.


Asunto(s)
Antineoplásicos , Cobre , Tiazoles , Tiosemicarbazonas , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacología , Tiosemicarbazonas/farmacocinética , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacocinética , Cobre/química , Tiazoles/química , Tiazoles/farmacología , Tiazoles/farmacocinética , Línea Celular Tumoral , Disponibilidad Biológica , Animales , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/farmacocinética , Administración Oral , Estructura Molecular , Células Hep G2 , Especies Reactivas de Oxígeno/metabolismo
11.
Int J Biol Macromol ; 276(Pt 1): 133489, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38964679

RESUMEN

Indole-based bis-acylhydrazone compounds can inhibit the activity of α-glucosidase and control the concentration of blood glucose. In this paper, the characteristics of three indole-based bis-acylhydrazone compounds with different inhibitory activities of α-glucosidase as well as the interaction with α-glucosidase were studied by experiments and computational simulation techniques. Enzyme kinetic and spectral experiments showed that the indole-based bis-acylhydrazone compounds were able to inhibit enzyme activity through mixed inhibition dominated by competitive inhibition, and during the binding reaction, indole-based bis-acylhydrazone compounds can quench the intrinsic fluorescence of α-glucosidase through static quenching and an aggregation of the indole-based bis-acylhydrazone with α-glucosidase produces a stable complex with a molar ratio of 1:1, and the combination of indole-based bis-acylhydrazone compounds could lead to slight change in the conformation of α-glucosidase. The theoretical simulation demonstrated that the stability of the complex systems was positively correlated with the inhibitory activity of indole-based bis-acylhydrazone compounds, and the indole-based bis-acylhydrazone compounds occupied the active site in the multi-ligand system, resulting in a significant decrease in the binding ability of starch to active amino acids. These results suggested that indole-based bis-acylhydrazone compound was expected to be a new type of α-glucosidase inhibitor.


Asunto(s)
Inhibidores de Glicósido Hidrolasas , Hidrazonas , Indoles , alfa-Glucosidasas , alfa-Glucosidasas/metabolismo , alfa-Glucosidasas/química , Inhibidores de Glicósido Hidrolasas/química , Inhibidores de Glicósido Hidrolasas/farmacología , Indoles/química , Indoles/farmacología , Hidrazonas/química , Hidrazonas/farmacología , Cinética , Simulación del Acoplamiento Molecular , Análisis Espectral
12.
Discov Med ; 36(186): 1477-1485, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-39054718

RESUMEN

BACKGROUND: Metastatic colorectal cancer (mCRC) is increasingly characterized by myriad genomic alterations beyond the well-known factors such as RAS, BRAF, and microsatellite instability (MSI). Novel genomic changes, including ERBB2 amplifications, mutations, and gene fusions, are now recognized as potential targets for precision therapy. This study aims to explore the genomic landscape of a Chinese cohort with mCRC to identify potentially targetable genetic alterations for personalized treatment strategies. METHODS: A total of 500 mCRC patients in China were enrolled, based on which genomic profiling was performed using capture-based targeted sequencing across a panel of 520 genes on tumor tissues to identify prevalent genomic alterations. The mutations were analyzed by optimized proprietary algorithms. MSI and mismatch repair deficiency status were analyzed using the read-count-distribution approach. Besides, the overall survival (OS) related to these molecular changes was estimated. RESULTS: The cohort's genomic profiling revealed TP53 mutations in 78%, APC in 60%, and KRAS in 47% of the patients. MSI-High status was confirmed in 5.8% of cases via a next-generation sequencing (NGS)-based algorithm. ERBB2/HER2 amplifications were found in 12% (60/500) of patients, with potential therapeutic implications for those without concurrent KRAS mutations. A subset of patients (1.2%; 6/500) showed fusions and DNA damage response (DDR) gene mutations (except TP53) that could be targeted therapeutically. The KRAS (G12C) variant was detected in 14 patients (2.8%), and 61 (12.2%) had a BRAF V600E mutation. Notably, survival analysis showed no significant differences in OS between KRAS mutant loci and NRAS mutations (p = 0.436). However, BRAF V600E mutations were associated with a poorer prognosis than BRAF wild-type and non-V600E mutations (16.3 months vs. 29.5 and 31.1 months, respectively; p < 0.001). CONCLUSIONS: This study validates the feasibility of using NGS to detect prognostic and therapeutically actionable genetic variants in Chinese mCRC patients, contributing to understanding the genomic variation within this population and highlighting the potential for personalized medicine in managing mCRC.


Asunto(s)
Neoplasias Colorrectales , Mutación , Metástasis de la Neoplasia , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Femenino , Masculino , Persona de Mediana Edad , Anciano , Adulto , China/epidemiología , Pueblo Asiatico/genética , Inestabilidad de Microsatélites , Genómica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Anciano de 80 o más Años , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Pueblos del Este de Asia
13.
Proc Natl Acad Sci U S A ; 121(28): e2322972121, 2024 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-38968116

RESUMEN

Rapid accumulation of repair factors at DNA double-strand breaks (DSBs) is essential for DSB repair. Several factors involved in DSB repair have been found undergoing liquid-liquid phase separation (LLPS) at DSB sites to facilitate DNA repair. RNF168, a RING-type E3 ubiquitin ligase, catalyzes H2A.X ubiquitination for recruiting DNA repair factors. Yet, whether RNF168 undergoes LLPS at DSB sites remains unclear. Here, we identified K63-linked polyubiquitin-triggered RNF168 condensation which further promoted RNF168-mediated DSB repair. RNF168 formed liquid-like condensates upon irradiation in the nucleus while purified RNF168 protein also condensed in vitro. An intrinsically disordered region containing amino acids 460-550 was identified as the essential domain for RNF168 condensation. Interestingly, LLPS of RNF168 was significantly enhanced by K63-linked polyubiquitin chains, and LLPS largely enhanced the RNF168-mediated H2A.X ubiquitination, suggesting a positive feedback loop to facilitate RNF168 rapid accumulation and its catalytic activity. Functionally, LLPS deficiency of RNF168 resulted in delayed recruitment of 53BP1 and BRCA1 and subsequent impairment in DSB repair. Taken together, our finding demonstrates the pivotal effect of LLPS in RNF168-mediated DSB repair.


Asunto(s)
Reparación del ADN , Ubiquitina-Proteína Ligasas , Humanos , Roturas del ADN de Doble Cadena , Histonas/metabolismo , Histonas/genética , Poliubiquitina/metabolismo , Proteína 1 de Unión al Supresor Tumoral P53/metabolismo , Proteína 1 de Unión al Supresor Tumoral P53/genética , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitinación
14.
Commun Biol ; 7(1): 843, 2024 Jul 10.
Artículo en Inglés | MEDLINE | ID: mdl-38987326

RESUMEN

Bcr-Abl transformation leads to chronic myeloid leukemia (CML). The acquirement of T315I mutation causes tyrosine kinase inhibitors (TKI) resistance. This study develops a compound, JMF4073, inhibiting thymidylate (TMP) and cytidylate (CMP) kinases, aiming for a new therapy against TKI-resistant CML. In vitro and in vivo treatment of JMF4073 eliminates WT-Bcr-Abl-32D CML cells. However, T315I-Bcr-Abl-32D cells are less vulnerable to JMF4073. Evidence is presented that ATF4-mediated upregulation of GSH causes T315I-Bcr-Abl-32D cells to be less sensitive to JMF4073. Reducing GSH biosynthesis generates replication stress in T315I-Bcr-Abl-32D cells that require dTTP/dCTP synthesis for survival, thus enabling JMF4073 susceptibility. It further shows that the levels of ATF4 and GSH in several human CML blast-crisis cell lines are inversely correlated with JMF4073 sensitivity, and the combinatory treatment of JMF4073 with GSH reducing agent leads to synthetic lethality in these CML blast-crisis lines. Altogether, the investigation indicates an alternative option in CML therapy.


Asunto(s)
Glutatión , Leucemia Mielógena Crónica BCR-ABL Positiva , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Glutatión/metabolismo , Humanos , Animales , Ratones , Inhibidores de Proteínas Quinasas/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Línea Celular Tumoral , Proteínas de Fusión bcr-abl/metabolismo , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/antagonistas & inhibidores
15.
iScience ; 27(7): 110346, 2024 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-39055920

RESUMEN

Over 80% of the patients with pancreatic ductal adenocarcinoma (PDAC) have cachexia/wasting syndrome. Cachexia is associated with reduced survival, decreased quality of life, and higher metastasis rates. Here, we demonstrate that fat loss is the earliest feature of PDAC-exosome-induced cachexia. MicroRNA sequencing of exosomal components from normal and cancer-derived exosomes revealed enrichment of miR-16-5p, miR-21-5p, miR-29a-3p, and miR-125b-5p in serum exosomes of mice harboring PDAC and patients with PDAC. Further, miR-16-5p and miR-29a-3p inhibited adipogenesis through decreasing Erlin2 and Cmpk1 expression which downregulates C/EBPß and PPARγ. Synergistically, miR-29a-3p promotes lipolysis through increasing ATGL expression by suppressing MCT1 expression. Furthermore, PDAC-exosomes deprived of miR-16-5p and miR-29a-3p fail to induce fat loss. Hence, miR-16-5p and miR-29a-3p exosomal miRs are essential for PDAC-induced fat loss. Thus, we unravel that PDAC induces adipose atrophy via exosomal miRs. This knowledge may provide new diagnostic and therapeutic strategies for PDAC-induced cachexia.

16.
Int J Mol Sci ; 25(13)2024 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-39000488

RESUMEN

The capsule-associated protein 10 gene (CAP10) is indispensable due to its involvement in pod formation and virulence maintenance in Cryptococcus neoformans. The function of the CAP10 gene in nematode-predatory fungi remains unreported. As a typical nematode-trapping fungus, Dactylellina haptotyla efficiently captures nematodes using adhesive knobs, which has potential applications in the biological control of plant-parasitic nematodes. In this study, we investigated the function of DHXT1 (a CAP10 homologous protein) in D. haptotyla-nematode interactions based on the disruption and overexpression of DHXT1, phenotypic analysis and metabolomic analysis. As a result, it was shown that the disruption of the DHXT1 gene causes a marked decrease in the number of adhesive knobs, and on the contrary, the overexpression of the DHXT1 gene causes a substantial increase in the number of adhesive knobs. Interestingly, the variety of metabolites increased with the disruption of the DHXT1 and decreased with the overexpression of the DHXT1 gene. The results suggest that DHXT1 effects pathogenicity through its involvement in adhesive knobs' formation and metabolite synthesis and serves as a key virulence factor in D. haptotyla.


Asunto(s)
Proteínas Fúngicas , Factores de Virulencia , Factores de Virulencia/metabolismo , Factores de Virulencia/genética , Animales , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/genética , Virulencia , Enfermedades de las Plantas/parasitología , Enfermedades de las Plantas/microbiología
17.
Biomark Med ; 18(8): 373-383, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39041842

RESUMEN

Aim: This retrospective clinical study was designed to examine the predictive value of thromboelastography (TEG) combined with coagulation function for venous thromboembolism (VTE) in hospitalized patients with cancer. Materials & methods: Among 215 patients admitted between May 2020 and January 2022, 39 (18.14%) were diagnosed with VTE during hospitalization. Results: Significant differences were found in D-dimer, ATIII and TEG parameters (maximum amplitude and coagulation index) between VTE-positive and VTE-negative patients (p < 0.05). Multivariate analysis revealed tumor node metastasis stage, concomitant infection, smoking history and D-dimer as independently associated with VTE. The constructed model and D-dimer areas under the curve were 0.809 and 0.764, respectively. Conclusion: TEG parameters were not significantly predictive indicators for VTE, with D-dimer remaining a key predictor.


[Box: see text].


Asunto(s)
Productos de Degradación de Fibrina-Fibrinógeno , Neoplasias , Tromboelastografía , Tromboembolia Venosa , Humanos , Tromboembolia Venosa/sangre , Tromboembolia Venosa/etiología , Tromboembolia Venosa/diagnóstico , Masculino , Femenino , Persona de Mediana Edad , Neoplasias/complicaciones , Neoplasias/sangre , Estudios Retrospectivos , Anciano , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Factores de Riesgo , Factores de Coagulación Sanguínea/metabolismo , Factores de Coagulación Sanguínea/análisis , Adulto
18.
Rev Cardiovasc Med ; 25(5): 183, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-39076489

RESUMEN

Background: Pulmonary artery catheters (PAC) are widely used in patients undergoing off-pump coronary artery bypass (OPCAB) grafting surgery. However, primary data suggested that the benefits of PAC in surgical settings were limited. Therefore, the present study sought to estimate the effects of PAC on the short-term outcomes of patients undergoing OPCAB surgery. Methods: The characteristics, intraoperative data, and postoperative outcomes of consecutive patients undergoing primary, isolated OPCAB surgery from November 2020 to December 2021 were retrospectively extracted. Patients were divided into two groups (PAC and no-PAC) based on PAC insertion status. Data were analyzed with a 1:1 nearest-neighbor propensity score matched-pair in PAC and no-PAC groups. Results: Of the 1004 Chinese patients who underwent primary, isolated OPCAB surgery, 506 (50.39%) had PAC. Propensity score matching yielded 397 evenly balanced pairs. Compared with the no-PAC group (only implanted a central venous catheter), PAC utilization was not associated with improved in-hospital mortality in the entire or matched cohort. Still, the matched cohort showed that PAC utilization increased epinephrine usage and hospital costs. Conclusions: The current study demonstrated no apparent benefit or harm for PAC utilization in OPCAB surgical patients. In addition, PAC utilization was more expensive.

19.
Polymers (Basel) ; 16(13)2024 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-39000642

RESUMEN

Wood-plastic composites are becoming increasingly recognized for their sustainability and their potential for use in various production processes. Nevertheless, enhancing their mechanical strength continues to be a difficult challenge. The objective of this research was to improve the mechanical strength of wood-plastic composite components manufactured through selective laser sintering (SLS). This was achieved by integrating a sustainable composite material, Prosopis chilensis (PCP), with polyethersulfone (PES) to form a composite referred to as PCPC. This study showcased the effect of various PCP particle sizes on mechanical strengths, dimensional accuracies (DAs), and surface roughness of PCPC parts manufactured using AFS-360 SLS. Single-layer sintering was employed to assess PCPC powder's formability with varying PCP particle sizes, and various tests were conducted to understand the materials' thermal properties and analyze particle dispersion and microstructure. The results demonstrated that PCP particle sizes ≤ 0.125 mm significantly enhanced the mechanical strength, forming quality, and DA compared to other particle sizes and pure PES. Key findings for PCPC parts with PCP ≤ 0.125 mm included a bending strength of 10.78 MPa, a tensile strength of 4.94 MPa, an impact strength of 0.91 kJ/m2, and a density of 1.003 g/cm3. Post-processing further improved these parameters, confirming that optimizing PCP particle size is crucial for enhancing the mechanical properties and overall quality of PCPC parts produced via SLS.

20.
Quant Imaging Med Surg ; 14(7): 4436-4449, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-39022267

RESUMEN

Background: Hepatocellular carcinoma (HCC) is often associated with the overexpression of multiple proteins and genes. For instance, patients with HCC and a high expression of the glypican-3 (GPC3) gene have a poor prognosis, and noninvasive assessment of GPC3 expression before surgery is helpful for clinical decision-making. Therefore, our primary aim in this study was to develop and validate multisequence magnetic resonance imaging (MRI) radiomics nomograms for predicting the expression of GPC3 in individuals diagnosed with HCC. Methods: We conducted a retrospective analysis of 143 patients with HCC, including 123 cases from our hospital and 20 cases from The Cancer Genome Atlas (TCGA) or The Cancer Imaging Archive (TCIA) public databases. We used preoperative multisequence MRI images of the patients for the radiomics analysis. We extracted and screened the imaging histologic features using fivefold cross-validation, Pearson correlation coefficient, and the least absolute shrinkage and selection operator (LASSO) analysis method. We used logistic regression (LR) to construct a radiomics model, developed nomograms based on the radiomics scores and clinical parameters, and evaluated the predictive performance of the nomograms using receiver operating characteristic (ROC) curves, calibration curves, and decision curves. Results: Our multivariate analysis results revealed that tumor morphology (P=0.015) and microvascular (P=0.007) infiltration could serve as independent predictors of GPC3 expression in patients with HCC. The nomograms integrating multisequence radiomics radiomics score, tumor morphology, and microvascular invasion had an area under the curve (AUC) value of 0.989. This approach was superior to both the radiomics model (AUC 0.979) and the clinical model (AUC 0.793). The sensitivity, specificity, and accuracy of 0.944, 0.800, and 0.913 for the test set, respectively, and the model's calibration curve demonstrated good consistency (Brier score =0.029). The decision curve analysis (DCA) indicated that the nomogram had a higher net clinical benefit for predicting the expression of GPC3. External validation of the model's prediction yielded an AUC value of 0.826. Conclusions: Our study findings highlight the close association of multisequence MRI imaging and radiomic features with GPC3 expression. Incorporating clinical parameters into nomograms can offer valuable preoperative insights into tailoring personalized treatment plans for patients diagnosed with HCC.

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