Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.810
Filtrar
1.
Anal Methods ; 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38946640

RESUMEN

High-frequency pulse lasers, applied in the form of rapid scanning, act upon the surface of aircraft skin paint layers, thereby removing the paint layers, exhibiting characteristics of efficiency and eco-friendliness. Real-time monitoring of the paint removal effect and prevention of substrate damage necessitates the continuous monitoring of paint removal thickness. Combining Laser-Induced Breakdown Spectroscopy (LIBS) online monitoring technology enables laser-controlled paint removal under multiple effects coupling, meeting the requirements of airworthiness maintenance. This paper, based on a high-frequency nanosecond infrared pulse laser paint removal LIBS monitoring platform, conducts research on laser paint removal thickness LIBS online monitoring of aluminum alloy plates coated with dual-layer paint. Spectra corresponding to the removal thickness of each group are collected and, respectively, paint removal thickness monitoring models based on LIBS spectra are established using the standard curve method and Principal Component Analysis-Support Vector Regression (PCA-SVR) algorithm. When monitoring paint removal thickness using the standard curve method, the intensity of five Ti element characteristic spectral lines selected is correlated with the paint removal thickness, and segmented curve fitting according to the paint layer structure satisfies the segmented curve fitting of topcoat and topcoat + primer. Among them, the average coefficient of the curve fitting of the Ti II 589.088 nm characteristic spectral line is 0.89, and the root mean square error (RMSE) is 12.28 µm. Its performance is superior in the five standard curves; thus, its fitting equation is used as the criterion for paint removal thickness monitoring. To further improve monitoring accuracy, research on paint removal thickness monitoring models based on PCA-SVR is conducted. Compared to the traditional univariate standard curve method, the PCA-SVR model does not require segmented monitoring. After parameter optimization, the average fitting coefficient reaches 0.97, and the RMSE is 2.92 µm. The results indicate that the PCA-SVR-based paint removal thickness monitoring model has higher accuracy, thereby forming the basis for paint removal thickness monitoring. Through comparative research on paint removal thickness monitoring models, two types of paint removal thickness monitoring criteria are obtained, providing model solutions for high-precision monitoring and automation of aircraft skin laser paint removal thickness.

2.
Biomater Res ; 28: 0044, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38952715

RESUMEN

Accurate measurement of gingiva's biomechanical properties in vivo has been an active field of research but remained an unmet challenge. Currently, there are no noninvasive tools that can accurately quantify tensile and shear moduli, which govern gingival health, with sufficiently high accuracy. This study presents the application of high-frequency optical coherence elastography (OCE) for characterizing gingival tissue in both porcine models and human subjects. Dynamic mechanical analysis, histology studies, and strain analysis are performed to support the OCE result. Our findings demonstrate substantial differences in tissue stiffness between supra-dental and inter-dental gingiva, validated by dynamic mechanical analysis and OCE. We confirmed the viscoelastic, nearly linear, and transverse-isotropic properties of gingiva in situ, establishing the reliability of OCE measurements. Further, we investigated the effects of tissue hydration, collagen degradation, and dehydration on gingival stiffness. These conditions showed a decrease and increase in stiffness, respectively. While preliminary, our study suggests OCE's potential in periodontal diagnosis and oral tissue engineering, offering real-time, millimeter-scale resolution assessments of tissue stiffness, crucial for clinical applications and biomaterial optimization in reconstructive surgeries.

3.
Expert Rev Anti Infect Ther ; : 1-12, 2024 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-38975666

RESUMEN

BACKGROUND: The potential of ursodeoxycholic acid (UDCA) in inhibiting angiotensin-converting enzyme 2 was demonstrated. However, conflicting evidence emerged regarding the association between UDCA and COVID-19 outcomes, prompting the need for a comprehensive investigation. RESEARCH DESIGN AND METHODS: Patients diagnosed with COVID-19 infection were retrospectively analyzed and divided into two groups: the UDCA-treated group and the control group. Kaplan-Meier recovery analysis and Cox proportional hazards models were used to evaluate the recovery time and hazard ratios. Additionally, study-level pooled analyses for multiple clinical outcomes were performed. RESULTS: In the 115-patient cohort, UDCA treatment was significantly associated with a reduced recovery time. The subgroup analysis suggests that the 300 mg subgroup had a significant (adjusted hazard ratio: 1.63 [95% CI, 1.01 to 2.60]) benefit with a shorter duration of fever. The results of pooled analyses also show that UDCA treatment can significantly reduce the incidence of severe/critical diseases in COVID-19 (adjusted odds ratio: 0.68 [95% CI, 0.50 to 0.94]). CONCLUSIONS: UDCA treatment notably improves the recovery time following an Omicron strain infection without observed safety concerns. These promising results advocate for UDCA as a viable treatment for COVID-19, paving the way for further large-scale and prospective research to explore the full potential of UDCA.

4.
Chem Biodivers ; : e202400977, 2024 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-38837616

RESUMEN

Two previously uncharacterized compounds, an aconitine-type C19-diterpenoid alkaloid (1) and a napelline-type diterpenoid alkaloid C20-diterpenoid alkaloid (2), as well as ten known compounds (3-12), were isolated from Aconitum pendulum. Their structures were elucidated based on spectroscopic data, including 1D and 2D NMR, IR, HR-ESI-MS, and single-crystal X-ray diffraction analysis. The anti-insecticidal activities of these compounds were evaluated by contact toxicity tests against two-spotted spider mites, and compounds 1, 2, and 9 showed moderate contact toxicity, with LC50 values of 0.86±0.09, 0.95±0.23, and 0.89±0.19 mg/mL, respectively. This study highlights the potential use of diterpenoid alkaloids as natural plant-derived pesticides for the management of plant pests.

5.
BMC Cancer ; 24(1): 755, 2024 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-38907210

RESUMEN

BACKGROUND: The role of hemoglobin (HGB) in common malignant tumors remains unclear. METHODS: A retrospective analysis was conducted to identify the correlation between HGB levels and risk of 15 malignant tumors using 50,085 samples from the National Health and Nutrition Examination Survey. Mendelian Randomization analyses (MRAs) were performed based on genome-wide association study data to assess the causal relationship between HGB levels and these malignant tumors using more than 700,000 samples. The robustness of the MRA results was confirmed through various analytical methods. Fifty-six in-house samples were used to investigate the correlation between HGB levels and the prognosis in prostate cancer (PRCA) using the Kaplan-Meier curve. RESULTS: High HGB levels were associated with a higher risk for patients with cervix cancer, melanoma, and non-melanoma skin cancer (OR > 1.000, p < 0.05). It served as a protective factor for colon cancer, esophagus cancer, stomach cancer, bone cancer, lung cancer, renal cancer, and PRCA (OR < 1.000, p < 0.05). Furthermore, MRAs suggested that elevated HGB levels were correlated with a reduced risk of PRCA (OR = 0.869, p < 0.05), with no significant association observed between this marker and the remaining 14 malignant tumors. No pleiotropy or heterogeneity was found in the ultimate results for MRAs (p-values > 0.05), suggesting the robustness of the results. The results derived from the in-house data revealed a relationship between higher HGB values and a more favorable prognosis in PRCA (p < 0.05). CONCLUSION: High circulating HGB levels may play a protective prognostic role for PRCA and serve as a protective factor against the occurrence of PRCA.


Asunto(s)
Hemoglobinas , Neoplasias , Humanos , Estudios Retrospectivos , Masculino , Femenino , Hemoglobinas/análisis , Neoplasias/epidemiología , Neoplasias/sangre , Neoplasias/genética , Estudio de Asociación del Genoma Completo , Pronóstico , Persona de Mediana Edad , Análisis de la Aleatorización Mendeliana , Factores de Riesgo , Encuestas Nutricionales , Adulto , Anciano , Biomarcadores de Tumor/sangre
6.
Zhongguo Gu Shang ; 37(6): 5605-4, 2024 Jun 25.
Artículo en Chino | MEDLINE | ID: mdl-38910377

RESUMEN

OBJECTIVE: To explore preemptive analgesic effect of preoperative intramural tramadol injection in percutaneous kyphoplasty (PKP) of vertebrae following local anesthesia. METHODS: From August 2019 to June 2021, 118 patients with thoraco lumbar osteoporotic fractures were treated and divided into observation group and control group, with 59 patients in each gruop. In observation group, there were 26 males and 33 females, aged from 57 to 80 years old with an average of (67.69±4.75)years old;14 patients on T11, 12 patients on T12, 18 patients on L1, 15 patients on L2;tramadol with 100 mg was injected intramuscularly half an hour before surgery in observation group. In control group, there were 24 males and 35 females, aged from 55 to 77 years old with an average of (68.00±4.43) years old;19 patients on T11, 11 patients on T12, 17patients on L1, 12 patients on L2;the same amount of normal saline was injected intramuscularly in control group. Observation indicators included operation time, intraoperative bleeding, visual analogue scale (VAS) evaluation and recording of preoperative (T0), intraoperative puncture(T1), and working cannula placement (T2) between two groups of patients, at the time of balloon dilation (T3), when the bone cement was injected into the vertebral body (T4), 2 hours after the operation (T5), and the pain degree at the time of discharge(T6);adverse reactions such as dizziness, nausea and vomiting were observed and recorded;the record the patient's acceptance of repeat PKP surgery. RESULTS: All patients were successfully completed PKP via bilateral pedicle approach, and no intravenous sedative and analgesic drugs were used during the operation. There was no significant difference in preoperative general data and VAS(T0) between two groups (P>0.05). There was no significant difference in operation time and intraoperative blood loss between the two groups (P>0.05). VAS of T1, T2, T3, T4 and T5 in observation group were all lower than those in control group(P<0.05), and there was no significant difference in T6 VAS (P>0.05). T6 VAS between two groups were significantly lower than those of T0, and the difference was statistically significant (P<0.05). There was no significant difference in incidence of total adverse reactions between two groups (P>0.05). There was a statistically significant difference in the acceptance of repeat PKP surgery (P<0.05). CONCLUSION: Half an hour before operation, intramuscular injection of tramadol has a clear preemptive analgesic effect for PKP of single-segment thoracolumbar osteoporotic fracture vertebral body under local anesthesia, which could increase the comfort of patients during operation and 2 hours after operation, and improve patients satisfaction with surgery.


Asunto(s)
Anestesia Local , Cifoplastia , Vértebras Lumbares , Fracturas Osteoporóticas , Vértebras Torácicas , Tramadol , Humanos , Femenino , Masculino , Anciano , Tramadol/administración & dosificación , Persona de Mediana Edad , Cifoplastia/métodos , Vértebras Torácicas/cirugía , Vértebras Torácicas/lesiones , Fracturas Osteoporóticas/cirugía , Vértebras Lumbares/cirugía , Anestesia Local/métodos , Anciano de 80 o más Años , Analgesia/métodos , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/prevención & control , Fracturas de la Columna Vertebral/cirugía , Analgésicos Opioides/administración & dosificación
7.
Regen Ther ; 26: 60-70, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38828010

RESUMEN

Background: Osteoarthritis (OA) is the most frequently diagnosed chronic joint disease. CircSEC24A is significantly elevated in OA chondrocytes upon IL-1ß stimulation. However, its biological function in OA is still not fully understood. Methods: The circRNAs-miRNA-mRNA network was predicted by bioinformatics analysis. An in vitro OA chondrocytes model was established by IL-1ß stimulation. The expression of circSEC24A, miR-107-5p, CASP3, apoptosis-related molecules and extracellular matrix (ECM) components were detected by Western blot and qRT-PCR. MTT assay and Annexin V/PI staining were employed to monitor cell viability and apoptosis, respectively. The interaction between circSEC24A and miR-107-5p, as well as the binding between miR-107-5p and CASP3 3' UTR were detected by luciferase reporter and RIP assays. Cytokine secretion was monitored by ELISA assay. The role of circSEC24A was also explored in anterior cruciate ligament transection (ACLT) rat models. Results: CircSEC24A and CASP3 were increased, but miR-107-5p was decreased in rat OA cartilage tissues and OA chondrocytes. CircSEC24A acted as a sponge of miR-107-5p. Knockdown of circSEC24A promoted chondrocyte proliferation, but suppressed chondrocyte apoptosis, ECM degradation and inflammation via sponging miR-107-5p. CASP3 was identified as a miR-107-5p target gene. MiR-107-5p mimics protected against OA progression via targeting CASP3. Silencing of circSEC24A alleviated OA progression in ACLT model. Conclusion: CircSEC24A promotes OA progression through miR-107-5p/CASP3 axis.

8.
J Hazard Mater ; 476: 134943, 2024 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-38936186

RESUMEN

Developing fast, accurate and sensitive triethylamine gas sensors with low detection limits is paramount to ensure the safety of workers and the public. However, sensors based on single metal oxide materials still suffer from drawbacks such as low response sensitivity and long response and recovery times. To address these challenges, in this work, a series of mesoporous CdO/CdGa2O4 microspheres were synthesized. We optimized the sensor's sensing performance to triethylamine by fine-tuning the ratio of CdO to CdGa2O4. Among them, CdO:3CdGa2O4-based sensor demonstrates a rapid response time of 2 s to detect 100 ppm of triethylamine, with a high response value of 211 and exceptional selectivity. Furthermore, it exhibits a low detection limit of 20 ppb for triethylamine, making it suitable for practically testing fish freshness. Crucially, electron transfer between the heterojunctions increases the chemically adsorbed oxygen on the materials' surface, thereby enhancing the sensor's response sensitivity to triethylamine. This discovery provides new insights and methodologies for the design of highly efficient triethylamine gas sensors.

9.
J Phys Condens Matter ; 36(38)2024 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-38848723

RESUMEN

The two-dimensional transition metal carbide/nitride family (MXenes) has garnered significant attention due to their highly customizable surface functional groups. Leveraging modern material science techniques, the customizability of MXenes can be enhanced further through the construction of associated heterostructures. As indicated by recent research, the Mo2CTx/NiS heterostructure has emerged as a promising candidate exhibiting superior physical and chemical application potential. The geometrical structure of Mo2CTx/NiS heterostructure is modeled and six possible configurations are validated by Density Functional Theory simulations. The variation in functional groups leads to structural changes in Mo2CTx/NiS interfaces, primarily attributed to the competition between van der Waals and covalent interactions. The presence of different functional groups results in significant band fluctuations near the Fermi level for Ni and Mo atoms, influencing the role of atoms and electron's ability to escape near the interface. This, in turn, modulates the strength of covalent interactions at the MXenes/NiS interface and alters the ease of dissociation of the MXenes/NiS complex. Notably, the Mo2CO2/NiS(P63/mmc) heterostructure exhibits polymorphism, signifying that two atomic arrangements can stabilize the structure. The transition process between these polymorphs is also simulated, further indicating the modulation of the electronic level of properties by a sliding operation.

11.
Genomics ; 116(5): 110889, 2024 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-38901654

RESUMEN

Cholangiocarcinoma (CCA) is widely noted for its high degree of malignancy, rapid progression, and limited therapeutic options. This study was carried out on transcriptome data of 417 CCA samples from different anatomical locations. The effects of lipid metabolism related genes and immune related genes as CCA classifiers were compared. Key genes were derived from MVI subtypes and better molecular subtypes. Pathways such as epithelial mesenchymal transition (EMT) and cell cycle were significantly activated in MVI-positive group. CCA patients were classified into three (four) subtypes based on lipid metabolism (immune) related genes, with better prognosis observed in lipid metabolism-C1, immune-C2, and immune-C4. IPTW analysis found that the prognosis of lipid metabolism-C1 was significantly better than that of lipid metabolism-C2 + C3 before and after correction. KRT16 was finally selected as the key gene. And knockdown of KRT16 inhibited proliferation, migration and invasion of CCA cells.

12.
Cell Rep ; 43(7): 114377, 2024 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-38889005

RESUMEN

Bone tissue represents the most frequent site of cancer metastasis. We developed a hemichannel-activating antibody, Cx43-M2. Cx43-M2, directly targeting osteocytes in situ, activates osteocytic hemichannels and elevates extracellular ATP, thereby inhibiting the growth and migration of cultured breast and osteosarcoma cancer cells. Cx43-M2 significantly decreases breast cancer metastasis, osteosarcoma growth, and osteolytic activity, while improving survival rates in mice. The antibody's inhibition of breast cancer and osteosarcoma is dose dependent in both mouse and human cancer metastatic models. Furthermore, Cx43-M2 enhances anti-tumor immunity by increasing the population and activation of tumor-infiltrating immune-promoting effector T lymphocytes, while reducing immune-suppressive regulatory T cells. Our results suggest that the Cx43-M2 antibody, by activating Cx43 hemichannels and facilitating ATP release and purinergic signaling, transforms the cancer microenvironment from a supportive to a suppressive state. Collectively, our study underscores the potential of Cx43-M2 as a therapeutic for treating breast cancer bone metastasis and osteosarcoma.

13.
World J Clin Cases ; 12(17): 2989-2994, 2024 Jun 16.
Artículo en Inglés | MEDLINE | ID: mdl-38898856

RESUMEN

BACKGROUND: Endovascular repair of aortic dissection is an effective method commonly used in the treatment of Stanford type B aortic dissection. Stent placement during the operation was one-time and could not be repeatedly adjusted during the operation. Therefore, it is of great significance for cardiovascular physicians to fully understand the branch status, position, angle, and other information regarding aortic arch dissection before surgery. AIM: To provide more references for clinical cardiovascular physicians to develop treatment plans. METHODS: Data from 153 patients who underwent endovascular repair of aortic dissection at our hospital between January 2021 and December 2022 were retrospectively collected. All patients underwent multi-slice spiral computed tomography angiography. Based on distinct post-image processing techniques, the patients were categorized into three groups: Multiplanar reconstruction (MPR) (n = 55), volume reconstruction (VR) (n = 46), and maximum intensity projection (MIP) (n = 52). The detection rate of aortic rupture, accuracy of the DeBakey classification, rotation, and tilt angles of the C-arm during the procedure, dispersion after stent release, and the incidence of late complications were recorded and compared. RESULTS: The detection rates of interlayer rupture in the MPR and VR groups were significantly higher than that in the MIP group (P < 0.05). The detection rates of DeBakey subtypes I, II, and III in the MPR group were higher than those in the MIP group, and the detection rate of type III in the MPR group was significantly higher than that in the VR group (P < 0.05). There was no statistically significant difference in the detection rates of types I and II compared to the VR group (P > 0.05). The scatter rate of markers and the incidence of complications in the MPR group were significantly lower than those in the VR and MIP groups (P < 0.05). CONCLUSION: The application of MPR in the endovascular repair of aortic dissection has improved the detection rate of dissection rupture, the accuracy of anatomical classification, and safety.

15.
Cardiovasc Res ; 2024 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-38838211

RESUMEN

AIMS: Although the cannabinoid CB1 receptor has been implicated in atherosclerosis, its cell-specific effects in this disease are not well understood. To address this, we generated a transgenic mouse model to study the role of myeloid CB1 signaling in atherosclerosis. METHODS AND RESULTS: Here, we report that male mice with myeloid-specific Cnr1 deficiency on atherogenic background developed smaller lesions and necrotic cores than controls, while only minor genotype differences were observed in females. Male Cnr1 deficient mice showed reduced arterial monocyte recruitment and macrophage proliferation with less inflammatory phenotype. The sex-specific differences in proliferation were dependent on estrogen receptor (ER)α-estradiol signaling. Kinase activity profiling identified a CB1-dependent regulation of p53 and cyclin-dependent kinases. Transcriptomic profiling further revealed chromatin modifications, mRNA processing and mitochondrial respiration among the key processes affected by CB1 signaling, which was supported by metabolic flux assays. Chronic administration of the peripherally-restricted CB1 antagonist JD5037 inhibited plaque progression and macrophage proliferation, but only in male mice. Finally, CNR1 expression was detectable in human carotid endarterectomy plaques and inversely correlated with proliferation, oxidative metabolism and inflammatory markers, suggesting a possible implication of CB1-dependent regulation in human pathophysiology. CONCLUSION: Impaired macrophage CB1 signaling is atheroprotective by limiting their arterial recruitment, proliferation and inflammatory reprogramming in male mice. The importance of macrophage CB1 signaling appears to be sex-dependent.

16.
Chem Commun (Camb) ; 60(50): 6340-6361, 2024 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-38832416

RESUMEN

The C(sp3)-N bond is ubiquitous in natural products, pharmaceuticals, biologically active molecules and functional materials. Consequently, the development of practical and efficient methods for C(sp3)-N bond formation has attracted more and more attention. Compared to the conventional ionic pathway-based thermal methods, photochemical processes that proceed through radical mechanisms by merging photoredox and transition-metal catalyses have emerged as powerful and alternative tools for C(sp3)-N bond formation. In this review, recent advances in the burgeoning field of C(sp3)-N bond formation via metallaphotoredox catalysis have been highlighted. The contents of this review are categorized according to the transition metals used (copper, nickel, cobalt, palladium, and iron) together with photocatalysis. Emphasis is placed on methodology achievements and mechanistic insight, aiming to inspire chemists to invent more efficient radical-involved C(sp3)-N bond-forming reactions.

17.
Nat Commun ; 15(1): 4784, 2024 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-38839772

RESUMEN

Two-dimensional topological insulators hosting the quantum spin Hall effect have application potential in dissipationless electronics. To observe the quantum spin Hall effect at elevated temperatures, a wide band gap is indispensable to efficiently suppress bulk conduction. Yet, most candidate materials exhibit narrow or even negative band gaps. Here, via elegant control of van der Waals epitaxy, we have successfully grown monolayer ZrTe5 on a bilayer graphene/SiC substrate. The epitaxial ZrTe5 monolayer crystalizes in two allotrope isomers with different intralayer alignments of ZrTe3 prisms. Our scanning tunneling microscopy/spectroscopy characterization unveils an intrinsic full band gap as large as 254 meV and one-dimensional edge states localized along the periphery of the ZrTe5 monolayer. First-principles calculations further confirm that the large band gap originates from strong spin-orbit coupling, and the edge states are topologically nontrivial. These findings thus provide a highly desirable material platform for the exploration of the high-temperature quantum spin Hall effect.

18.
Int J Antimicrob Agents ; : 107258, 2024 Jun 22.
Artículo en Inglés | MEDLINE | ID: mdl-38914142

RESUMEN

Tandem amplification of carbapenemase genes increases gene copy number and enhances carbapenem resistance. These amplifications are often heterogeneous, transient, and located on plasmids, which also contribute to heteroresistance. Amplification of encoding genes is especially important for enzymes with low hydrolysis activity, which are often overlooked. Here, we reported an intrinsic oxacillinase oxaAb amplification flanked by ISAba1. The amplification is in the chromosome and contains up to twenty-five repeats. We provided genomic, transcriptomic, and proteomic evidence that the amplification resulted in oxacillinase overproduction. Notably, no point mutations of oxaAb were found during the amplification process. Strains of A. baumannii with intrinsic amplified or external transformed ISAba1-oxaAb exhibited higher meropenem hydrolysis activity. Furthermore, the number of repeats in the amplification decreased gradually over a period of 21 days cultured with carbapenem withdrawal. However, upon re-exposure to meropenem, the ISAba1 flanked oxaAb responded rapidly, with repeat numbers reaching or exceeding pre-carbapenem withdrawal levels within 24 hours. Taken together, these findings suggest that ISAba1-mediated gene amplification and overproduction of intrinsic low-activity oxacillinase oxaAb resulted in carbapenem resistance.

19.
Sci Bull (Beijing) ; 69(13): 2122-2135, 2024 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-38811338

RESUMEN

Targeting oncogenic mutant p53 represents an attractive strategy for cancer treatment due to the high frequency of gain-of-function mutations and ectopic expression in various cancer types. Despite extensive efforts, the absence of a druggable active site for small molecules has rendered these mutants therapeutically non-actionable. Here we develop a selective and effective proteolysis-targeting chimera (PROTAC) for p53-R175H, a common hotspot mutant with dominant-negative and oncogenic activity. Using a novel iterative molecular docking-guided post-SELEX (systematic evolution of ligands by exponential enrichment) approach, we rationally engineer a high-performance DNA aptamer with improved affinity and specificity for p53-R175H. Leveraging this resulting aptamer as a binder for PROTACs, we successfully developed a selective p53-R175H degrader, named dp53m. dp53m induces the ubiquitin-proteasome-dependent degradation of p53-R175H while sparing wildtype p53. Importantly, dp53m demonstrates significant antitumor efficacy in p53-R175H-driven cancer cells both in vitro and in vivo, without toxicity. Moreover, dp53m significantly and synergistically improves the sensitivity of these cells to cisplatin, a commonly used chemotherapy drug. These findings provide evidence of the potential therapeutic value of dp53m in p53-R175H-driven cancers.


Asunto(s)
Aptámeros de Nucleótidos , Neoplasias , Proteolisis , Proteína p53 Supresora de Tumor , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Humanos , Aptámeros de Nucleótidos/farmacología , Proteolisis/efectos de los fármacos , Animales , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Línea Celular Tumoral , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Técnica SELEX de Producción de Aptámeros , Cisplatino/farmacología , Cisplatino/uso terapéutico , Simulación del Acoplamiento Molecular , Mutación , Ensayos Antitumor por Modelo de Xenoinjerto , Complejo de la Endopetidasa Proteasomal/metabolismo , Ratones Desnudos
20.
World J Clin Cases ; 12(14): 2412-2419, 2024 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-38765752

RESUMEN

BACKGROUND: Rectal mucinous adenocarcinoma (MAC) is a rare pathological type of rectal cancer with unique pathological features and a poor prognosis. It is difficult to diagnose and treat early because of the lack of specific manifestations in some aspects of the disease. The common metastatic organs of rectal cancer are the liver and lung; however, rectal carcinoma with metastasis to subcutaneous soft tissue is a rare finding. CASE SUMMARY: In this report, the clinical data, diagnosis and treatment process, and postoperative pathological features of a patient with left waist subcutaneous soft tissue masses were retrospectively analyzed. The patient underwent surgical treatment after admission and recovered well after surgery. The final pathological diagnosis was rectal MAC with left waist subcutaneous soft tissue metastasis. CONCLUSION: Subcutaneous soft tissue metastasis of rectal MAC is rare, and it can suggest that the tumor is disseminated, and it can appear even earlier than the primary malignant tumor, which is occult and leads to a missed diagnosis and misdiagnosis clinically. When a subcutaneous soft tissue mass of unknown origin appears in a patient with rectal cancer, a malignant tumor should be considered.

SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA