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BACKGROUND: To elucidate the relationship between inherited retinal disease, visual acuity and refractive error development in Asian patients. SUBJECTS: Five hundred phakic eyes with refractive data were analysed in this retrospective cohort. Diseases were categorized by clinical phenotypes, and the prevalent genotypes identified in the Taiwan Inherited Retinal Degeneration Project were analysed. Consecutive surveys in Taiwan have provided the rates of myopia in the general population. RESULTS: No differences were observed among the disease phenotypes with respect to myopia (P = 0.098) and high myopia rates (P = 0.037). The comparison of refractive error between retinitis pigmentosa and diseases mainly affecting the central retina showed no difference, and the refraction analyses in diseases of different onset ages yielded no significance. Moreover, there was no difference in the myopia rate between the diseases and general population. Among the genotypes, a higher spherical equivalent was seen in RPGR and PROM1-related patients and emmetropic trends were observed in patients with CRB1 and PRPF31 mutations. Furthermore, significantly poorer visual acuity was found in ABCA4, CRB1 and PROM1-related patients, and more preserved visual acuity was seen in patients with EYS, USH2A, and RDH12 mutations. CONCLUSIONS: No significant differences were observed in visual acuity, refractive state and myopia rate between patients with inherited retinal disease and the general population, and different subtypes of inherited retinal disease shared similar refractive state, except for higher cylindrical dioptres found in patients with Leber's congenital amaurosis. The heterogeneity of disease-causing genes in Asian patients may lead to variable refractive state.
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Objective: For elective cesarean section patients with gestational diabetes mellitus (GDM), there is a lack of evidence-based research on the use of enhanced recovery after surgery (ERAS). This study aims to compare the ERAS after-surgery protocol and traditional perioperative management. Research design and methods: In this retrospective cohort study, singleton pregnancies with good glucose control GDM, delivered by elective cesarean sections under intravertebral anesthesia at least 37 weeks from January 1 to December 31, 2022, were collected at the Third Affiliated Hospital of Sun Yat-sen University. We divided all enrolled pregnant women and newborns into an ERAS group and a control group (the traditional perioperative management group) based on their adherence to the ERAS protocol. The primary outcome was the preoperative blood glucose level, with an increase of more than 1 mmol/L indicating clinical significance when compared to the control group. The secondary outcome was centered around an adverse composite outcome that affected both mothers and newborns. Results: We collected a total of 161 cases, with 82 in the ERAS group and 79 in the control group. Although the mean preoperative blood glucose level in the ERAS group was significantly higher than in the control group (5.01 ± 1.06 mmol/L vs. 4.45 ± 0.90 mmol/L, p<0.001), the primary outcome revealed that the mean glycemic difference between the groups was 0.47 mmol/L (95% CI 0.15-0.80 mmol/L), which was below the clinically significant difference of 1 mmol/L. For the secondary outcomes, the ERAS group had an 86% lower risk of a composite adverse outcome compared to the control group. This included a 73% lower risk of perioperative maternal hypoglycemia and a 92% lower rate of neonatal hypoglycemia, all adjusted by age, hypertensive disorder of pregnancy, BMI, gestational weeks, primigravidae, primary pregnancy, GDM, surgery duration, and fasting glucose. Conclusion: Implementing a low-dose carbohydrate ERAS in pregnant women with GDM prior to elective cesarean section, compared to traditional perioperative management, does not lead to clinically significant maternal glucose increases and thus glucose-related maternal or neonatal perioperative complications.
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Glucemia , Cesárea , Diabetes Gestacional , Procedimientos Quirúrgicos Electivos , Recuperación Mejorada Después de la Cirugía , Humanos , Femenino , Embarazo , Cesárea/efectos adversos , Estudios Retrospectivos , Adulto , Recién Nacido , Procedimientos Quirúrgicos Electivos/efectos adversos , Glucemia/metabolismo , Glucemia/análisis , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/prevención & control , Complicaciones Posoperatorias/epidemiologíaRESUMEN
Background: Mitochondria are the center of cellular metabolism. The relationship between mitochondria and diseases has also been studied for a long time. However, the prognostic role of mitochondrial-related genes (MRGs) in patients with glioma and their biological effects are still unclear. The aim of the study was to construct a mitochondria-related model to assess prognosis and potential biological effects like immune infiltration, gene pathway and mutation, and give some predictive chemotherapeutic agents. Methods: The data of 675 patients from The Cancer Genome Atlas (TCGA) database were used to identify MRG signature and construct a prognostic model. After validating its robustness in Chinese Glioma Genome Atlas (CGGA), two risk groups derived from the prognostic model were then conducted with Gene Set Enrichment Analysis (GSEA), immune status, mutation status and chemotherapeutic agents prediction. Results: The prognostic model built from six gene signatures can successfully predict the prognosis and reflect clinicopathological characteristics. Patients in high-risk group displayed significantly worse overall survival (OS), immunosuppression effects, and mutation markers with worse prognosis. Twelve chemotherapeutic agents with strongly correlated sensitivity and risk scores were selected as potential agents. Conclusions: The novel MRG signatures (TYMP, TSFM, MGME1, BOLA3, TRMT5, NDUFA9) can predict prognosis and immunological status in glioma.
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Defect engineering is widely used to impart the desired functionalities on materials. Despite the widespread application of atomic-resolution scanning transmission electron microscopy (STEM), traditional methods for defect analysis are highly sensitive to random noise and human bias. While deep learning (DL) presents a viable alternative, it requires extensive amounts of training data with labeled ground truth. Herein, employing cycle generative adversarial networks (CycleGAN) and U-Nets, we propose a method based on a single experimental STEM image to tackle high annotation costs and image noise for defect detection. Not only atomic defects but also oxygen dopants in monolayer MoS2 are visualized. The method can be readily extended to other two-dimensional systems, as the training is based on unit-cell-level images. Therefore, our results outline novel ways to train the model with minimal data sets, offering great opportunities to fully exploit the power of DL in the materials science community.
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PURPOSE: To explore the impact of different intraoperative intraocular pressure (IOP) settings on the safety and prognosis in phacoemulsification. METHODS: Age related cataract patients who met the inclusion criteria and underwent phacoemulsification by using active sentry handpiece and active fluidics system. According to different intraoperative IOP settings during surgery, they were randomly divided into two groups: the 20mmHg group and the 60mmHg group. The best corrected visual acuity (BCVA), cumulative dissipated energy (CDE), total U/S time, active surge mitigation (ASM), estimated fluid usage (EFU) as well as the changes in corneal thickness (CT), corneal epithelial layer thickness (CELT) and endothelial cell density (ECD) were collected. The post-operative follow-up was only 1 day. RESULTS: A total of 110 cases (110 eyes) were included in the study. There were 55 eyes in each group. There was no statistically significant difference in postoperative BCVA (p = 0.839). The CDE, total U/S time and EFU during surgery were (5.22 ± 3.31), (30.60 ± 15.06), (45.07 ± 12.68) and (4.70 ± 2.83), (27.39 ± 13.75), (42.38 ± 11.93) in the 20mmHg group and 60mmHg group (p = 0.381, 0.246, 0.254). The ASM during surgery in the 20mmHg group and 60mmHg group were (0.95 ± 2.77) and (7.24 ± 6.34), respectively. The 20mmHg group showed a significant decrease in ASM (p < 0.001). There was no statistically significant difference in the changes in CT, CELT and ECD before and after surgery between the two groups (p = 0.913, 0.825, 0.624). Both groups did not experience any intraoperative complications, such as posterior capsule rupture. CONCLUSION: A lower IOP setting of 20 mmHg can significantly reduce the occurrence of intraoperative surges during phacoemulsification. And there was no increase in rate of complications. TRIAL REGISTRATION: The trial registration number is ChiCTR2100050240. The registered date is August 24th, 2021.
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Presión Intraocular , Facoemulsificación , Agudeza Visual , Humanos , Facoemulsificación/métodos , Masculino , Femenino , Presión Intraocular/fisiología , Anciano , Agudeza Visual/fisiología , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Anciano de 80 o más Años , Estudios de Seguimiento , Catarata/complicaciones , Catarata/fisiopatología , Endotelio Corneal/patologíaRESUMEN
BACKGROUND: Heart failure (HF), which is caused by cardiac overload and injury, is linked to significant mortality. Writers of RNA modification (WRMs) play a crucial role in the regulation of epigenetic processes involved in immune response and cardiovascular disease. However, the potential roles of these writers in the immunological milieu of HF remain unknown. METHODS: We comprehensively characterized the expressions of 28 WRMs using datasets GSE145154 and GSE141910 to map the cardiac immunological microenvironment in HF patients. Based on the expression of WRMs, the immunological cells in the datasets were scored. RESULTS: Single-cell transcriptomics analysis (GSE145154) revealed immunological dysregulation in HF as well as differential expression of WRMs in immunological cells from HF and non-HF (NHF) samples. WRM-scored immunological cells were positively correlated with the immunological response, and the high WRM score group exhibited elevated immunological cell infiltration. WRMs are involved in the differentiation of T cells and myeloid cells. WRM scores of T cell and myeloid cell subtypes were significantly reduced in the HF group compared to the NHF group. We identified a myogenesis-related resident macrophage population in the heart, Macro-MYL2, that was characterized by an increased expression of cardiomyocyte structural genes (MYL2, TNNI3, TNNC1, TCAP, and TNNT2) and was regulated by TRMT10C. Based on the WRM expression pattern, the transcriptomics data (GSE141910) identified two distinct clusters of HF samples, each with distinct functional enrichments and immunological characteristics. CONCLUSION: Our study demonstrated a significant relationship between the WRMs and immunological microenvironment in HF, as well as a novel resident macrophage population, Macro-MYL2, characterized by myogenesis. These results provide a novel perspective on the underlying mechanisms and therapeutic targets for HF. Further experiments are required to validate the regulation of WRMs and Macro-MYL2 macrophage subtype in the cardiac immunological milieu.
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Perfilación de la Expresión Génica , Insuficiencia Cardíaca , Macrófagos , Análisis de la Célula Individual , Transcriptoma , Humanos , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/inmunología , Insuficiencia Cardíaca/metabolismo , Macrófagos/metabolismo , Macrófagos/inmunología , Bases de Datos Genéticas , Microambiente Celular , Procesamiento Postranscripcional del ARN , Animales , Estudios de Casos y Controles , Regulación de la Expresión GénicaRESUMEN
IMPORTANCE: Successful needle puncture of the renal collecting system is a critical but difficult procedure in percutaneous nephrolithotomy (PCNL). Although fluoroscopy and ultrasound are the standard imaging techniques to guide puncture during PCNL, both have known limitations. OBJECTIVE: To assess the feasibility and safety of a new navigation system for needle puncture in ultrasound-guided PCNL. DESIGN: This study employed a single-center randomized controlled trial (RCT) design to assess the feasibility and safety of a new navigation system for needle puncture in ultrasound-guided PCNL. Conducted between May 2021 and November 2021, the trial utilized computer-generated random numbers for participant allocation to control for selection bias. SETTING: The trial was executed at the *********, which serves as an academic medical center. PARTICIPANTS: All patients who met the inclusion criteria were randomly divided into two groups, with 29 patients in each group. One group underwent PCNL procedures using the new navigation system, while the control group underwent standard ultrasound-guided PCNL procedures. Included patients had renal pelvis or caliceal calculi larger than 2.0 cm in diameter or had multiple or staghorn stones. The puncture procedure was performed with the support of real-time ultrasound imaging and visual guidance displayed on the screen. MAIN OUTCOMES AND MEASURES: The primary outcome was system feasibility and puncture success rate. Secondary outcomes included puncture time, total surgical time, number of attempts, post-procedure complications, and one-year and three-year stone recurrence rates. Stone clearance was defined by postoperative CT. Descriptive statistics summarized patient demographics, stone size, and location. Independent samples t-tests analyzed puncture time and total surgical time. Chi-square or Fisher's exact tests compared stone clearance, complications, socioeconomic status, renal hydronephrosis, stone location, race, and medical history. Linear regression examined the correlation between BMI and puncture time. Significance was set at P<0.05. RESULTS: For all 58 patients undergoing PCNL, needle punctures of the renal collecting system were completed with a success rate of 100%. The average time from planning the puncture protocol to successful puncture was significantly shorter in the AcuSee guidance system group (3.12 min, range 0.2-6.88 min) compared to the standard ultrasound-guided group (7.58 min, range 5.41-10.68 min), representing a reduction of approximately 59%. The total surgical time was also shorter in the AcuSee group for patients with no and mild hydronephrosis (P<0.05). Complication rates were lower in the AcuSee group, with no major complications observed. However, 3 patients in the standard ultrasound-guided group have adverse effects after the PCNL procedure. The one-year stone recurrence rate was significantly lower in the AcuSee group (3.4%) compared to the standard group (24.1%), and the three-year recurrence rate was also lower (6.9% vs. 41.4%). Patient-specific factors such as BMI, renal morphology, and prior surgical history did not significantly affect the performance of the AcuSee system. CONCLUSIONS AND RELEVANCE: We report the first clinical application of a new navigation system for needle puncture in ultrasound-guided PCNL. It has been demonstrated that it is feasible and safe compared to the standard ultrasound-guided group in percutaneous renal puncture. This technology provides intuitive and easy-to-use visual guidance, which may facilitate safe, accurate and fast needle puncture of the kidney.
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Renal cancer is one of the most common malignancies of the urinary system, and the number of deaths continues to increase. The standardized management of the diagnosis and treatment of renal cancer is challenging due to the great differences in the diagnosis and treatment of renal cancer in different regions. The Renal Cancer Expert Committee of the National Cancer Quality Control Center (NCQCC) identified a lack of authoritative quality control standards as an opportunity to utilize its multidisciplinary membership to improve the standardized diagnosis and treatment of renal cancer. The Renal Cancer Expert Committee of the NCQCC aims to promote quality control and national standardization, uniformity, and normalization of renal cancer diagnosis and treatment, which ultimately improved the survival rate and quality of life of renal cancer patients. A panel of experts with renal cancer surgery, renal cancer medicine, medical imaging, pathology and radiotherapy were drawn together and determined the quality control standards for the standardized diagnosis and treatment of renal cancer. The Indices includes 20 items that cover all key areas in the diagnosis and treatment of renal cancer, such as standard diagnosis, surgery treatment, systemic treatment, and prognostic evaluation.
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The objective of this article is to comprehensively review the effect of environmental lighting on ocular growth and refractive status in both animal and clinical studies, with an emphasis on the underlying mechanisms. This review was performed by searching research articles and reviews utilizing the terms "myopia," "light therapy," "axial length," "refractive error," and "emmetropization" in PubMed datasets. The review was finalized in December 2023. In the animal studies, high lighting brightness, illumination periods aligning with circadian rhythm, and color contrast signals including multiple wavelengths all help regulate ocular growth against myopia. Long wavelengths have been found to induce myopia in chicks, mice, fish, and guinea pigs, whereas shorter wavelengths lead to hyperopia. In contrast, red light has been observed to have a protective effect against myopia in tree shrews and rhesus monkeys. Apart from wavelength, flicker status also showed inconsistent effects on ocular growth, which could be attributed to differences in ocular refractive status, evolutionary disparities in retinal cone cells across species, and the selection of myopia induction models in experiments. In the clinical studies, current evidence suggests a control effect with red light therapy. Although the lighting conditions diverge from those in animal experiments, further reports are needed to assess the long-term effects. In conclusion, this review encompasses research related to the impact of light exposure on myopia and further explores the retinoscleral signaling pathway in refractive development. The aim is to establish a theoretical foundation for optimizing environmental factors in lighting design to address the epidemic of childhood myopia.
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OBJECTIVES: This study pursued two main purposes. The first aim was to expound on the microscopic factors of radiation-related caries (RRC). Further, it aimed to compare the remineralization effect of different remineralizing agents on demineralized teeth after radiotherapy. METHODS: The enamel and dentin samples of bovine teeth were irradiated with different doses of radiation. After analysis of scanning electron microscope (SEM), X-Ray diffraction (XRD), and energy dispersive spectrometer (EDS), the samples irradiated with 50 Gy radiation were selected and divided into the demineralization group, the double distilled water (DDW) group, the Sodium fluoride (NaF) group, the Casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) group, the NaF + CPP-ACP group, and the Titanium tetrafluoride (TiF4) group. After demineralization, remineralizing agents treatment, and remineralization, the samples were evaluated using SEM, atomic force microscope (AFM), EDS, and transverse microradiography (TMR). RESULTS: A radiation dose of 30 Gy was sufficient to cause damage to the dentinal tubules, but 70 Gy radiation had little effect on the microstructure of enamel. Additionally, the NaF + CPP-ACP group and the TiF4 group significantly promoted deposit formation, decreased surface roughness, and reduced mineral loss and lesion depth of demineralized enamel and dentin samples after radiation. CONCLUSIONS: Radiation causes more significant damage to dentin compared to enamel. NaF + CPP-ACP and TiF4 had a promising ability to promote remineralization of irradiated dental hard tissues. ADVANCES IN KNOWLEDGE: This in vitro study contributes to determining a safer radiation dose range for teeth and identifying the most effective remineralization approach for RRC.
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Caseínas , Esmalte Dental , Dentina , Microscopía Electrónica de Rastreo , Fluoruro de Sodio , Remineralización Dental , Animales , Bovinos , Remineralización Dental/métodos , Caseínas/uso terapéutico , Dentina/efectos de la radiación , Dentina/efectos de los fármacos , Fluoruro de Sodio/uso terapéutico , Esmalte Dental/efectos de la radiación , Esmalte Dental/efectos de los fármacos , Difracción de Rayos X , Titanio , Cariostáticos/uso terapéutico , Microrradiografía , Microscopía de Fuerza Atómica , Fluoruros/uso terapéutico , Espectrometría por Rayos X , Caries Dental/etiología , Desmineralización Dental/etiología , Técnicas In VitroRESUMEN
As a complementary and alternative therapy, acupuncture is widely used in the prevention and treatment of various diseases. However, the understanding of the mechanism of acupuncture effects is still limited due to the lack of systematic biological validation. Notably, proteomics technologies in the field of acupuncture are rapidly evolving, and these advances are greatly contributing to the research of acupuncture. In this study, we review the progress of proteomics research in analyzing the molecular mechanisms of acupuncture for neurological disorders, pain, circulatory disorders, digestive disorders, and other diseases, with an in-depth discussion around acupoint prescription and acupuncture manipulation modalities. The study found that proteomics has great potential in understanding the mechanisms of acupuncture. This study will help explore the mechanisms of acupuncture from a proteomic perspective and provide information to support future clinical decisions.
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Transport and localization of melanosome at the periphery region of melanocyte are depended on myosin-5a (Myo5a), which associates with melanosome by interacting with its adaptor protein melanophilin (Mlph). Mlph contains four functional regions, including Rab27a-binding domain, Myo5a GTD-binding motif (GTBM), Myo5a exon F-binding domain (EFBD), and actin-binding domain (ABD). The association of Myo5a with Mlph is known to be mediated by two specific interactions: the interaction between the exon-F-encoded region of Myo5a and Mlph-EFBD and that between Myo5a-GTD and Mlph-GTBM. Here, we identify a third interaction between Myo5a and Mlph, that is, the interaction between the exon-G-encoded region of Myo5a and Mlph-ABD. The exon-G/ABD interaction is independent from the exon-F/EFBD interaction and is required for the association of Myo5a with melanosome. Moreover, we demonstrate that Mlph-ABD interacts with either the exon-G or actin filament, but cannot interact with both of them simultaneously. Based on above findings, we propose a new model for the Mlph-mediated Myo5a transportation of melanosomes.
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Proteínas Adaptadoras Transductoras de Señales , Melanosomas , Miosina Tipo V , Unión Proteica , Melanosomas/metabolismo , Miosina Tipo V/metabolismo , Miosina Tipo V/genética , Animales , Ratones , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Humanos , Cadenas Pesadas de Miosina/metabolismo , Cadenas Pesadas de Miosina/genética , Melanocitos/metabolismoRESUMEN
Complementary to brain-computer interface (BCI) based on motor imagery (MI) task, sensory imagery (SI) task provides a way for BCI construction using brain activity from somatosensory cortex. The underlying neurophysiological correlation between SI and MI was unclear and difficult to measure through behavior recording. In this study, we investigated the underlying neurodynamic of motor/tactile imagery and tactile sensation tasks through a high-density electroencephalogram (EEG) recording, and EEG source imaging was used to systematically explore the cortical activation differences and correlations between the tasks. In the experiment, participants were instructed to perform the left and right hand tasks in MI paradigm, sensory stimulation (SS) paradigm and SI paradigm. The statistical results demonstrated that the imagined MI and SI tasks differed from each other within ipsilateral sensorimotor scouts, frontal and right temporal areas in α bands, whereas real SS and imagined SI showed a similar activation pattern. The similarity between SS and SI may provide a way to train the BCI system, while the difference between MI and SI may provide a way to integrate the discriminative information between them to enhance BCI performance. The combination of the tasks and its underlying neurodynamic would provide a new approach for BCI designation for a wider application. BCI studies concentrate on the hybrid decoding method combining MI or SI with SS, but the underlining neurophysiological correlates between them were unclear. MI and SI differed from each other within the ipsilateral sensorimotor cortex in alpha bands. This is a first study to investigate the neurophysiological relationship between MI and SI through an EEG source imaging approach from high-density EEG recording.
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Deqi is an important prerequisite for acupuncture to achieve optimal efficacy. Chinese medicine has long been concerned with the relationship between Deqi and the clinical efficacy of acupuncture. However, the underlying mechanisms of Deqi are complex and there is a lack of systematic summaries of objective quantitative studies of Deqi. Acupuncture Deqi can achieve the purpose of treating diseases by regulating the interaction of local and neighboring acupoints, brain centers, and target organs. At local and neighboring acupoints, Deqi can change their tissue structure, temperature, blood perfusion, energy metabolism, and electrophysiological indicators. At the central brain level, Deqi can activate the brain regions of the thalamus, parahippocampal gyrus, postcentral gyrus, insular, middle temporal gyrus, cingulate gyrus, etc. It also has extensive effects on the limbic-paralimbic-neocortical-network and default mode network. The brain mechanisms of Deqi vary depending on the acupuncture techniques and points chosen. In addition, Deqi 's mechanism of action involves correcting abnormalities in target organs. The mechanisms of acupuncture Deqi are multi-targeted and multi-layered. The biological mechanisms of Deqi are closely related to brain centers. This study will help to explore the mechanism of Deqi from a local-central-target-organ perspective and provide information for future clinical decision-making.
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BACKGROUND: The status of the lung adenocarcinoma (LUAD) grading system and the association between LUAD differentiation, driver genes, and clinicopathological features remain to be elucidated. METHODS: We included patients with invasive non-mucinous LUAD, evaluated their differentiation, and collected available clinicopathological information, gene mutations, and analyzed clinical outcomes. RESULTS: Among the 907 patients with invasive non-mucinous LUAD, 321 (35.4 %) were poorly differentiated, 422 (46.5 %) were moderately differentiated, and 164 (18.1 %) were well differentiated. EGFR mutation was more common in the LUADs accompanied without CGP (complex glandular pattern) than LUADs with CGP (p < 0.001). Correlation analysis between mutations and clinical characteristics showed that EGFR gene mutation (p < 0.001), KRAS gene mutation (p < 0.05), and ALK gene rearrangement (p < 0.001) were significantly related to the degree of tumor differentiation, and the KRAS and ALK gene mutation frequencies were higher in the low-differentiation group than in the high and medium differentiation groups. The EGFR mutation frequency was higher in the well/moderately differentiated adenocarcinoma group. CONCLUSIONS: Our study adds to the evidence regarding the role of the grading system in prognosis. EGFR, KRAS, and ALK are related to the degree of tumor differentiation.
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Adenocarcinoma del Pulmón , Receptores ErbB , Neoplasias Pulmonares , Mutación , Clasificación del Tumor , Proteínas Proto-Oncogénicas p21(ras) , Humanos , Masculino , Femenino , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Persona de Mediana Edad , Anciano , Clasificación del Tumor/métodos , Proteínas Proto-Oncogénicas p21(ras)/genética , Receptores ErbB/genética , Adulto , Anciano de 80 o más Años , Quinasa de Linfoma Anaplásico/genética , Adenocarcinoma/genética , Adenocarcinoma/patología , Biomarcadores de Tumor/genéticaRESUMEN
BACKGROUND: Cholesteryl ester (CE) accumulation in intracellular lipid droplets (LDs) is an essential signature of clear cell renal cell carcinoma (ccRCC), but its molecular mechanism and pathological significance remain elusive. METHODS: Enabled by the label-free Raman spectromicroscopy, which integrated stimulated Raman scattering microscopy with confocal Raman spectroscopy on the same platform, we quantitatively analyzed LD distribution and composition at the single cell level in intact ccRCC cell and tissue specimens in situ without any processing or exogenous labeling. Since we found that commonly used ccRCC cell lines actually did not show the CE-rich signature, primary cancer cells were isolated from human tissues to retain the lipid signature of ccRCC with CE level as high as the original tissue, which offers a preferable cell model for the study of cholesterol metabolism in ccRCC. Moreover, we established a patient-derived xenograft (PDX) mouse model that retained the CE-rich phenotype of human ccRCC. FINDINGS: Surprisingly, our results revealed that CE accumulation was induced by tumor suppressor VHL mutation, the most common mutation of ccRCC. Moreover, VHL mutation was found to promote CE accumulation by upregulating HIFα and subsequent PI3K/AKT/mTOR/SREBPs pathway. Inspiringly, inhibition of cholesterol esterification remarkably suppressed ccRCC aggressiveness in vitro and in vivo with negligible toxicity, through the reduced membrane cholesterol-mediated downregulations of integrin and MAPK signaling pathways. INTERPRETATION: Collectively, our study improves current understanding of the role of CE accumulation in ccRCC and opens up new opportunities for treatment. FUNDING: This work was supported by National Natural Science Foundation of China (No. U23B2046 and No. 62027824), National Key R&D Program of China (No. 2023YFC2415500), Fundamental Research Funds for the Central Universities (No. YWF-22-L-547), PKU-Baidu Fund (No. 2020BD033), Peking University First Hospital Scientific and Technological Achievement Transformation Incubation Guidance Fund (No. 2022CX02), and Beijing Municipal Health Commission (No. 2020-2Z-40713).
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Carcinoma de Células Renales , Ésteres del Colesterol , Neoplasias Renales , Mutación , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau , Animales , Humanos , Ratones , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Ésteres del Colesterol/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Neoplasias Renales/metabolismo , Neoplasias Renales/genética , Neoplasias Renales/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismoRESUMEN
There is growing acknowledgment that the properties of the electrochemical interfaces play an increasingly pivotal role in improving the performance of the hydrogen evolution reaction (HER). Here, we present, for the first time, direct dynamic spectral evidence illustrating the impact of the interaction between interfacial water molecules and adsorbed hydroxyl species (OHad) on the HER properties of Ni(OH)2 using Au/core-Ni(OH)2/shell nanoparticle-enhanced Raman spectroscopy. Notably, our findings highlight that the interaction between OHad and interfacial water molecules promotes the formation of weakly hydrogen-bonded water, fostering an environment conducive to improving the HER performance. Furthermore, the participation of OHad in the reaction is substantiated by the observed deprotonation step of Au@2 nm Ni(OH)2 during the HER process. This phenomenon is corroborated by the phase transition of Ni(OH)2 to NiO, as verified through Raman and X-ray photoelectron spectroscopy. The significant redshift in the OH-stretching frequency of water molecules during the phase transition confirms that surface OHad disrupts the hydrogen-bond network of interfacial water molecules. Through manipulation of the shell thickness of Au@Ni(OH)2, we additionally validate the interaction between OHad and interfacial water molecules. In summary, our insights emphasize the potential of electrochemical interfacial engineering as a potent approach to enhance electrocatalytic performance.
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The traceability of geographic origin is essential for guaranteeing the quality, safety, and protection of oyster brands. However, the current outcomes of traceability lack credibility as they do not adequately explain the model's predictions. Consequently, we conducted a study to evaluate the efficacy of utilizing explainable machine learning combined with mineral elements analysis. The study findings revealed that 18 elements have the ability to determine regional orientation. Simultaneously, individuals should pay closer attention to the potential risks associated with oyster consumption due to the regional differences in essential and toxic elements they contain. Light gradient boosting machine (LightGBM) model exhibited indistinguishable performance, achieving flawless accuracy, precision, recall, F1 score and AUC, with values of 96.77%, 96.43%, 98.53%, 97.32% and 0.998, respectively. The SHapley Additive exPlanations (SHAP) method was used to evaluate the output of the LightGBM model, revealing differences in feature interactions among oysters from different provinces. Specifically, the features Na, Zn, V, Mg, and K were found to have a significant impact on the predictive process of the model. Consistent with existing research, the use of explainable machine learning techniques can provide insights into the complex connections between important product attributes and relevant geographical information.
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Single-step retrosynthesis in organic chemistry increasingly benefits from deep learning (DL) techniques in computer-aided synthesis design. While template-free DL models are flexible and promising for retrosynthesis prediction, they often ignore vital 2D molecular information and struggle with atom alignment for node generation, resulting in lower performance compared to the template-based and semi-template-based methods. To address these issues, we introduce node-aligned graph-to-graph (NAG2G), a transformer-based template-free DL model. NAG2G combines 2D molecular graphs and 3D conformations to retain comprehensive molecular details and incorporates product-reactant atom mapping through node alignment, which determines the order of the node-by-node graph outputs process in an autoregressive manner. Through rigorous benchmarking and detailed case studies, we have demonstrated that NAG2G stands out with its remarkable predictive accuracy on the expansive data sets of USPTO-50k and USPTO-FULL. Moreover, the model's practical utility is underscored by its successful prediction of synthesis pathways for multiple drug candidate molecules. This proves not only NAG2G's robustness but also its potential to revolutionize the prediction of complex chemical synthesis processes for future synthetic route design tasks.
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Osteosarcoma is a malignant tumor originating from bone tissue that progresses rapidly and has a poor patient prognosis. Immunotherapy has shown great potential in the treatment of osteosarcoma. However, the immunosuppressive microenvironment severely limits the efficacy of osteosarcoma treatment. The dual pH-sensitive nanocarrier has emerged as an effective antitumor drug delivery system that can selectively release drugs into the acidic tumor microenvironment. Here, we prepared a dual pH-sensitive nanocarrier, loaded with the photosensitizer Chlorin e6 (Ce6) and CD47 monoclonal antibodies (aCD47), to deliver synergistic photodynamic and immunotherapy of osteosarcoma. On laser irradiation, Ce6 can generate reactive oxygen species (ROS) to kill cancer cells directly and induces immunogenic tumor cell death (ICD), which further facilitates the dendritic cell maturation induced by blockade of CD47 by aCD47. Moreover, both calreticulin released during ICD and CD47 blockade can accelerate phagocytosis of tumor cells by macrophages, promote antigen presentation, and eventually induce T lymphocyte-mediated antitumor immunity. Overall, the dual pH-sensitive nanodrug loaded with Ce6 and aCD47 showed excellent immune-activating and anti-tumor effects in osteosarcoma, which may lay the theoretical foundation for a novel combination model of osteosarcoma treatment.