RESUMEN
Thrombosis is the primary cause of death in patients with cancer. Resveratrol inhibits platelet activation, a crucial pathophysiological basis of thrombosis, in healthy individuals. However, its effects and mechanisms of action in patients with colon cancer remain unknown. Here, we investigated the effect of resveratrol on platelet adhesion and aggregation in patients with colon cancer. Through numerous in vitro and in vivo analyses, including flow cytometry, western blotting, ELISA, and immunofluorescence and colon cancer rat models, we demonstrated that resveratrol reduced thrombosis in patients with colon cancer by inhibiting the phosphorylation of the MAPK and activating the cyclic-GMP/vasodilator-stimulated phosphoprotein pathway. These findings demonstrate the potential of resveratrol in reducing thrombosis in patients with colon cancer and could be used to develop novel therapeutic strategies for this condition.
Asunto(s)
Moléculas de Adhesión Celular , Neoplasias del Colon , GMP Cíclico , Fosfoproteínas , Activación Plaquetaria , Resveratrol , Trombosis , Resveratrol/farmacología , Resveratrol/uso terapéutico , Trombosis/tratamiento farmacológico , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/complicaciones , Humanos , Animales , Activación Plaquetaria/efectos de los fármacos , Masculino , Ratas , GMP Cíclico/metabolismo , Moléculas de Adhesión Celular/metabolismo , Fosfoproteínas/metabolismo , Femenino , Estilbenos/farmacología , Estilbenos/uso terapéutico , Ratas Sprague-Dawley , Persona de Mediana Edad , Transducción de Señal/efectos de los fármacos , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Agregación Plaquetaria/efectos de los fármacos , Proteínas de MicrofilamentosRESUMEN
Microhydrated closo-boranes have attracted great interest due to their superchaotropic activity related to the well-known Hofmeister effect and important applications in biomedical and battery fields. In this work, we report a combined negative ion photoelectron spectroscopy and quantum chemical investigation on hydrated closo-decaborate clusters [B10H10]2-·nH2O (n = 1-7) with a direct comparison to their analogues [B12H12]2-·nH2O and free water clusters. A single H2O molecule is found to be sufficient to stabilize the intrinsically unstable [B10H10]2- dianion. The first two water molecules strongly interact with the solute forming B-H···H-O dihydrogen bonds while additional water molecules show substantially reduced binding energies. Unlike [B12H12]2-·nH2O possessing a highly structured water network with the attached H2O molecules arranged in a unified pattern by maximizing B-H···H-O dihydrogen bonding, distinct structural arrangements of the water clusters within [B10H10]2-·nH2O are achieved with the water cluster networks from trimer to heptamer resembling free water clusters. Such a distinct difference arises from the variations in size, symmetry, and charge distributions between these two dianions. The present finding again confirms the structural diversity of hydrogen-bonding networks in microhydrated closo-boranes and enriches our understanding of aqueous borate chemistry.
RESUMEN
OBJECTIVE: This study aimed to investigate the efficacy and safety of 3-dimensional printing noncoplanar template (3D-PNCT)-assisted computed tomography (CT)-guided high-dose-rate interstitial brachytherapy (HDR-ISBT) for reirradiation of pelvic recurrent cervical carcinoma after external beam radiotherapy. METHODS: From January 2019 to August 2023, 45 eligible patients were enrolled in this prospective cohort. All patients underwent 3D-PNCT-assisted CT-guided HDR-ISBT with a prescribed dose of 4-7 Gy/fraction to the high-risk clinical target volume (HR-CTV) over 3-8 fractions, either for curative or palliative purposes. The primary endpoints were local progression-free survival (LPFS) and tumor response rate (TRR). The secondary outcome measures included overall survival (OS), toxicities, and symptom resolution. RESULTS: Forty-five patients received 261 fractions of 3D-PNCT-assisted HDR-ISBT. Twenty-nine patients had isolated pelvic recurrence, and 16 patients had simultaneous extra-pelvic or distant recurrences. The TRR was 66.7%. The 2- and 5-year LPFS rates were 30.0% and 25.7%, respectively. The median OS was 23.2 months, and 2- and 5-year OS rates were 49.5% and 34.0%, respectively. The multivariate analysis indicated that squamous cell carcinoma, radical surgery, recurrence-free interval≥12 months, tumor diameter, pelvic recurrence type, and HR-CTV D90≥45 Gy were independent factors influencing LPFS (all p<0.05). D100≥21 Gy, V100≥83%, and V150≥45% were associated with better LPFS (all p<0.05). Tumor diameter and metastasis were independent predictive factors for OS (all p<0.05). The pain relief rate was 66.7% (10/15). Grade 3-4 toxicities occurred in 20.0% of patients. CONCLUSION: 3D-PNCT-assisted HDR-ISBT for reirradiation of recurrent cervical cancer proved to be an effective and safe alternative to radical surgery.
RESUMEN
Fatty infiltration denotes the anomalous accrual of adipocytes in non-adipose tissue, thereby generating toxic substances with the capacity to impede the ordinary physiological functions of various organs. With aging, the musculoskeletal system undergoes pronounced degenerative alterations, prompting heightened scrutiny regarding the contributory role of fatty infiltration in its pathophysiology. Several studies have demonstrated that fatty infiltration affects the normal metabolism of the musculoskeletal system, leading to substantial tissue damage. Nevertheless, a definitive and universally accepted generalization concerning the comprehensive effects of fatty infiltration on the musculoskeletal system remains elusive. As a result, this review summarizes the characteristics of different types of adipose tissue, the pathological mechanisms associated with fatty infiltration in bone, muscle, and the entirety of the musculoskeletal system, examines relevant clinical diseases, and explores potential therapeutic modalities. This review is intended to give researchers a better understanding of fatty infiltration and to contribute new ideas to the prevention and treatment of clinical musculoskeletal diseases.
Asunto(s)
Tejido Adiposo , Enfermedades Musculoesqueléticas , Sistema Musculoesquelético , Humanos , Tejido Adiposo/patología , Tejido Adiposo/metabolismo , Enfermedades Musculoesqueléticas/patología , Enfermedades Musculoesqueléticas/metabolismo , Sistema Musculoesquelético/patología , Sistema Musculoesquelético/metabolismo , Sistema Musculoesquelético/fisiopatología , Animales , Músculo Esquelético/patología , Músculo Esquelético/metabolismo , Adipocitos/patología , Adipocitos/metabolismoRESUMEN
A series of anionic transition metal halides, OsCln- (n = 3-5), have been investigated using a newly developed, home-constructed, cryogenic anion cluster photoelectron spectroscopy. The target anionic species are generated through collision-induced dissociation in a two-stage ion funnel. The measured vertical detachment energies (VDEs) are 3.48, 4.54, and 4.81 eV for n = 3, 4, and 5, respectively. Density functional theory calculations at the B3LYP-D3(BJ)//aug-cc-pVTZ(-pp) level predict the lowest energy structures of the atomic form of OsCln- (n = 3-5) to be a quintet triangle, quartet square, and quintet square-based pyramid, respectively. The CCSD(T)-calculated VDEs and corresponding adiabatic detachment energies agree well with our experimental measurements. Analysis of the corresponding frontier molecular orbitals and charge density differences suggests that the d-orbitals of the transition metal Os play a primary role in the single-photon detachment processes, and the detached electrons originating from different molecular orbitals are distinguishable.
RESUMEN
OBJECTIVE: Our study aimed to explore the influence of gut microbiota and their metabolites on intracranial aneurysms (IA) progression and pinpoint-related metabolic biomarkers derived from the gut microbiome. DESIGN: We recruited 358 patients with unruptured IA (UIA) and 161 with ruptured IA (RIA) from two distinct geographical regions for conducting an integrated analysis of plasma metabolomics and faecal metagenomics. Machine learning algorithms were employed to develop a classifier model, subsequently validated in an independent cohort. Mouse models of IA were established to verify the potential role of the specific metabolite identified. RESULTS: Distinct shifts in taxonomic and functional profiles of gut microbiota and their related metabolites were observed in different IA stages. Notably, tryptophan metabolites, particularly indoxyl sulfate (IS), were significantly higher in plasma of RIA. Meanwhile, upregulated tryptophanase expression and indole-producing microbiota were observed in gut microbiome of RIA. A model harnessing gut-microbiome-derived tryptophan metabolites demonstrated remarkable efficacy in distinguishing RIA from UIA patients in the validation cohort (AUC=0.97). Gut microbiota depletion by antibiotics decreased plasma IS concentration, reduced IA formation and rupture in mice, and downregulated matrix metalloproteinase-9 expression in aneurysmal walls with elastin degradation reduction. Supplement of IS reversed the effect of gut microbiota depletion. CONCLUSION: Our investigation highlights the potential of gut-microbiome-derived tryptophan metabolites as biomarkers for distinguishing RIA from UIA patients. The findings suggest a novel pathogenic role for gut-microbiome-derived IS in elastin degradation in the IA wall leading to the rupture of IA.
RESUMEN
Circular RNAs (circRNAs) are involved in osteoarthritis (OA) progression. This study aimed to investigate the role and molecular mechanisms of circMYO1C in OA. CircMYO1C was upregulated in OA- and interleukin-1ß (IL-1ß)-exposed chondrocytes. The results indicated that circMYO1C knockdown repressed the inflammatory factors (tumor necrosis factor alpha [TNF-α], interleukin-6 [IL-6], interleukin-8 [IL-8], etc.) and apoptosis of chondrocytes following IL-1ß exposure. CircMYO1C was an N6-methyladenosine (m6A)-modified circRNA with m6A characteristics. High mobility group box 1 (HMGB1) was a target of circMYO1C. IL-1ß exposure increased the stability and half-life (t1/2) of HMGB1 mRNA, while silencing circMYO1C reduced HMGB1 mRNA stability. Taken together, circMYO1C targets the m6A/HMGB1 axis to promote chondrocyte apoptosis and inflammation. The present study demonstrates that the circMYO1C/m6A/HMGB1 axis is essential for OA progression, highlighting a novel potential therapeutic target for clinical OA.
RESUMEN
PURPOSE: This study aims to develop radiomics models and a nomogram based on machine learning techniques, preoperative dual-energy computed tomography (DECT) images, clinical and pathological characteristics, to explore the tumor microenvironment (TME) of clear cell renal cell carcinoma (ccRCC). METHODS: We retrospectively recruited of 87 patients diagnosed with ccRCC through pathological confirmation from Center I (training set, n = 69; validation set, n = 18), and collected their DECT images and clinical information. Feature selection was conducted using variance threshold, SelectKBest, and the least absolute shrinkage and selection operator (LASSO). Radiomics models were then established using 14 classifiers to predict TME cells. Subsequently, we selected the most predictive radiomics features to calculate the radiomics score (Radscore). A combined model was constructed through multivariate logistic regression analysis combining the Radscore and relevant clinical characteristics, and presented in the form of a nomogram. Additionally, 17 patients were recruited from Center II as an external validation cohort for the nomogram. The performance of the models was assessed using methods such as the area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis (DCA). RESULTS: The validation set AUC values for the radiomics models assessing CD8+, CD163+, and αSMA+ cells were 0.875, 0.889, and 0.864, respectively. Additionally, the external validation cohort AUC value for the nomogram reaches 0.849 and shows good calibration. CONCLUSION: Radiomics models could allow for non-invasive assessment of TME cells from DECT images in ccRCC patients, promising to enhance our understanding and management of the tumor.
RESUMEN
Alginate is a commercially important polysaccharide widely distributed in brown algae. Carbohydrate-binding modules (CBMs), a class of commonly used polysaccharide-binding proteins, have greatly facilitated the investigations of polysaccharides. Few alginate-binding CBMs have been hitherto reported and structurally characterized. Herein, an unknown domain from a potential PL6 family alginate lyase in the marine bacterium Vibrio breoganii was discovered and recombinantly expressed. The obtained protein, designated VbCBM106, displayed the favorable specificity to alginate. The unique sequence and well-defined function of VbCBM106 reveal a new CBM family (CBM106). Moreover, the structure of VbCBM106 was determined at a 1.5 Å resolution by the X-ray crystallography, which shows a typical ß-sandwich fold comprised of two antiparallel ß-sheets. Site-directed mutagenesis assays confirmed that positively charged polar residues are crucial for the ligand binding of VbCBM106. The discovery of VbCBM106 enriches the toolbox of alginate-binding proteins, and the elucidation of critical residues would guide the future practical applications of VbCBM106.
RESUMEN
Objective: The objective of this study was to evaluate the clinical feasibility of deep learning reconstruction-accelerated thin-slice single-breath-hold half-Fourier single-shot turbo spin echo imaging (HASTEDL) for detecting pancreatic lesions, in comparison with two conventional T2-weighted imaging sequences: compressed-sensing HASTE (HASTECS) and BLADE. Methods: From March 2022 to January 2023, a total of 63 patients with suspected pancreatic-related disease underwent the HASTEDL, HASTECS, and BLADE sequences were enrolled in this retrospectively study. The acquisition time, the pancreatic lesion conspicuity (LCP), respiratory motion artifact (RMA), main pancreatic duct conspicuity (MPDC), overall image quality (OIQ), signal-to-noise ratio (SNR), and contrast-noise-ratio (CNR) of the pancreatic lesions were compared among the three sequences by two readers. Results: The acquisition time of both HASTEDL and HASTECS was 16 s, which was significantly shorter than that of 102 s for BLADE. In terms of qualitative parameters, Reader 1 and Reader 2 assigned significantly higher scores to the LCP, RMA, MPDC, and OIQ for HASTEDL compared to HASTECS and BLADE sequences; As for the quantitative parameters, the SNR values of the pancreatic head, body, tail, and lesions, the CNR of the pancreatic lesion measured by the two readers were also significantly higher for HASTEDL than for HASTECS and BLADE sequences. Conclusions: Compared to conventional T2WI sequences (HASTECS and BLADE), deep-learning reconstructed HASTE enables thin slice and single-breath-hold acquisition with clinical acceptable image quality for detection of pancreatic lesions.
RESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) has a poor prognosis, often characterized by microvascular invasion (MVI). Radiomics and habitat imaging offer potential for preoperative MVI assessment. PURPOSE: To identify MVI in HCC by habitat imaging, tumor radiomic analysis, and peritumor habitat-derived radiomic analysis. STUDY TYPE: Retrospective. SUBJECTS: Three hundred eighteen patients (53 ± 11.42 years old; male = 276) with pathologically confirmed HCC (training:testing = 224:94). FIELD STRENGTH/SEQUENCE: 1.5 T, T2WI (spin echo), and precontrast and dynamic T1WI using three-dimensional gradient echo sequence. ASSESSMENT: Clinical model, habitat model, single sequence radiomic models, the peritumor habitat-derived radiomic model, and the combined models were constructed for evaluating MVI. Follow-up clinical data were obtained by a review of medical records or telephone interviews. STATISTICAL TESTS: Univariable and multivariable logistic regression, receiver operating characteristic (ROC) curve, calibration, decision curve, Delong test, K-M curves, log rank test. A P-value less than 0.05 (two sides) was considered to indicate statistical significance. RESULTS: Habitat imaging revealed a positive correlation between the number of subregions and MVI probability. The Radiomic-Pre model demonstrated AUCs of 0.815 (95% CI: 0.752-0.878) and 0.708 (95% CI: 0.599-0.817) for detecting MVI in the training and testing cohorts, respectively. Similarly, the AUCs for MVI detection using Radiomic-HBP were 0.790 (95% CI: 0.724-0.855) for the training cohort and 0.712 (95% CI: 0.604-0.820) for the test cohort. Combination models exhibited improved performance, with the Radiomics + Habitat + Dilation + Habitat 2 + Clinical Model (Model 7) achieving the higher AUC than Model 1-4 and 6 (0.825 vs. 0.688, 0.726, 0.785, 0.757, 0.804, P = 0.013, 0.048, 0.035, 0.041, 0.039, respectively) in the testing cohort. High-risk patients (cutoff value >0.11) identified by this model showed shorter recurrence-free survival. DATA CONCLUSION: The combined model including tumor size, habitat imaging, radiomic analysis exhibited the best performance in predicting MVI, while also assessing prognostic risk. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.
RESUMEN
Hexavalent chromium, Cr(VI), is a ubiquitous toxic metal that can be reduced to Cr(III) by nano-zero-valent iron (nZVI). Finding out effects of continuous rainfall leaching on the Cr(VI) release and availability remains a problem, needing to be addressed. Whether the Cr(VI) reduction by nZVI and continuous rainfall leaching lead to localized heterogeneity in soil is unclear. Therefore, two in situ high-resolution (HR) techniques of the diffusive gradients in thin-films (DGT) and planar optode were combined with ex situ sampling experiments here. Results demonstrate that nZVI decreased Cr(VI) leaching by 5.60-8.50 % compared to control soils. DGT-measured concentrations of Cr(VI), CDGT-Cr(VI), ranged from 7.31 to 19.4 µg L-1 in the control soils, increasing with depth while CDGT-Cr(VI) in nZVI-treated soils (2.41-6.18 µg L-1) decreased or remained stable with depth. However, simulated acid-rain leaching increases CDGT-Cr(VI) by 1.61-fold in nZVI-treated soils, negatively affecting the remediation. DGT measurements in bulk soils using disc devices are better at capturing the change of Cr(VI) availability at different conditions, whereas 2D-HR DGT mappings did not characterize significant mobilization of Cr(VI) at the micro-scale. These findings emphasize the importance of monitoring Cr(VI) release and availability in remediated soil under acid-rain leaching conditions for effective environment management.
RESUMEN
BACKGROUND: Promoting the balance between bone formation and bone resorption is the main therapeutic goal for postmenopausal osteoporosis (PMOP), and bone marrow mesenchymal stem cells (BMSCs) osteogenic differentiation plays an important regulatory role in this process. Recently, several long non-coding RNAs (lncRNAs) have been reported to play an important regulatory role in the occurrence and development of OP and participates in a variety of physiological and pathological processes. However, the role of lncRNA tissue inhibitor of metalloproteinases 3 (lncTIMP3) remains to be investigated. METHODS: The characteristics of BMSCs isolated from the PMOP rat model were verified by flow cytometry assay, alkaline phosphatase (ALP), alizarin red and Oil Red O staining assays. Micro-CT and HE staining assays were performed to examine histological changes of the vertebral trabeculae of the rats. RT-qPCR and western blotting assays were carried out to measure the RNA and protein expression levels. The subcellular location of lncTIMP3 was analyzed by FISH assay. The targeting relationships were verified by luciferase reporter assay and RNA pull-down assay. RESULTS: The trabecular spacing was increased in the PMOP rats, while ALP activity and the expression levels of Runx2, Col1a1 and Ocn were all markedly decreased. Among the RNA sequencing results of the clinical samples, lncTIMP3 was the most downregulated differentially expressed lncRNA, also its level was significantly reduced in the OVX rats. Knockdown of lncTIMP3 inhibited osteogenesis of BMSCs, whereas overexpression of lncTIMP3 exhibited the reverse results. Subsequently, lncTIMP3 was confirmed to be located in the cytoplasm of BMSCs, implying its potential as a competing endogenous RNA for miRNAs. Finally, the negative targeting correlations of miR-214 between lncTIMP3 and Smad4 were elucidated in vitro. CONCLUSION: lncTIMP3 may delay the progress of PMOP by promoting the activity of BMSC, the level of osteogenic differentiation marker gene and the formation of calcium nodules by acting on the miR-214/Smad4 axis. This finding may offer valuable insights into the possible management of PMOP.
Asunto(s)
Diferenciación Celular , Células Madre Mesenquimatosas , MicroARNs , Osteogénesis , Osteoporosis Posmenopáusica , ARN Largo no Codificante , Proteína Smad4 , Animales , Femenino , Humanos , Ratas , Células de la Médula Ósea/metabolismo , Diferenciación Celular/genética , Modelos Animales de Enfermedad , Células Madre Mesenquimatosas/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Osteogénesis/genética , Osteoporosis Posmenopáusica/genética , Osteoporosis Posmenopáusica/metabolismo , Osteoporosis Posmenopáusica/patología , Ratas Sprague-Dawley , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Proteína Smad4/metabolismo , Proteína Smad4/genética , Inhibidor Tisular de Metaloproteinasa-3/genéticaRESUMEN
In the original publication [...].
RESUMEN
Aggressive nature of colon cancer and current imprecise therapeutic scenarios simulate the development of precise and effective treatment strategies. To achieve this, a tumor environment-activated photosensitized biomimetic nanoplatform (PEG2000-SiNcTI-Ph/CpG-ZIF-8@CM) is fabricated by encapsulating metal-organic framework loaded with developed photosensitizer PEG2000-SiNcTI-Ph and immunoadjuvant CpG oligodeoxynucleotide within fusion cell membrane expressing programmed death protein 1 (PD-1) and cluster of differentiation 47 (CD47). By stumbling across, systematic evaluation, and deciphering with quantum chemical calculations, a unique attribute of tumor environment (low pH plus high concentrations of adenosine 5'-triphosphate (ATP))-activated photodynamic effect sensitized by long-wavelength photons is validated for PEG2000-SiNcTI-Ph/CpG-ZIF-8@CM, advancing the precision of cancer therapy. Moreover, PEG2000-SiNcTI-Ph/CpG-ZIF-8@CM evades immune surveillance to target CT26 colon tumors in mice mediated by CD47/signal regulatory proteins α (SIRPα) interaction and PD-1/programmed death ligand 1 (PD-L1) interaction, respectively. Tumor environment-activated photodynamic therapy realized by PEG2000-SiNcTI-Ph/CpG-ZIF-8@CM induces immunogenic cell death (ICD) to elicit anti-tumor immune response, which is empowered by enhanced dendritic cells (DC) uptake of CpG and PD-L1 blockade contributed by the nanoplatform. The photodynamic immunotherapy efficiently combats primary and distant CT26 tumors, and additionally generates immune memory to inhibit tumor recurrence and metastasis. The nanoplatform developed here provides insights for the development of precise cancer therapeutic strategies.
Asunto(s)
Neoplasias del Colon , Inmunoterapia , Fotoquimioterapia , Fármacos Fotosensibilizantes , Animales , Ratones , Fotoquimioterapia/métodos , Neoplasias del Colon/inmunología , Neoplasias del Colon/terapia , Neoplasias del Colon/tratamiento farmacológico , Inmunoterapia/métodos , Fármacos Fotosensibilizantes/farmacología , Modelos Animales de Enfermedad , Microambiente Tumoral/efectos de los fármacos , Oligodesoxirribonucleótidos/farmacología , Biomimética/métodos , Ratones Endogámicos BALB C , Nanopartículas/química , Línea Celular Tumoral , Receptor de Muerte Celular Programada 1/inmunología , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/farmacologíaRESUMEN
Fluorescent imaging and biosensing in the near-infrared-II (NIR-II) window holds great promise for non-invasive, radiation-free, and rapid-response clinical diagnosis. However, it's still challenging to develop bright NIR-II fluorophores. In this study, we report a new strategy to enhance the brightness of NIR-II aggregation-induced emission (AIE) fluorophores through intramolecular electrostatic locking. By introducing sulfur atoms into the side chains of the thiophene bridge in TSEH molecule, the molecular motion of the conjugated backbone can be locked through intramolecular interactions between the sulfur and nitrogen atoms. This leads to enhanced NIR-II fluorescent emission of TSEH in both solution and aggregation states. Notably, the encapsulated nanoparticles (NPs) of TSEH show enhanced brightness, which is 2.6-fold higher than TEH NPs with alkyl side chains. The in vivo experiments reveal the feasibility of TSEH NPs in vascular and tumor imaging with a high signal-to-background ratio and precise resection for tiny tumors. In addition, polystyrene nanospheres encapsulated with TSEH are utilized for antigen detection in lateral flow assays, showing a signal-to-noise ratio 1.9-fold higher than the TEH counterpart in detecting low-concentration antigens. This work highlights the potential for developing bright NIR-II fluorophores through intramolecular electrostatic locking and their potential applications in clinical diagnosis and biomedical research.
Asunto(s)
Colorantes Fluorescentes , Rayos Infrarrojos , Imagen Óptica , Electricidad Estática , Colorantes Fluorescentes/química , Humanos , Nanopartículas/química , Tiofenos/química , Animales , Ratones , Estructura MolecularRESUMEN
Nucleases are a super family of enzymes that hydrolyze phosphodiester bonds present in genomes. They widely vary in substrates, causing differentiation in cleavage patterns and having a diversified role in maintaining genetic material. Through cellular evolution of prokaryotic to eukaryotic, nucleases become structure-specific in recognizing its own or foreign genomic DNA/RNA configurations as its substrates, including flaps, bubbles, and Holliday junctions. These special structural configurations are commonly found as intermediates in processes like DNA replication, repair, and recombination. The structure-specific nature and diversified functions make them essential to maintaining genome integrity and evolution in normal and cancer cells. In this article, we review their roles in various pathways, including Okazaki fragment maturation during DNA replication, end resection in homology-directed recombination repair of DNA double-strand breaks, DNA excision repair and apoptosis DNA fragmentation in response to exogeneous DNA damage, and HIV life cycle. As the nucleases serve as key points for the DNA dynamics, cellular apoptosis, and cancer cell survival pathways, we discuss the efforts in the field in developing the therapeutic regimens, taking advantage of recently available knowledge of their diversified structures and functions.
RESUMEN
An experimental validation of a robotic system for radioactive iodine-125 seed implantation (RISI) in tumor treatment was conducted using customized phantom models and animal models simulating liver and lung lesions. The robotic system, consisting of planning, navigation, and implantation modules, was employed to implant dummy radioactive seeds into the models. Fiducial markers were used for target localization. In phantom experiments across 40 cases, the mean errors between planned and actual seed positions were 0.98 ± 1.05 mm, 1.14 ± 0.62 mm, and 0.90 ± 1.05 mm in the x, y, and z directions, respectively. The x, y, and z directions correspond to the left-right, anterior-posterior, and superior-inferior anatomical planes. Silicone phantoms exhibiting significantly smaller x-axis errors compared to liver and lung phantoms (p < 0.05). Template assistance significantly reduced errors in all axes (p < 0.05). No significant dosimetric deviations were observed in parameters such as D90, V100, and V150 between plans and post-implant doses (p > 0.05). In animal experiments across 23 liver and lung cases, the mean implantation errors were 1.28 ± 0.77 mm, 1.66 ± 0.69 mm, and 1.86 ± 0.93 mm in the x, y, and z directions, slightly higher than in phantoms (p < 0.05), with no significant differences between liver and lung models. The dosimetric results closely matched planned values, confirming the accuracy of the robotic system for RISI, offering new possibilities in clinical tumor treatment.
Asunto(s)
Radioisótopos de Yodo , Neoplasias Pulmonares , Fantasmas de Imagen , Procedimientos Quirúrgicos Robotizados , Procedimientos Quirúrgicos Robotizados/métodos , Procedimientos Quirúrgicos Robotizados/instrumentación , Radioisótopos de Yodo/uso terapéutico , Animales , Neoplasias Pulmonares/radioterapia , Braquiterapia/métodos , Braquiterapia/instrumentación , Neoplasias Hepáticas/radioterapia , Humanos , Marcadores FiducialesRESUMEN
Background: Previous observational studies have demonstrated a link between diabetes mellitus(DM) and primary biliary cholangitis (PBC). Nevertheless, since these relationships might be confused, whether there is any causal connection or in which direction it exists is unclear. Our investigation aimed to identify the causal associations between DM and PBC. Methods: We acquired genome-wide association study (GWAS) datasets for PBC, Type 1 diabetes(T1DM), and Type 2 diabetes(T2DM) from published GWASs. Inverse variance-weighted (IVW), MR-Egger, weighted median (WM), Simple mode, and weighted mode methods were used to determine the causal relationships between DM(T1DM or T2DM) and PBC. Sensitivity analyses were also carried out to ensure the results were robust. To determine the causal relationship between PBC and DM(T1DM or T2DM), we also used reverse MR analysis. Results: T1DM was associated with a higher risk of PBC (OR 1.1525; 95% CI 1.0612-1.2517; p = 0.0007) in the IVW method, but no evidence of a causal effect T2DM on PBC was found (OR 0.9905; 95% CI 0.8446-1.1616; p = 0.9071) in IVW. Results of the reverse MR analysis suggested genetic susceptibility that PBC was associated with an increased risk of T1DM (IVW: OR 1.1991; 95% CI 1.12-1.2838; p = 1.81E-07), but no evidence of a causal effect PBC on T2DM was found (IVW: OR 1.0101; 95% CI 0.9892-1.0315; p = 0.3420). Conclusion: The current study indicated that T1DM increased the risk of developing PBC and vice versa. There was no proof of a causal connection between PBC probability and T2DM. Our results require confirmation through additional replication in larger populations.