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BACKGROUND: The tumor suppressor and proapoptotic transcription factor P53 is induced (and activated) in several forms of heart failure, including cardiotoxicity and dilated cardiomyopathy; however, the precise mechanism that coordinates its induction with accessibility to its transcriptional promoter sites remains unresolved, especially in the setting of mature terminally differentiated (nonreplicative) cardiomyocytes. METHODS: Male and female control or TRIM35 (tripartite motif containing 35) overexpression adolescent (aged 1-3 months) and adult (aged 4-6 months) transgenic mice were used for all in vivo experiments. Primary adolescent or adult mouse cardiomyocytes were isolated from control or TRIM35 overexpression transgenic mice for all in vitro experiments. Adenovirus or small-interfering RNA was used for all molecular experiments to overexpress or knockdown, respectively, target genes in primary mouse cardiomyocytes. Patient dilated cardiomyopathy or nonfailing left ventricle samples were used for translational and mechanistic insight. Chromatin immunoprecipitation and DNA sequencing or quantitative real-time polymerase chain reaction (qPCR) was used to assess P53 binding to its transcriptional promoter targets, and RNA sequencing was used to identify disease-specific signaling pathways. RESULTS: Here, we show that E3-ubiquitin ligase TRIM35 can directly monoubiquitinate lysine-120 (K120) on histone 2B in postnatal mature cardiomyocytes. This epigenetic modification was sufficient to promote chromatin remodeling, accessibility of P53 to its transcriptional promoter targets, and elongation of its transcribed mRNA. We found that increased P53 transcriptional activity (in cardiomyocyte-specific Trim35 overexpression transgenic mice) was sufficient to initiate heart failure and these molecular findings were recapitulated in nonischemic human LV dilated cardiomyopathy samples. CONCLUSIONS: These findings suggest that TRIM35 and the K120Ub-histone 2B epigenetic modification are molecular features of cardiomyocytes that can collectively predict dilated cardiomyopathy pathogenesis.
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Insuficiencia Cardíaca , Histonas , Ratones Transgénicos , Miocitos Cardíacos , Proteína p53 Supresora de Tumor , Ubiquitinación , Animales , Femenino , Humanos , Masculino , Ratones , Cardiomiopatía Dilatada/metabolismo , Cardiomiopatía Dilatada/genética , Cardiomiopatía Dilatada/patología , Células Cultivadas , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/patología , Histonas/metabolismo , Ratones Endogámicos C57BL , Miocitos Cardíacos/metabolismo , Regiones Promotoras Genéticas , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Digital mask projection lithography (DMPL) technology is gaining significant attention due to its characteristics of free-mask, flexibility, and low cost. However, when dealing with target layouts featuring sizes smaller than the wavelength scale, accurately producing resist patterns that closely match the target layout using conventional methods to design the modulation coefficients of digital masks produced by spatial light modulators (SLM) becomes challenging. Here, we present digital inversion lithography technology (DILT), which offers what we believe to be a novel approach to reverse engineer the modulation coefficients of digital masks. In the case of binary amplitude modulation, DILT achieves a remarkable reduction in pattern errors (PE), reaching the original 0.26. At the same time, in the case of the gray amplitude modulation, the PE can be reduced to the original 0.05, which greatly improves the high-fidelity transfer of the target layout. This significant improvement enhances the accuracy of target design transfer. By leveraging the capabilities of DILT, DMPL can now attain higher precision and reliability, paving the way for more advanced applications in the field of micro-nano device manufacturing.
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When the critical dimension (CD) of resist patterns nears the resolution limit of the digital micromirror device (DMD) maskless projection lithography (DMD-MPL), significant distortion can emerge in the silicon wafer due to the optical proximity effect (OPE). The significant distortion (breakpoints, line-end scaling, corner rounding, etc.) between resist patterns and target patterns results in reduced lithographic quality. To address this issue, we have proposed a pixel-based optical proximity correction (PB-OPC) method used for the hot-spot patterns with subwavelength sizes specifically designed for DMD-MPL. Employing an end-to-end learning neural network, the PB-OPC algorithm is both straightforward and efficient. A well-trained U-net framework facilitates the mapping from unoptimized masks to optimized masks. Experimental exposure trials have demonstrated that this method not only corrects OPC in general patterns but also effectively rectifies hot-spot patterns. The pattern error (PE) value can be reduced by about 30% in the design layouts. We believe this approach holds the potential to enhance the resolution and fidelity of resist patterns in DMD maskless lithography.
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Recently, chiral metal-organic coordination materials have emerged as promising candidates for a wide range of applications in chiroptoelectronics, chiral catalysis, and information encryption, etc. Notably, the chiroptical effect of coordination chromophores makes them appealing for applications such as photodetectors, OLEDs, 3D displays, and bioimaging. The direct synthesis of chiral coordination materials using chiral organic ligands or complexes with metal-centered chirality is very often tedious and costly. In the case of ionic coordination materials, the combination of chiral anions with cationic, achiral coordination compounds through noncovalent interactions may endow molecular materials with desirable chiroptical properties. The use of such a simple chiral strategy has been proven effective in inducing promising circular dichroism and/or circularly polarized luminescence signals. This concept article mainly delves into the latest advances in exploring the efficacy of such a chiral anion strategy for transforming achiral coordination materials into chromophores with superb photo- or electro-chiroptical properties. In particular, ionic small-molecular metal complexes, metal clusters, coordination supramolecular assemblies, and metal-organic frameworks containing chiral anions are discussed. A perspective on the future opportunities on the preparation of chiroptical materials with the chiral anion strategy is also presented.
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Photonic heterostructures with codable properties have shown great values as versatile information carriers at the micro and nanoscale. These heterostructures are typically prepared by a step-by-step growth or post-functionalization method to achieve varied emission colors among different building blocks. In order to realize high-throughput and multivariate information loading, we report here a strategy to integrate polarization signals into photonic heterojunctions. A U-shaped di-Pt(II) complex is assembled into highly-polarized yellow-phosphorescent crystalline microrods (Y-rod) by strong intermolecular Pt···Pt interaction. Upon end-initiated desorption of the incorporated CH2Cl2 solvents, Y-rod is transformed in a domino fashion into tri-block polarized photonic heterojunctions (PPHs) with alternate red-yellow-red emissions or red-phosphorescent microrods (R-rod). The red emissions of these structures are also highly polarized; however, their polarization directions are just orthogonal to those of the yellow phosphorescence of Y-rod. With the aid of a patterned mask, R-rod is further programmed into multi-block PPHs with precisely-controlled block sizes by side-allowed adsorption of CH2Cl2 vapor. X-ray diffraction analysis and theoretical calculations suggest that the solvent-regulated modulation of intramolecular and intermolecular excited states is critical for the construction of these PPHs.
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Given that type I photosensitizers (PSs) possess a good hypoxic tolerance, developing an innovative tactic to construct type I PSs is crucially important, but remains a challenge. Herein, we present a smart molecular design strategy based on the Förster resonance energy transfer (FRET) mechanism to develop a type I photodynamic therapy (PDT) agent with an encouraging amplification effect for accurate hypoxic tumor therapy. Of note, benefiting from the FRET effect, the obtained nanostructured type I PDT agent (NanoPcSZ) with boosted light-harvesting ability not only amplifies superoxide radical (O2 â¢-) production but also promotes heat generation upon near-infrared light irradiation. These features facilitate NanoPcSZ to realize excellent phototherapeutic response under both normal and hypoxic environments. As a result, both in vitro and in vivo experiments achieved a remarkable improvement in therapeutic efficacy via the combined effect of photothermal action and type I photoreaction. Notably, NanoPcSZ can be eliminated from organs (including the liver, lung, spleen, and kidney) apart from the tumor site and excreted through urine within 24â h of its systemic administration. In this way, the potential biotoxicity of drug accumulation can be avoided and the biosafety can be further enhanced.
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Purpose: This study aimed to develop and validate a nomogram for predicting positive colonoscopy results using the data from non-invasive screening strategies. Methods: The volunteers participated in primary colorectal cancer (CRC) screenings using Asia-Pacific colorectal screening (APCS) scoring, faecal immunochemical testing (FIT) and stool deoxyribonucleic acid (sDNA) testing and underwent a colonoscopy. The positive colonoscopy results included CRC, advanced adenoma (AA), high-grade intraepithelial neoplasia (HGIN), and low-grade intraepithelial neoplasia (LGIN). The enrolled participants were randomly selected for training and validation sets in a 7:3 ratio. A model for predicting positive colonoscopy results was virtualized by the nomogram using logistic regression analysis. Results: Among the 179 enrolled participants, 125 were assigned to training set, while 54 were assigned to validation set. After multivariable logistic regression was done, APCS score, FIT result, and sDNA result were all identified as the predictors for positive colonoscopy results. A model that incorporated the above independent predictors was developed and presented as a nomogram. The C-index of the nomogram in the validation set was 0.768 (95% CI, 0.644-0.891). The calibration curve demonstrated a good agreement between prediction and observation. The decision curve analysis (DCA) curve showed that the model achieved a net benefit across all threshold probabilities. The AUC of the prediction model for predicting positive colonoscopy results was much higher than that of the FIT + sDNA test scheme. Conclusion: The nomogram for predicting positive colonoscopy results was successfully developed based on 3 non-invasive screening tools (APCS scoring, FIT and sDNA test).
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Cancer treatment requires precise tumor-specific targeting at specific sites that allows for high-resolution diagnostic imaging and long-term patient-tailorable cancer therapy; while, minimizing side effects largely arising from non-targetability. This can be realized by harnessing exogenous remote stimuli, such as tissue-penetrative ultrasound, magnetic field, light, and radiation, that enable local activation for cancer imaging and therapy in deep tumors. A myriad of nanomedicines can be efficiently activated when the energy of such remote stimuli can be transformed into another type of energy. This review discusses the remote control of energy transformation for targetable, efficient, and long-term cancer imaging and therapy. Such ultrasonic, magnetic, photonic, radiative, and radioactive energy can be transformed into mechanical, thermal, chemical, and radiative energy to enable a variety of cancer imaging and treatment modalities. The current review article describes multimodal energy transformation where a serial cascade or multiple types of energy transformation occur. This review includes not only mechanical, chemical, hyperthermia, and radiation therapy but also emerging thermoelectric, pyroelectric, and piezoelectric therapies for cancer treatment. It also illustrates ultrasound, magnetic resonance, fluorescence, computed tomography, photoluminescence, and photoacoustic imaging-guided cancer therapies. It highlights afterglow imaging that can eliminate autofluorescence for sustained signal emission after the excitation.
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Neoplasias , Humanos , Neoplasias/diagnóstico por imagen , Neoplasias/terapia , Animales , Técnicas Fotoacústicas/métodos , Diagnóstico por Imagen/métodosRESUMEN
BACKGROUND: Patients with breast cancer brain metastases (BCBM) experience a rapid decline in their quality of life. Recently, tertiary lymphoid structures (TLSs), analogs of secondary lymphoid organs, have attracted extensive attention. However, the potential clinical implications of TLSs in BCBMs are poorly understood. In this study, we evaluated the density and composition of TLSs in BCBMs and described their prognostic value. METHODS: Clinicopathological data were collected from 98 patients (2015-2021). TLSs were evaluated, and a TLS scoring system was constructed. Differences in progression-free survival (PFS) and overall survival (OS) between groups were calculated using the Kaplan-Meier method. Immunohistochemistry and multiplex immunofluorescence (mIF) were used to assess TLSs heterogeneity. RESULTS: TLSs were identified in 47 patients with BCBM. High TLSs density indicated favorable survival (OS, p=0.003; PFS, p<0.001). TLS was positively associated with OS (p=0.0172) and PFS (p=0.0161) in the human epidermal growth factor receptor type 2-positive subtype, and with prolonged OS (p=0.0482) in the triple-negative breast cancer subtype. The mIF results showed significant differences in the percentages of T follicular helper (Tfh) cells, M2 macrophages, cytotoxic T lymphocytes, and CD8+TIM-3+ T lymphocytes between the groups of TLS scores 0-3 (cytotoxic T lymphocytes, p=0.044; Tfh, p=0.021; M2 macrophages, p=0.033; CD8+TIM-3+ T lymphocytes, p=0.018). Furthermore, novel nomograms incorporating the TLS scores and other clinicopathological predictors demonstrated prominent predictability of the 1-year, 3-year, and 5-year outcomes of BCBMs (area under the curve >0.800). CONCLUSION: Our results highlight the impact of TLSs abundance on the OS and PFS of patients with BCBM. Additionally, we described the immune composition of TLSs and proposed novel nomograms to predict the prognosis of patients with BCBM.
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Neoplasias Encefálicas , Neoplasias de la Mama , Estructuras Linfoides Terciarias , Humanos , Femenino , Estructuras Linfoides Terciarias/inmunología , Estructuras Linfoides Terciarias/patología , Neoplasias de la Mama/patología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/mortalidad , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/mortalidad , Persona de Mediana Edad , Pronóstico , Adulto , AncianoRESUMEN
Aim: This population-based analysis aimed to explore the associations among marital status, prognosis and treatment of stage I non-small-cell lung cancer. Materials & methods: The propensity score matching (PSM), logistic regression and Cox proportional hazards model were used in this study. Results: A total of 13,937 patients were included. After PSM, 10579 patients were co-insured. The married were more likely to receive surgical treatment compared with the unmarried patients (OR: 1.841, p < 0.001), and patients who underwent surgery also tended to have better survival (HR: 0.293, p < 0.001). Conclusion: Compared with unmarried patients, a married group with stage I NSCLC had timely treatment and more satisfactory survival. This study highlights the importance of prompt help and care for unmarried patients.
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Objective: This study aimed to evaluate the efficacy and safety of buccal acupuncture on postoperative analgesia, perioperative stress response and adverse events in elderly patients undergoing laparoscopic radical gastrectomy. Methods: It was a prospective, outcome assessor-blinded, randomized controlled trial, involving 90 patients aged 65-80 years who were treated with an elective laparoscopic radical gastrectomy. They were randomly assigned to buccal acupuncture group (Group B) and control group (Group C). Buccal acupuncture was applied to patients of Group B before the induction of general anesthesia, while no additional application was given to those in Group C. Patient-controlled intravenous analgesia (PCIA) with sufentanil was postoperatively performed in both groups. Sufentanil consumption and the Visual Analog Scale (VAS) score within 48 h postoperatively were assessed as primary outcomes. Secondary outcomes included peripheral levels of stress markers, intraoperative consumptions of anesthetic drugs and postoperative recovery. Results: Patients in Group B presented significantly lower VAS scores within 24 h and less consumption of sufentanil within 48 h postoperatively (both p < 0.01). The awaking time, time to extubation and length of stay were significantly shorter in Group B than in Group C (p = 0.005, 0.001 and 0.028, respectively). Compared with Group C, stress response and inflammatory response within 24 h postoperatively were also significantly milder in Group B. Conclusion: The use of buccal acupuncture before general anesthesia induction favors the postoperative analgesic effect and recovery in elderly patients undergoing laparoscopic radical gastrectomy, the mechanism of which involves relieving postoperative stress response and inflammatory response. Clinical trial registration: This study was registered in the Chinese Clinical Trial Registry (www.chictr.org.cn) on 15/06/2023 (ChiCTR2300072500).
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Objective: To explore the effect of applying the online to offline teaching mode in the training of non-anesthesiology residents in department of anesthesiology. Trial design: The randomized controlled trial was performed on non-anesthesiology residents from Affiliated Jiangning Hospital of Nanjing Medical University. Methods: All selected residents were randomly divided into the traditional teaching group (Group T) and the online to offline teaching group (Group O) by the random number table method. Traditional teaching mode was used in Group T, while the online to offline teaching mode was used in Group O. The training period lasted for two months. At the end of the training, theoretical and clinical skills were assessed for all residents, and students' satisfaction scores on teaching were investigated from the aspects of teaching mode, stimulating learning interest, improving learning process and teaching satisfaction. The teaching efficiency was compared and analyzed in the two groups. Results: In total, 39 cases in Group O and 38 cases in Group T were included in the statistical analysis. Compared with Group T, theory test scores, clinical skills test scores, and overall scores improved significantly in Group O (82.2 ± 8.1 vs. 91.3 ± 7.6; 85.1 ± 4.7 vs. 93.3 ± 5.4 and 83.4 ± 6.4 vs. 92.1 ± 6.7, respectively, p < 0.01). Compared with Group T, scores on teaching mode, stimulating learning interest, improving learning process and teaching satisfaction were higher in Group O (81.1 ± 6.9 vs. 93.7 ± 5.2; 83.6 ± 5.8 vs. 91.6 ± 6.4; 82.4 ± 5.3 vs. 90.9 ± 4.8 and 82.1 ± 5.9 vs. 92.1 ± 5.5, respectively, p < 0.01). Conclusion: The online to offline teaching mode can improve the level of professional theory and clinical skill operation, and teaching satisfaction of the non-anesthesiology residents in department of anesthesiology, thus improving the teaching effectiveness.
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BACKGROUND: Gut microbiota dysbiosis significantly contributes to progression of depression. Hypericum perforatum L. (HPL) is traditionally used in Europe for treating depression. However, its mechanism remains largely underexplored. PURPOSE: This study aims to investigate the pivotal gut microbiota species and microbial signaling metabolites associated with the antidepressant effects of HPL. METHODS: Fecal microbiota transplantation was used to assess whether HPL mitigates depression through alterations in gut microbiota. Microbiota and metabolic profiling of control, chronic restraint stress (CRS)-induced depression, and HPL-treated CRS mice were examined using 16S rRNA gene sequencing and metabolomics analysis. The influence of gut microbiota on HPL's antidepressant effects was assessed by metabolite and bacterial intervention experiments. RESULTS: HPL significantly alleviated depression symptoms in a manner dependent on gut microbiota and restored gut microbial composition by enriching Akkermansia muciniphila (AKK). Metabolomic analysis indicated that HPL regulated tryptophan metabolism, reducing kynurenine (KYN) levels derived from microbiota and increasing 5-hydroxytryptophan (5-HTP) levels. Notably, supplementation with KYN activated the NFκB-NLRP2-Caspase1-IL1ß pathway and increased proinflammatory IL1ß in the hippocampus of mice with depression. Interestingly, mono-colonization with AKK notably increased 5-hydroxytryptamine (5-HT) and decreased KYN levels, ameliorating depression symptoms through modulation of the NFκB-NLRP2-Caspase1-IL1ß pathway. CONCLUSIONS: The promising therapeutic role of HPL in treating depression is primarily attributed to its regulation of the NFκB-NLRP2-Caspase1-IL1ß pathway, specifically by targeting AKK and tryptophan metabolites.
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Akkermansia , Antidepresivos , Depresión , Microbioma Gastrointestinal , Hypericum , Interleucina-1beta , FN-kappa B , Triptófano , Animales , Hypericum/química , Microbioma Gastrointestinal/efectos de los fármacos , Depresión/tratamiento farmacológico , Triptófano/metabolismo , Triptófano/farmacología , Masculino , FN-kappa B/metabolismo , Interleucina-1beta/metabolismo , Ratones , Antidepresivos/farmacología , Ratones Endogámicos C57BL , Caspasa 1/metabolismo , Trasplante de Microbiota Fecal , Verrucomicrobia , Extractos Vegetales/farmacología , Transducción de Señal/efectos de los fármacos , Disbiosis/tratamiento farmacológico , Disbiosis/microbiología , Modelos Animales de EnfermedadRESUMEN
Rationale: Dynamin-related protein 1 (Drp1), a large GTPase, mediates mitochondrial fission. Increased Drp1-mediated fission permits accelerated mitosis, contributing to hyperproliferation of pulmonary artery smooth muscle cells (PASMC), which characterizes pulmonary arterial hypertension (PAH). We developed a Drp1 inhibitor, Drpitor1a, and tested its ability to regress PAH. Objectives: Assess Drpitor1a's efficacy and toxicity in: a)normal and PAH human PASMC (hPASMC); b)normal rats versus rats with established monocrotaline (MCT)-induced PAH. Methods: Drpitor1a's effects on recombinant and endogenous Drp1-GTPase activity, mitochondrial fission, and cell proliferation were studied in hPASMCs (normal=3; PAH=5). Drpitor1a's pharmacokinetics and tissue concentrations were measured (n=3 rats/sex). In a pilot study (n=3-4/sex/dose), Drpitor1a (1mg/kg/48-hours, intravenous) reduced adverse PA remodeling only in females. Consequently, we compared Drpitor1a to vehicle in normal (n=6 versus 8) and MCT-PAH (n=9 and 11) females, respectively. Drpitor1a treatment began 17-days post-MCT with echocardiography and cardiac catheterization performed 28-29 days post-MCT. Results: Drpitor1a inhibited recombinant and endogenous Drp1 GTPase activity, which was increased in PAH hPASMC. Drpitor1a inhibited mitochondrial fission and proliferation and induced apoptosis, in PAH hPASMC but not normal hPASMC. Drpitor1a tissue levels were higher in female versus male RVs. In MCT-PAH females, Drpitor1a regressed PA obstruction, lowered pulmonary vascular resistance, and improved RV function, without hematologic, renal, or hepatic toxicity. Conclusions: Drpitor1a inhibits Drp1 GTPase, reduces mitochondrial fission, and inhibits cell proliferation in PAH hPASMC. Drpitor1a caused no toxicity in MCT-PAH and had no significant effect on normal rats or hPASMCs. Drpitor1a is a potential PAH therapeutic which displays an interesting therapeutic sexual dimorphism.