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1.
Magn Reson Med ; 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38730565

RESUMO

PURPOSE: To develop a highly accelerated multi-echo spin-echo method, TEMPURA, for reducing the acquisition time and/or increasing spatial resolution for kidney T2 mapping. METHODS: TEMPURA merges several adjacent echoes into one k-space by either combining independent echoes or sharing one echo between k-spaces. The combined k-space is reconstructed based on compressed sensing theory. Reduced flip angles are used for the refocusing pulses, and the extended phase graph algorithm is used to correct the effects of indirect echoes. Two sequences were developed: a fast breath-hold sequence; and a high-resolution sequence. The performance was evaluated prospectively on a phantom, 16 healthy subjects, and two patients with different types of renal tumors. RESULTS: The fast TEMPURA method reduced the acquisition time from 3-5 min to one breath-hold (18 s). Phantom measurements showed that fast TEMPURA had a mean absolute percentage error (MAPE) of 8.2%, which was comparable to a standardized respiratory-triggered sequence (7.4%), but much lower than a sequence accelerated by purely k-t undersampling (21.8%). High-resolution TEMPURA reduced the in-plane voxel size from 3 × 3 to 1 × 1 mm2, resulting in improved visualization of the detailed anatomical structure. In vivo T2 measurements demonstrated good agreement (fast: MAPE = 1.3%-2.5%; high-resolution: MAPE = 2.8%-3.3%) and high correlation coefficients (fast: R = 0.85-0.98; high-resolution: 0.82-0.96) with the standardized method, outperforming k-t undersampling alone (MAPE = 3.3-4.5%, R = 0.57-0.59). CONCLUSION: TEMPURA provides fast and high-resolution renal T2 measurements. It has the potential to improve clinical throughput and delineate intratumoral heterogeneity and tissue habitats at unprecedented spatial resolution.

2.
Immunol Cell Biol ; 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38714318

RESUMO

The development of in vitro models is essential for a comprehensive understanding and investigation of pulmonary fibrosis (PF) at both cellular and molecular levels. This study presents a literature review and an analysis of various cellular models used in scientific studies, specifically focusing on their applications in elucidating the pathogenesis of PF. Our study highlights the importance of taking a comprehensive approach to studing PF, emphasizing the necessity of considering multiple cell types and organs and integrating diverse analytical perspectives. Notably, primary cells demonstrate remarkable cell growth characteristics and gene expression profiles; however, their limited availability, maintenance challenges, inability for continuous propagation and susceptibility to phenotypic changes over time significantly limit their utility in scientific investigation. By contrast, immortalized cell lines are easily accessible, cultured and continuously propagated, although they may have some phenotypic differences from primary cells. Furthermore, in vitro coculture models offer a more practical and precise method to explore complex interactions among cells, tissues and organs. Consequently, when developing models of PF, researchers should thoroughly assess the advantages, limitations and relevant mechanisms of different cell models to ensure their selection is consistent with the research objectives.

3.
Transl Pediatr ; 13(4): 682-689, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38715676

RESUMO

Background: Caroli syndrome or Caroli disease is characterized by focal dilation of the intrahepatic bile ducts, with or without congenital liver fibrosis. Mutations in the WDR19 gene can result in nephropathy, an autosomal recessive cystic kidney disease. However, this genetic mutation is clinically associated with Caroli syndrome or disease. We hypothesize that WDR19 gene mutations may contribute to extrarenal phenotypes such as Caroli disease or syndrome. Case Description: The outpatient department received a 1-year-old male patient with persistent dilated bile ducts for over four months. Subsequent ultrasound examination revealed liver cirrhosis, splenomegaly, and cystic dilatation of the intrahepatic bile duct. He was subsequently admitted for comprehensive diagnosis and treatment. Accordingly, we performed computed tomography (CT)-hepatic portal venography, magnetic resonance-cholangiography, and the plain liver scan, the results revealed liver cirrhosis, splenomegaly, cystic dilatation of the intrahepatic bile duct, as well as atypical hyperplasia nodules in the right posterior lobe of the liver and lymphatic hyperplasia and enlargement in the porta hepatis and the space between the liver and stomach. As the possibility of early small liver cancer could not be excluded due to the presence of nodules, surgical resection was performed followed by pathological examination and whole genome exome testing. The pathological findings revealed hepatocyte swelling, hydropic degeneration, and sporadic necrosis. Fibrous tissue hyperplasia was observed in the portal vein area, along with local pseudolobule formation. Also, numerous small bile duct hyperplasia was observed with lymphocyte infiltration, which is consistent with cirrhosis. Moreover, the hepatocytes of the small focal area showed atypical hyperplasia. Considering the above findings, Caroli syndrome was diagnosed. The genetic results showed two heterozygous mutations in the WDR19 gene, c.2290delC (p.Q764Nfs*29) and c.2401G>C (p.G801R). Therefore, the child's intrahepatic bile duct dilatation and cirrhosis were considered as the manifestations of Caroli syndrome caused by mutations in the WDR19 gene. Conclusions: Mutations in the WDR19 gene can manifest as Caroli disease or Caroli syndrome. For the definite diagnosis of liver diseases of unknown etiology, whole exome sequencing may be more conducive.

4.
Comput Med Imaging Graph ; 115: 102388, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38692200

RESUMO

Rib cross-sectional shapes (characterized by the outer contour and cortical bone thickness) affect the rib mechanical response under impact loading, thereby influence the rib injury pattern and risk. A statistical description of the rib shapes or their correlations to anthropometrics is a prerequisite to the development of numerical human body models representing target demographics. Variational autoencoders (VAE) as anatomical shape generators remain to be explored in terms of utilizing the latent vectors to control or interpret the representativeness of the generated results. In this paper, we propose a pipeline for developing a multi-rib cross-sectional shape generative model from CT images, which consists of the achievement of rib cross-sectional shape data from CT images using an anatomical indexing system and regular grids, and a unified framework to fit shape distributions and associate shapes to anthropometrics for different rib categories. Specifically, we collected CT images including 3193 ribs, surface regular grid is generated for each rib based on anatomical coordinates, the rib cross-sectional shapes are characterized by nodal coordinates and cortical bone thickness. The tensor structure of shape data based on regular grids enable the implementation of CNNs in the conditional variational autoencoder (CVAE). The CVAE is trained against an auxiliary classifier to decouple the low-dimensional representations of the inter- and intra- variations and fit each intra-variation by a Gaussian distribution simultaneously. Random tree regressors are further leveraged to associate each continuous intra-class space with the corresponding anthropometrics of the subjects, i.e., age, height and weight. As a result, with the rib class labels and the latent vectors sampled from Gaussian distributions or predicted from anthropometrics as the inputs, the decoder can generate valid rib cross-sectional shapes of given class labels (male/female, 2nd to 11th ribs) for arbitrary populational percentiles or specific age, height and weight, which paves the road for future biomedical and biomechanical studies considering the diversity of rib shapes across the population.

5.
Cancer Med ; 13(7): e6966, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38572962

RESUMO

OBJECTIVE: Examine the influence of household income on health-related quality of life (HRQOL) among children with newly diagnosed acute myeloid leukemia (AML). DESIGN: Secondary analysis of data prospectively collected from pediatric patients receiving treatment for AML at 14 hospitals across the United States. EXPOSURE: Household income was self-reported on a demographic survey. The examined mediators included the acuity of presentation and treatment toxicity. OUTCOME: Caregiver proxy reported assessment of patient HRQOL from the Peds QL 4.0 survey. RESULT: Children with AML (n = 131) and caregivers were prospectively enrolled to complete PedsQL assessments. HRQOL scores were better for patients in the lowest versus highest income category (mean ± SD: 76.0 ± 14 household income <$25,000 vs. 59.9 ± 17 income ≥$75,000; adjusted mean difference: 11.2, 95% CI: 2.2-20.2). Seven percent of enrolled patients presented with high acuity (ICU-level care in the first 72 h), and 16% had high toxicity (any ICU-level care); there were no identifiable differences by income, refuting mediating roles in the association between income and HRQOL. Enrolled patients were less likely to be Black/African American (9.9% vs. 22.2%), more likely to be privately insured (50.4% vs. 40.7%), and more likely to have been treated on a clinical trial (26.7% vs. 18.5%) compared to eligible unenrolled patients not enrolled. Evaluations of potential selection bias on the association between income and HRQOL suggested differences in HRQOL may be smaller than observed or even in the opposing direction. CONCLUSIONS: While primary analyses suggested lower household income was associated with superior HRQOL, differential participation may have biased these results. Future studies should partner with patients/families to identify strategies for equitable participation in clinical research.


Assuntos
Equidade em Saúde , Leucemia Mieloide Aguda , Criança , Humanos , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/terapia , Qualidade de Vida , Viés de Seleção , Inquéritos e Questionários , Ensaios Clínicos como Assunto
6.
Biomater Sci ; 12(10): 2660-2671, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38592706

RESUMO

The endo-lysosomal pathway is a major barrier for the trans-epithelial transport of nanoparticles (NPs), but escape strategies could facilitate trans-epithelial delivery. Based on the polarization properties of the epithelium, different escape compartments may result in different exocytosis fates of NPs and further affect the delivery efficiency. Therefore, optimizing the escape sites is critical for trans-epithelial delivery. Here, commonly used PEG-coated-poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles were fabricated as model nanoparticles (MNPs) and the intestinal epithelium was chosen as the polarized epithelium. The MNPs were incubated with different endosomolytic agents for early endosomal escape, late endosomal escape and lysosomal escape, respectively. According to in vitro and in vivo studies, MNPs escaping from early endosomes and late endosomes exhibited stronger capacity for trans-epithelial transport than those escaping from lysosomes. By further probing into the mechanism, we surprisingly found that although MNPs escaping from early endosomes quickly egressed from the apical side of epithelia, they were subsequently followed by "reuptake" via caveolae and trafficked through the endoplasmic reticulum-Golgi apparatus (ER/GA) secretory pathway, achieving efficient trans-epithelial transport; MNPs escaping from late endosomes, which were located near the nucleus, were prone to enter the ER/GA for efficient basolateral exocytosis. However, MNPs escaping from lysosomes were detained within cells by autophagosomes. Collectively, our research suggested that early endosomes and late endosomes were ideal escape sites for trans-epithelial delivery.


Assuntos
Endossomos , Exocitose , Lisossomos , Nanopartículas , Lisossomos/metabolismo , Exocitose/fisiologia , Animais , Nanopartículas/química , Endossomos/metabolismo , Polietilenoglicóis/química , Humanos , Camundongos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Cães , Mucosa Intestinal/metabolismo
7.
Int J Mol Sci ; 25(7)2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38612752

RESUMO

Excessive sodium intake is associated with nephrolithiasis, but the impact of sodium-deficient (SD) diets is unknown. Hence, we investigated the effects of short- and long-term SD diets on the expression of renal aquaporins and sodium transporters, and thus calcium oxalate (CaOx) crystal formation in hyperoxaluria rats. In a short-term sodium balance study, six male rats received drinking water and six received 0.75% ethylene glycol (EG) to induce hyperoxaluria. After a 30-day period of feeding on normal chow, both groups were treated with a normal-sodium diet for 5 days, followed by a sodium-free diet for the next 5 days. In a long-term SD study (42 days), four groups, induced with EG or not, were treated with normal-sodium water and sodium-free drinking water, alternately. Short-term sodium restriction in EG rats reversed the daily positive sodium balance, but progressively caused a negative cumulative water balance. In the long-term study, the abundant levels of of Na/H exchanger, thiazide-sensitive Na-Cl cotransporter, Na-K-ATPase, and aquaporins-1 from SD + EG rats were markedly reduced, corresponding to a decrease in Uosm, as compared to SD rats. Increased urine calcium, AP(CaOx)index, and renal CaOx deposition were also noted in SD + EG rats. Although the SD treatment reduced sodium excretion, it also increased urinary calcium and impaired renal function, ultimately causing the formation of more CaOx crystals.


Assuntos
Água Potável , Hipercalcemia , Hiperoxalúria , Hiponatremia , Masculino , Animais , Ratos , Sódio , Oxalato de Cálcio , Cálcio , Rim
8.
Front Plant Sci ; 15: 1371435, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38660445

RESUMO

Introduction: Low-light-stress is a common meteorological disaster that can result in slender seedlings. The photoreceptors play a crucial role in perceiving and regulating plants' tolerance to low-light-stress. However, the low-light-stress tolerance of cucumber has not been effectively evaluated, and the functions of these photoreceptor genes in cucumber, particularly under low-light-stress conditions, are not clear. Methods: Herein, we evaluated the growth characteristics of cucumber seedlings under various LED light treatment. The low-light-stress tolerant cucumber CR and intolerant cucumber CR were used as plant materials for gene expression analysis, and then the function of CsCRY1 was analyzed. Results: The results revealed that light treatment below 40 µmol m-2 s-1 can quickly and effectively induce low-light-stress response. Then, cucumber CR exhibited remarkable tolerance to low-light-stress was screened. Moreover, a total of 11 photoreceptor genes were identified and evaluated. Among them, the cryptochrome 1 (CRY1) had the highest expression level and was only induced in the low-light sensitive cucumber CS. The transcript CsaV3_3G047490.1 is predicted to encode a previously unknown CsCRY1 protein, which lacks 70 amino acids at its C-terminus due to alternative 5' splice sites within the final intron of the CsCRY1 gene. Discussion: CRY1 is a crucial photoreceptor that plays pivotal roles in regulating plants' tolerance to low-light stress. In this study, we discovered that alternative splicing of CsCRY1 generates multiple transcripts encoding distinct CsCRY1 protein variants, providing valuable insights for future exploration and utilization of CsCRY1 in cucumber.

9.
J Control Release ; 370: 152-167, 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38641020

RESUMO

Ligand-modified nanocarriers can promote oral or inhalative administration of macromolecular drugs across the intestinal or pulmonary mucosa. However, enhancing the unidirectional transport of the nanocarriers through "apical uptake→intracellular transport→basolateral exocytosis" route remains a hot topic and challenge in current research. Forskolin is a naturally occurring diterpenoid compound extracted from the roots of C. forskohlii. In our studies, we found that forskolin could increase the transcellular transport of butyrate-modified nanoparticles by 1.67-fold and 1.20-fold in Caco-2 intestinal epithelial cell models and Calu-3 lung epithelial cell models, respectively. Further mechanistic studies revealed that forskolin, on the one hand, promoted the cellular uptake of butyrate-modified nanoparticles by upregulating the expression of monocarboxylic acid transporter-1 (MCT-1) on the apical membrane. On the other hand, forskolin facilitated the binding of MCT-1 to caveolae, thereby mediating butyrate-modified nanoparticles hijacking caveolae to promote the basolateral exocytosis of butyrate-modified nanoparticles. Studies in normal mice model showed that forskolin could promote the transmucosal absorption of butyrate-modified nanoparticles by >2-fold, regardless of oral or inhalative administration. Using semaglutide as the model drug, both oral and inhalation delivery approaches demonstrated significant hypoglycemic effects in type 2 diabetes mice model, in which inhalative administration was more effective than oral administration. This study optimized the strategies aimed at enhancing the transmucosal absorption of ligand-modified nanocarriers in the intestinal or pulmonary mucosa.

10.
Cardiovasc Diabetol ; 23(1): 139, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38664790

RESUMO

BACKGROUND: Diabetic cardiomyopathy (DCM) poses a growing health threat, elevating heart failure risk in diabetic individuals. Understanding DCM is crucial, with fibroblasts and endothelial cells playing pivotal roles in driving myocardial fibrosis and contributing to cardiac dysfunction. Advances in Multimodal single-cell profiling, such as scRNA-seq and scATAC-seq, provide deeper insights into DCM's unique cell states and molecular landscape for targeted therapeutic interventions. METHODS: Single-cell RNA and ATAC data from 10x Multiome libraries were processed using Cell Ranger ARC v2.0.1. Gene expression and ATAC data underwent Seurat and Signac filtration. Differential gene expression and accessible chromatin regions were identified. Transcription factor activity was estimated with chromVAR, and Cis-coaccessibility networks were calculated using Cicero. Coaccessibility connections were compared to the GeneHancer database. Gene Ontology analysis, biological process scoring, cell-cell communication analysis, and gene-motif correlation was performed to reveal intricate molecular changes. Immunofluorescent staining utilized various antibodies on paraffin-embedded tissues to verify the findings. RESULTS: This study integrated scRNA-seq and scATAC-seq data obtained from hearts of WT and DCM mice, elucidating molecular changes at the single-cell level throughout the diabetic cardiomyopathy progression. Robust and accurate clustering analysis of the integrated data revealed altered cell proportions, showcasing decreased endothelial cells and macrophages, coupled with increased fibroblasts and myocardial cells in the DCM group, indicating enhanced fibrosis and endothelial damage. Chromatin accessibility analysis unveiled unique patterns in cell types, with heightened transcriptional activity in myocardial cells. Subpopulation analysis highlighted distinct changes in cardiomyocytes and fibroblasts, emphasizing pathways related to fatty acid metabolism and cardiac contraction. Fibroblast-centered communication analysis identified interactions with endothelial cells, implicating VEGF receptors. Endothelial cell subpopulations exhibited altered gene expressions, emphasizing contraction and growth-related pathways. Candidate regulators, including Tcf21, Arnt, Stat5a, and Stat5b, were identified, suggesting their pivotal roles in DCM development. Immunofluorescence staining validated marker genes of cell subpopulations, confirming PDK4, PPARγ and Tpm1 as markers for metabolic pattern-altered cardiomyocytes, activated fibroblasts and endothelial cells with compromised proliferation. CONCLUSION: Our integrated scRNA-seq and scATAC-seq analysis unveils intricate cell states and molecular alterations in diabetic cardiomyopathy. Identified cell type-specific changes, transcription factors, and marker genes offer valuable insights. The study sheds light on potential therapeutic targets for DCM.


Assuntos
Cardiomiopatias Diabéticas , Análise de Célula Única , Transcriptoma , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Cardiomiopatias Diabéticas/fisiopatologia , Animais , Perfilação da Expressão Gênica , Cromatina/metabolismo , Cromatina/genética , Camundongos Endogâmicos C57BL , Redes Reguladoras de Genes , Montagem e Desmontagem da Cromatina , Modelos Animais de Doenças , Masculino , RNA-Seq , Regulação da Expressão Gênica , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Camundongos , Células Endoteliais/metabolismo , Células Endoteliais/patologia
11.
J Mater Chem B ; 12(16): 3970-3983, 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38563351

RESUMO

Lipoic acid (LA), which has good safety and oral absorption, is obtained from various plant-based food sources and needs to be supplemented through human diet. Moreover, substances with a disulfide structure can enter cells through dynamic covalent disulfide exchange with thiol groups on the cell membrane surface. Based on these factors, we constructed LA-modified nanoparticles (LA NPs). Our results showed that LA NPs can be internalized into intestinal epithelial cells through surface thiols, followed by intracellular transcytosis via the endoplasmic reticulum-Golgi pathway. Further mechanistic studies indicated that disulfide bonds within the structure of LA play a critical role in this transport process. In a type I diabetes rat model, the oral administration of insulin-loaded LA NPs exhibited a more potent hypoglycemic effect, with a pharmacokinetic bioavailability of 5.42 ± 0.53%, representing a 1.6 fold enhancement compared to unmodified PEG NPs. Furthermore, a significant upregulation of surface thiols in inflammatory macrophages was reported. Thus, we turned our direction to investigate the uptake behavior of inflammatory macrophages with increased surface thiols towards LA NPs. Inflammatory macrophages showed a 2.6 fold increased uptake of LA NPs compared to non-inflammatory macrophages. Surprisingly, we also discovered that the antioxidant resveratrol facilitates the uptake of LA NPs in a concentration-dependent manner. This is mainly attributed to an increase in glutathione, which is involved in thiol uptake. Consequently, we employed LA NPs loaded with resveratrol for the treatment of colitis and observed a significant alleviation of colitis symptoms. These results suggest that leveraging the variations of thiol expression levels on cell surfaces under both healthy and diseased states through an oral drug delivery system mediated by the small-molecule nutrient LA can be employed for the treatment of diabetes and certain inflammatory diseases.


Assuntos
Compostos de Sulfidrila , Ácido Tióctico , Ácido Tióctico/química , Animais , Compostos de Sulfidrila/química , Administração Oral , Ratos , Humanos , Nanopartículas/química , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/administração & dosagem , Sistemas de Liberação de Medicamentos , Masculino , Inflamação/tratamento farmacológico , Camundongos , Propriedades de Superfície , Portadores de Fármacos/química , Insulina/metabolismo , Ratos Sprague-Dawley , Tamanho da Partícula , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Células RAW 264.7
13.
Artigo em Inglês | MEDLINE | ID: mdl-38639909

RESUMO

Building envelope features (BEFs) have attracted more and more attention as they have a significant impact on flow structure and pollutant dispersion within street canyons. This paper conducted CFD numerical models validated by wind-tunnel experiments, to explore the effects of the BEFs on characteristics of the airflow and pollutant distribution inside a symmetric street canyon under perpendicular incoming flow. Three different BEFs (balconies, overhangs, and wing walls) and their locations and continuity/discontinuity structures were considered. For each canyon with various BEFs, the air exchange rate (ACH), airflow patterns, and pollutant distributions were evaluated and compared in detail. The results show that compared to the regular canyon, the BEFs will reduce the ACH of the canyon, but increase the disturbances (the proportion of ACH') inside the canyon. The BEFs on the leeward wall have the least influence on the in-canyon airflow and pollutant distributions, followed by that on the windward wall. Then when the BEFs are on both walls, the ventilation capacity of the canyon is weakened greatly, and the pollutant concentration in the ground center is increased significantly, especially near the windward side. Moreover, the discontinuity BEFs will weaken the effect of the continuity BEFs on the in-canyon flow and dispersion, specifically, the discontinuity BEFs reduced the region of high pollutant concentration distributions. These findings can help optimize the BEFs design to enhance ventilation and mitigate traffic pollution.

14.
Adv Mater ; : e2313511, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38597395

RESUMO

Moiré superlattices, consisting of rotationally aligned 2D atomically thin layers, provide a highly novel platform for the study of correlated quantum phenomena. However, reliable and efficient construction of moiré superlattices is challenging because of difficulties to accurately angle-align small exfoliated 2D layers and the need to shun wet-transfer processes. Here, efficient and precise construction of various moiré superlattices is demonstrated by picking up and stacking large-area 2D mono- or few-layer crystals with predetermined crystal axes, made possible by a gold-template-assisted mechanical exfoliation method. The exfoliated 2D layers are semiconductors, superconductors, or magnets and their high quality is confirmed by photoluminescence and Raman spectra and by electrical transport measurements of fabricated field-effect transistors and Hall devices. Twisted homobilayers with angle-twisting accuracy of ≈0.3°, twisted heterobilayers with sub-degree angle-alignment accuracy, and multilayer superlattices are precisely constructed and characterized by their moiré patterns, interlayer excitons, and second harmonic generation. The present study paves the way for exploring emergent phenomena in moiré superlattices.

15.
Breast Cancer ; 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38630392

RESUMO

Triple-negative breast cancer (TNBC) is a highly heterogeneous tumor lacking estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. It has higher aggressiveness and metastasis than other subtypes, with limited effective therapeutic strategies, leading to a poor prognosis. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling pathway is prevalently over-activated in human cancers and contributes to breast cancer (BC) growth, survival, proliferation, and angiogenesis, which could be an interesting therapeutic target. This review summarizes the PI3K/AKT/mTOR signaling pathway activation mechanism in TNBC and discusses the relationship between its activation and various TNBC subtypes. We also report the latest clinical studies on kinase inhibitors related to this pathway for treating TNBC. Our review discusses the issues that need to be addressed in the clinical application of these inhibitors.

16.
Int Neurourol J ; 28(1): 59-66, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38569621

RESUMO

PURPOSE: This study was conducted to evaluate the efficacy of bladder outlet surgery in patients with detrusor underactivity (DU) and to identify factors associated with successful outcomes. METHODS: We conducted a retrospective review of men diagnosed with DU in urodynamic studies who underwent bladder outlet surgery for lower urinary tract symptoms between May 2018 and April 2023. The International Prostate Symptom Score (IPSS) questionnaire, uroflowmetry (UFM), and multichannel urodynamic studies were administered. Successful treatment outcomes were defined as either an IPSS improvement of at least 50% or the regaining of spontaneous voiding in patients urethral catheterization prior to surgery. RESULTS: The study included 93 male patients. Men diagnosed with significant or equivocal bladder outlet obstruction (BOO) experienced significant postoperative improvements in IPSS (from 20.6 to 6.0 and from 17.4 to 6.5, respectively), maximum urine flow rate (from 5.0 mL/sec to 14.4 mL/sec and from 8.8 mL/sec to 12.2 mL/sec, respectively) and voiding efficiency (from 48.8% to 86.0% and from 61.2% to 85.1%, respectively). However, in the group without obstruction, the improvements in IPSS and UFM results were not significant. The presence of detrusor overactivity (odds ratio [OR], 3.152; P=0.025) and preoperative urinary catheterization (OR, 2.756; P=0.040) were associated with favorable treatment outcomes. Conversely, an unobstructed bladder outlet was identified as a negative prognostic factor. CONCLUSION: In men with DU accompanied by equivocal or significant BOO, surgical intervention to alleviate the obstruction may enhance the IPSS, quality of life, and UFM results. However, those with DU and an unobstructed bladder outlet face a comparatively high risk of treatment failure. Preoperative detrusor overactivity and urinary catheterization are associated with more favorable surgical outcomes. Consequently, active deobstructive surgery should be considered for patients with DU who are experiencing urinary retention.

17.
Artigo em Inglês | MEDLINE | ID: mdl-38557614

RESUMO

As post-transcriptional regulators of gene expression, micro-ribonucleic acids (miRNAs) are regarded as potential biomarkers for a variety of diseases. Hence, the prediction of miRNA-disease associations (MDAs) is of great significance for an in-depth understanding of disease pathogenesis and progression. Existing prediction models are mainly concentrated on incorporating different sources of biological information to perform the MDA prediction task while failing to consider the fully potential utility of MDA network information at the motif-level. To overcome this problem, we propose a novel motif-aware MDA prediction model, namely MotifMDA, by fusing a variety of high- and low-order structural information. In particular, we first design several motifs of interest considering their ability to characterize how miRNAs are associated with diseases through different network structural patterns. Then, MotifMDA adopts a two-layer hierarchical attention to identify novel MDAs. Specifically, the first attention layer learns high-order motif preferences based on their occurrences in the given MDA network, while the second one learns the final embeddings of miRNAs and diseases through coupling high- and low-order preferences. Experimental results on two benchmark datasets have demonstrated the superior performance of MotifMDA over several state-of-the-art prediction models. This strongly indicates that accurate MDA prediction can be achieved by relying solely on MDA network information. Furthermore, our case studies indicate that the incorporation of motif-level structure information allows MotifMDA to discover novel MDAs from different perspectives. The data and codes are available at https://github.com/stevejobws/MotifMDA.

18.
Materials (Basel) ; 17(3)2024 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-38591400

RESUMO

This paper introduces a method for high-resolution lattice image reconstruction and dislocation analysis based on diffraction extinction. The approach primarily involves locating extinction spots in the Fourier transform spectrum (reciprocal space) and constructing corresponding diffraction wave functions. By the coherent combination of diffraction and transmission waves, the lattice image of the extinction planes is reconstructed. This lattice image is then used for dislocation localization, enabling the observation and analysis of crystal planes that exhibit electron diffraction extinction effects and atomic jump arrangements during high-resolution transmission electron microscopy (HRTEM) characterization. Furthermore, due to the method's effectiveness in localizing dislocations, it offers a unique advantage when analyzing high-resolution images with relatively poor quality. The feasibility of this method is theoretically demonstrated in this paper. Additionally, the method was successfully applied to observed edge dislocations, such as 1/6[211-], 1/6[2-11-], and 1/2[01-1], which are not easily observable in conventional HRTEM characterization processes, in electro-deposited Cu thin films. The Burgers vectors were determined. Moreover, this paper also attempted to observe screw dislocations that are challenging to observe in high-resolution transmission electron microscopy. By shifting a pair of diffraction extinction spots and superimposing the reconstructed images before and after the shift, screw dislocations with a Burgers vector of 1/2[011-] were successfully observed in electro-deposited Cu thin films.

19.
Drug Discov Today ; 29(5): 103979, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38608830

RESUMO

Drug discovery often begins with a new target. Protein-protein interactions (PPIs) are crucial to multitudinous cellular processes and offer a promising avenue for drug-target discovery. PPIs are characterized by multi-level complexity: at the protein level, interaction networks can be used to identify potential targets, whereas at the residue level, the details of the interactions of individual PPIs can be used to examine a target's druggability. Much great progress has been made in target discovery through multi-level PPI-related computational approaches, but these resources have not been fully discussed. Here, we systematically survey bioinformatics tools for identifying and assessing potential drug targets, examining their characteristics, limitations and applications. This work will aid the integration of the broader protein-to-network context with the analysis of detailed binding mechanisms to support the discovery of drug targets.


Assuntos
Biologia Computacional , Descoberta de Drogas , Descoberta de Drogas/métodos , Biologia Computacional/métodos , Humanos , Proteínas/metabolismo , Mapas de Interação de Proteínas/efeitos dos fármacos , Mapeamento de Interação de Proteínas/métodos , Ligação Proteica
20.
Mob DNA ; 15(1): 5, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38486291

RESUMO

Transposable elements (TEs) are a major component of eukaryotic genomes and are present in almost all eukaryotic organisms. TEs are highly dynamic between and within species, which significantly affects the general applicability of the TE databases. Orthoptera is the only known group in the class Insecta with a significantly enlarged genome (0.93-21.48 Gb). When analyzing the large genome using the existing TE public database, the efficiency of TE annotation is not satisfactory. To address this limitation, it becomes imperative to continually update the available TE resource library and the need for an Orthoptera-specific library as more insect genomes are publicly available. Here, we used the complete genome data of 12 Orthoptera species to de novo annotate TEs, then manually re-annotate the unclassified TEs to construct a non-redundant Orthoptera-specific TE library: Orthoptera-TElib. Orthoptera-TElib contains 24,021 TE entries including the re-annotated results of 13,964 unknown TEs. The naming of TE entries in Orthoptera-TElib adopts the same naming as RepeatMasker and Dfam and is encoded as the three-level form of "level1/level2-level3". Orthoptera-TElib can be directly used as an input reference database and is compatible with mainstream repetitive sequence analysis software such as RepeatMasker and dnaPipeTE. When analyzing TEs of Orthoptera species, Orthoptera-TElib performs better TE annotation as compared to Dfam and Repbase regardless of using low-coverage sequencing or genome assembly data. The most improved TE annotation result is Angaracris rhodopa, which has increased from 7.89% of the genome to 53.28%. Finally, Orthoptera-TElib is stored in Sqlite3 for the convenience of data updates and user access.

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