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BACKGROUND: Targeted protein degradation of neosubstrates plays a crucial role in hematological cancer treatment involving immunomodulatory imide drugs (IMiDs) therapy. Nevertheless, the persistence of inevitable drug resistance and hematological toxicities represents a significant obstacle to their clinical effectiveness. METHODS: Phenotypic profiling of a small molecule compounds library in multiple hematological cancer cell lines was conducted to screen for hit degraders. Molecular dynamic-based rational design and cell-based functional assays were conducted to develop more potent degraders. Multiple myeloma (MM) tumor xenograft models were employed to investigate the antitumor efficacy of the degraders as single or combined agents with standard of care agents. Unbiased proteomics was employed to identify multiple therapeutically relevant neosubstrates targeted by the degraders. MM patient-derived cell lines (PDCs) and a panel of solid cancer cell lines were utilized to investigate the effects of candidate degrader on different stage of MM cells and solid malignancies. Unbiased proteomics of IMiDs-resistant MM cells, cell-based functional assays and RT-PCR analysis of clinical MM specimens were utilized to explore the role of BRD9 associated with IMiDs resistance and MM progression. RESULTS: We identified a novel cereblon (CRBN)-dependent lead degrader with phthalazinone scaffold, MGD-4, which induced the degradation of Ikaros proteins. We further developed a novel potent candidate, MGD-28, significantly inhibited the growth of hematological cancer cells and induced the degradation of IKZF1/2/3 and CK1α with nanomolar potency via a Cullin-CRBN dependent pathway. Oral administration of MGD-4 and MGD-28 effectively inhibited MM tumor growth and exhibited significant synergistic effects with standard of care agents. MGD-28 exhibited preferentially profound cytotoxicity towards MM PDCs at different disease stages and broad antiproliferative activity in multiple solid malignancies. BRD9 modulated IMiDs resistance, and the expression of BRD9 was significant positively correlated with IKZF1/2/3 and CK1α in MM specimens at different stages. We also observed pronounced synergetic efficacy between the BRD9 inhibitor and MGD-28 for MM treatment. CONCLUSIONS: Our findings present a strategy for the multi-targeted degradation of Ikaros proteins and CK1α against hematological cancers, which may be expanded to additional targets and indications. This strategy may enhance efficacy treatment against multiple hematological cancers and solid tumors.
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Neoplasias Hematológicas , Humanos , Animales , Línea Celular Tumoral , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/metabolismo , Ratones , Ensayos Antitumor por Modelo de Xenoinjerto , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Proteolisis/efectos de los fármacos , Ubiquitina-Proteína Ligasas/metabolismo , Factor de Transcripción Ikaros/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Proteínas Adaptadoras Transductoras de SeñalesRESUMEN
To evaluate different Lynch syndrome (LS) screening approaches and establish an efficient and sensitive strategy are critical for clinical practice. In total, 583 patients with colorectal carcinoma (CRC) at Fudan University Shanghai Cancer Center were enrolled. Patient samples were examined by immunohistochemistry (IHC) and next-generation sequencing (NGS), and MLH1 promoter hypermethylation (MPH) was detected in MLH1-deficient cases. Germline genetic testing was performed in cases with deleterious variants and large genomic rearrangements (LGRs) of tumor MMR genes were detected in cases with dMMR or MSI-H cases with no MMR germline variants. Our results showed that triage with IHC and followed by BRAF/MLH1 methylation testing (Strategy 1) identified 93.3% (70/75) of LS cases. IHC followed by germline NGS (Strategy 2) or direct tumor NGS (Strategy 3) both identified 98.7% (74/75) of LS cases. The proportion of LGRs in LS cases was 16.0% (12/75), while 84.0% (63/75) showed SNV/Indel. The average cost per patient was ¥6010.81, ¥6058.48, and ¥8029.98 for Strategy 1, Strategy 2 and Strategy 3, respectively. The average time spent on different strategies was 4.74 days (Strategy 1), 4.89 days (Strategy 2), and 14.50 days (Strategy 3) per patient, respectively. LS and Lynch-like syndrome (LLS) were associated with an earlier onset age than MPH. In conclusion, we compared different workflows for LS screening and IHC plus germline NGS is recommended for LS screening when taking sensitivity, time, and cost into account. Moreover, multiplex ligation-dependent probe amplification made up for the shortcoming of NGS and should be incorporated into routine screening.
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This study sought to explore potential roles of endothelial ferroptosis in radiation-associated atherosclerosis (RAA) and molecular mechanisms behind this phenomenon. Here, an in vivo RAA mouse model was used and treated with ferroptosis inhibitors. We found that the RAA group had a higher plaque burden and a reduction in endothelial cells with increased lipid peroxidation compared to the control group, while ameliorated by liproxstatin-1. In vitro experiments further confirmed that radiation induced the occurrence of ferroptosis in human artery endothelial cells (HAECs). Then, proteomics analysis of HAECs identified domain-containing protein 2 (DDHD2) as a co-differentially expressed protein, which was enriched in the lipid metabolism pathway. In addition, the level of lipid peroxidation was elevated in DDHD2-knockdown HAECs. Mechanistically, a significant decrease in the protein and mRNA expression of glutathione peroxidase 4 (GPX4) was observed in HAECs following DDHD2 knockdown. Co-immunoprecipitation assays indicated a potential interaction between DDHD2 and nuclear factor erythroid 2-related factor 2 (Nrf2). The downregulation of Nrf2 protein was also detected in DDHD2-knockdown HAECs. In conclusion, our findings suggest that radiation-induced endothelial ferroptosis accelerates atherosclerosis, and DDHD2 is a potential regulatory protein in radiation-induced endothelial ferroptosis through the Nrf2/GPX4 pathway.
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Aterosclerosis , Células Endoteliales , Ferroptosis , Factor 2 Relacionado con NF-E2 , Fosfolipasas , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Animales , Humanos , Masculino , Ratones , Aterosclerosis/metabolismo , Aterosclerosis/patología , Aterosclerosis/etiología , Aterosclerosis/genética , Células Endoteliales/metabolismo , Células Endoteliales/patología , Peroxidación de Lípido , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Transducción de Señal , Fosfolipasas/genética , Fosfolipasas/metabolismoRESUMEN
The continuously refined genome assembly of the Chinese cabbage accession Chiifu is widely recognized as the reference for Brassica rapa. However, the high self-incompatibility of Chiifu limits its broader utilization. In this study, we report the development of self-compatible Chiifu lines through a meticulous marker-assisted selection (MAS) strategy, involving the substitution of the Chiifu allele of MLPK (M-locus protein kinase) with that from the self-compatible Yellow Sarson (YS). A YS-based marker (SC-MLPK) was employed to screen 841 B. rapa accessions, confirming that all eight accessions with the mlpk/mlpk (mm) genotype exhibited self-compatibility. Additionally, we designed 131 High-Resolution Melting (HRM) markers evenly distributed across the B. rapa genome as genomic background selection (GBS) markers to facilitate the introgression of self-compatibility from YS into Chiifu along with SC-MLPK. Genome background screening revealed that the BC3S1 population had a proportion of the recurrent parent genome (PR) ranging from 93.9% to 98.5%. From this population, we identified self-compatible individuals exhibiting a high number of pollen tubes penetrating stigmas (NPT) (>25) and a maximum compatibility index (CI) value of 7.5. Furthermore, we selected two individuals demonstrating significant similarity to Chiifu in both genetic background and morphological appearance, alongside self-compatibility. These selected individuals were self-pollinated to generate two novel lines designated as SC-Chiifu Lines. The development of these self-compatible Chiifu lines, together with the SC-MLPK marker and the set of HRM markers, represents valuable tools for B. rapa genetics and breeding.
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BACKGROUND: The late-stage diagnosis and distant metastasis of oral squamous cell carcinoma (OSCC) remain a huge challenge to clinical treatment for OSCC. During the past decades, targeting glycolysis-inducing factors becomes an attractive new strategy in OSCC therapies. METHODS: OSCC cells were stimulated with hypoxia or transfected with agomir-199a-5p, antagomir-199a-5p, and siRNA for HIF1A, cell proliferation was detected by CCK-8 assay; HIF1α, GLUT1, HK2 and LDHA expression levels were examined with western blot; miR-199 expression was determined with RT-PCR; cell migratory and invasive abilities were examined using wound healing and transwell assays; the lactate and glucose in culture medium were also determined. Luciferase assay or CHIP assay was applied for confirm the binding between miR-199a-5p and HIF1A 3'UTR, or between HIF1α and miR-199a promoter. RESULTS: HIF1α showed to be abnormally up-regulated, and miR-199a-5p showed to be abnormally down-regulated within OSCC under hypoxia. Hypoxia considerably enhanced OSCC cell proliferation, glycolysis, migratory ability, and invasive ability. MiR-199a-5p bound to HIF1A 3'-UTR and suppressed HIF1A expression; HIF1α targeted miR-199a-5p promoter region and downregulated miR-199a-5p expression. Under hypoxia, miR-199a-5p overexpression significantly repressed HIF1α up-regulation inresponse to hypoxia, OSCC cell proliferation, glycolysis, migratory ability, and invasive ability. CONCLUSION: miR-199a-5p and HIF1α form a dual-regulatory axis in OSCC cells; the miR-199a-5p/HIF1α dual-regulatory axis contributes to hypoxia-induced aggressive OSCC phenotypes.
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Carcinoma de Células Escamosas , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Subunidad alfa del Factor 1 Inducible por Hipoxia , MicroARNs , Neoplasias de la Boca , Humanos , MicroARNs/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Neoplasias de la Boca/patología , Neoplasias de la Boca/genética , Neoplasias de la Boca/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , Proliferación Celular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Glucólisis/genética , Hipoxia de la Célula/genética , Invasividad Neoplásica/genética , FenotipoRESUMEN
Bimetallic metal-organic frameworks (BMOFs) have shown a superior oxygen evolution reaction (OER) performance, attributed to the synergistic effects of dual metal sites. However, the significant role of these dual-metal synergies in the OER is not yet fully understood. In this study, we employed density functional theory to systematically investigate the OER performance of NiAl- and NiFe-based BMOFs by examining all possible spin states of each intermediate across diverse external potentials and pH environments. We found that the spin state featuring a shallow hole trap state and Ni ions with a higher oxidation state serve as strong oxidizing agents, promoting the OER. An external potential-induced spin crossover was observed in each intermediate, resulting in significant changes in the overall reaction and activation energies due to altered energy levels. Combining the constant potential method and the electrochemical nudged elastic band method, we mapped the minimum free energy barriers of the OER under varied external potential and pH by considering the spin crossover effect for both NiAl and NiFe BMOFs. The results showed that NiFe exhibits better OER thermodynamics and kinetics, which is in good agreement with experimentally measured OER polarization curves and Tafel plots. Moreover, we found that the improved OER kinetics of NiFe not only is attributed to lower barriers but also is a result of improved electrical conductivity arising from the synergistic effects of Ni-Fe dual-metal sites. Specifically, replacing the second metal Al with Fe leads to two significant outcomes: a reduction in both the band gap and the effective hole mass compared to NiAl, and the initiation of super- and double-exchange interactions within the Ni-F-Fe chain, thereby enhancing electron transfer and hopping and leading to the improved OER kinetics.
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RN-9893, a TRPV4 antagonist identified by Renovis Inc., showcased notable inhibition of TRPV4 channels. This research involved synthesizing and evaluating three series of RN-9893 analogues for their TRPV4 inhibitory efficacy. Notably, compounds 1b and 1f displayed a 2.9 to 4.5-fold increase in inhibitory potency against TRPV4 (IC50 = 0.71 ± 0.21 µM and 0.46 ± 0.08 µM, respectively) in vitro, in comparison to RN-9893 (IC50 = 2.07 ± 0.90 µM). Both compounds also significantly outperformed RN-9893 in TRPV4 current inhibition rates (87.6 % and 83.2 % at 10 µM, against RN-9893's 49.4 %). For the first time, these RN-9893 analogues were profiled in an in vivo mouse model, where intraperitoneal injections of 1b or 1f at 10 mg/kg notably mitigated symptoms of acute lung injury induced by lipopolysaccharide (LPS). These outcomes indicate that compounds 1b and 1f are promising candidates for acute lung injury treatment.
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Lesión Pulmonar Aguda , Bencenosulfonamidas , Sulfonamidas , Canales Catiónicos TRPV , Relación Estructura-Actividad , Canales Catiónicos TRPV/antagonistas & inhibidores , Canales Catiónicos TRPV/metabolismo , Lesión Pulmonar Aguda/tratamiento farmacológico , Sulfonamidas/química , Sulfonamidas/farmacología , Sulfonamidas/síntesis química , Animales , Ratones , Humanos , Estructura Molecular , Relación Dosis-Respuesta a Droga , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Masculino , Ratones Endogámicos C57BLRESUMEN
Zinc finger protein 471 (ZNF471) is a member of the Krüppel-related domain zinc finger protein family, and has recently attracted attention because of its anti-cancer effects. N-glycosylation regulates expression and functions of the protein. This study aimed to investigate the effects of ZNF471 N-glycosylation on the proliferation, invasion, and docetaxel sensitivity of tongue squamous cell carcinoma (TSCC). It analyzed the expression, function, and prognostic significance of ZNF471 in TSCC using bioinformatics techniques such as gene differential expression analysis, univariate Cox regression analysis, functional enrichment analysis, and gene set enrichment analysis. Using site-specific mutagenesis, this study generated three mutant sites for ZNF471 N-glycosylation to determine the effect of N-glycosylation on ZNF471 protein levels and function. Quantitative real-time PCR, Western blot analysis, and immunohistochemistry tests confirmed the down-regulation of ZNF471 expression in TSCC. Low expression of ZNF471 is associated with poor prognosis of patients with TSCC. Overexpression of ZNF471 in vitro retarded the proliferation of TSCC cells and suppressed cell invasion and migration ability. Asparagine 358 was identified as a N-glycosylation site of ZNF471. Suppressing N-glycosylation of ZNF471 enhanced the protein stability and promoted the translocation of protein to the cell nucleus. ZNF471 binding to c-Myc gene promoter suppressed oncogene c-Myc expression, thereby playing the anti-cancer effect and enhancing TSCC sensitivity to docetaxel. In all, N-glycosylation of ZNF471 affects the proliferation, invasion, and docetaxel sensitivity of TSCC via regulation of c-Myc.
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Proliferación Celular , Docetaxel , Invasividad Neoplásica , Proteínas Proto-Oncogénicas c-myc , Proteínas Represoras , Neoplasias de la Lengua , Femenino , Humanos , Masculino , Antineoplásicos/farmacología , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Docetaxel/farmacología , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glicosilación/efectos de los fármacos , Pronóstico , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Neoplasias de la Lengua/patología , Neoplasias de la Lengua/metabolismo , Neoplasias de la Lengua/tratamiento farmacológico , Neoplasias de la Lengua/genética , Proteínas Represoras/genética , Proteínas Represoras/metabolismoRESUMEN
Poly(triazine imide)·Li+Cl- (PTI/Li+Cl-) as one of the most reported crystalline carbon nitrides has shown exciting potential for photocatalysis. However, understanding the role of Li+/Cl- in the photoexcited charge transfer in the time and space of PTI is a challenging problem. Here, we have investigated the nonradiative charge recombination of series ion intercalated PTI systems (PTI/Li+X-, where X = F, Cl, Br, and I) by performing the ab initio nonadiabatic molecular dynamics simulations. The results indicate that the intercalated anions in PTI/Li+Cl- and PTI/Li+Br- have the potential to trap holes, separate the electrons and holes, and prolong the nonradiative electron-hole recombination. In particular, â¼70% of holes in PTI/Li+Cl- can transport among interlayers toward the {0001} planes, while most of the electrons are transferred to the {101Ì 0} planes, exhibiting different transport pathways and directions. Furthermore, PTI/Li+Cl- has an electron-hole recombination time as long as 136 ns, which explains its excellent optoelectronic properties. This work provides a theoretical baseline for the reported facet engineering improvement of crystalline carbon nitride for overall water splitting.
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OBJECTIVE: To evaluate the biomechanical characteristics of grafts from three different anterior cruciate ligament (ACL) reconstructive surgeries and to determine which method is better at restoring knee joint stability. METHODS: A 31-year-old female volunteer was enrolled in the study. According to the magnetic resonance imaging of her left knee, a three-dimensional model consisting of the distal femur, proximal tibia and fibula, ACL, posterior cruciate ligament, medial collateral ligament and lateral collateral ligament was established. Then, the ACL was removed from the original model to simulate the knee joint after ACL rupture. Based on the knee joint model without the ACL, single-bundle ACL reconstruction, double-bundle ACL reconstruction, and flat-tunnel ACL reconstruction were performed. The cross-sectional diameters of the grafts were equally set as 6 mm in the three groups. The bone tissues had a Young's modulus of 17 GPa and a Poisson's ratio of 0.36. The ligaments and grafts had a Young's modulus of 390 MPa and a Poisson's ratio of 0.4. Six probes were placed in an ACL or a graft to obtain the values of the equivalent stress, maximum principal stress, and maximum shear stress. After pulling the proximal tibia with a forward force of 134 N, the distance that the tibia moved and the stress distribution in the ACL or the graft, reflected by 30 mechanical values, were measured. RESULTS: The anterior tibial translation values were similar among the three groups, with the double-bundle ACL reconstruction group performing the best, followed closely by the patellar tendon ACL reconstruction group. In terms of stress distribution, 13 out of 30 mechanical values indicated that the grafts reconstructed by flat bone tunnels had better performance than the grafts in the other groups, while 12 out of 30 showed comparable outcomes, and 5 out of 30 had worse outcomes. CONCLUSION: Compared with traditional single-bundle and double-bundle ACL reconstructions, flat-tunnel ACL reconstruction has advantages in terms of stress dispersion. Additionally, flat-tunnel ACL reconstruction falls between traditional double-bundle and single-bundle ACL reconstructions in terms of restoring knee joint stability and is superior to single-bundle ACL reconstruction.
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Reconstrucción del Ligamento Cruzado Anterior , Análisis de Elementos Finitos , Humanos , Reconstrucción del Ligamento Cruzado Anterior/métodos , Femenino , Adulto , Fenómenos Biomecánicos , Imagenología Tridimensional/métodos , Ligamento Cruzado Anterior/cirugía , Tibia/cirugía , Tibia/diagnóstico por imagen , Estrés Mecánico , Articulación de la Rodilla/cirugía , Articulación de la Rodilla/diagnóstico por imagen , Articulación de la Rodilla/fisiopatologíaRESUMEN
Slippery liquid-infused porous surface (SLIPS), inspired by the Nepenthes pitcher plant, exhibits excellent performances as it has a smooth surface and extremely low contact angle hysteresis. Biomimetic SLIPS attracts considerable attention from the researchers for different applications in self-cleaning, anti-icing, anticorrosion, antibacteria, antithrombotic, and other fields. Hence, SLIPS has shown promise for applications across both the biomedical and industrial fields. However, the manufacturing of SLIPS with strong bonding ability to different substrates and powerful liquid locking performance remains highly challenging. In this review, a comprehensive overview of research on SLIPS for medical applications is conducted, and the design parameters and common fabrication methods of such surfaces are summarized. The discussion extends to the mechanisms of interaction between microbes, cells, proteins, and the liquid layer, highlighting the typical antifouling applications of SLIPS. Furthermore, it identifies the potential of utilizing the controllable factors provided by SLIPS to develop innovative materials and devices aimed at enhancing human health.
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Propiedades de Superficie , Porosidad , Humanos , Materiales Biocompatibles Revestidos/químicaRESUMEN
AIMS: MNDA (myeloid nuclear differentiation antigen) has been considered as a potential diagnostic marker for marginal zone lymphoma (MZL), but its utility in distinguishing MZL from other B-cell non-Hodgkin lymphomas (B-NHLs) and its clinicopathologic relevance in diffuse large B-cell lymphoma (DLBCL) are ambiguous. We comprehensively investigated MNDA expression in a large series of B-NHLs and evaluated its diagnostic value. METHODS: MNDA expression in a cohort of 1293 cases of B-NHLs and 338 cases of reactive lymphoid hyperplasia (RLH) was determined using immunohistochemistry and compared among different types of B-NHL. The clinicopathologic relevance of MNDA in DLBCL was investigated. RESULTS: MNDA was highly expressed in MZLs (437/663, 65.9%), compared with the confined staining in marginal zone B-cells in RLH; whereas neoplastic cells with plasmacytic differentiation lost MNDA expression. MNDA expression was significantly higher in mantle cell lymphoma (MCL, 79.6%, p = 0.006), whereas lower in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL, 44.8%, p = 0.001) and lymphoplasmacytic lymphoma (LPL, 25%, p = 0.016), and dramatically lower in follicular lymphoma (FL, 5.2%, p < 0.001), compared with MZL. 29.6% (63/213) of DLBCLs were positive for MNDA. The cases in non-GCB group exhibited a higher rate of MNDA positivity (39.8%) compared to those in GCB group (16.3%) (p < 0.001), and MNDA staining was more frequently observed in DLBCLs with BCL2/MYC double-expression (50%) than those without BCL2/MYC double-expression (24.8%) (p = 0.001). Furthermore, there was a significant correlation between MNDA and CD5 expression in DLBCL (p = 0.036). CONCLUSIONS: MNDA was highly expressed in MZL with a potential utility in differential diagnosis between MZL and RLH as well as FL, whereas its value in distinguishing MZL from MCL, CLL/SLL is limited. In addition, MNDA expression in DLBCL was more frequently seen in the non-GCB group and the BCL2/MYC double-expression group, and demonstrated a correlation with CD5, which deserves further investigation. The clinical relevance of MNDA and its correlation with the prognosis of these lymphomas also warrant to be fully elucidated.
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Leucemia Linfocítica Crónica de Células B , Linfoma de Células B de la Zona Marginal , Linfoma Folicular , Humanos , Antígenos de Diferenciación Mielomonocítica/metabolismo , Diagnóstico Diferencial , Leucemia Linfocítica Crónica de Células B/diagnóstico , Linfoma de Células B de la Zona Marginal/metabolismo , Linfoma Folicular/patología , Proteínas Proto-Oncogénicas c-bcl-2 , Factores de Transcripción/metabolismoRESUMEN
This study investigated the clinicopathological, immunohistochemical, and molecular features of primary leptomeningeal melanocytic neoplasms (LMNs). Twelve LMN cases were retrospectively reviewed. We performed Fluorescence in-situ hybridization (including a 4-probe FISH assay with CDKN2A and MYC assay) and Next-Generation sequencing analyses on available cases. Histologically, 2 tumours were classified as melanocytomas (MC), 2 as intermediate-grade melanocytomas (IMC), and 8 as leptomeningeal melanomas (LMM). Two rare cases of LMM were associated with large plaque-like blue nevus. One MC case was associated with Ota. Ten cases (83.3%) showed melanocytic cells with benign features diffusely proliferating within the meninges. The Ki-67 in three categories differed (MC 0-1%, IMC 0-3%, LMM 3-10%). 57.1% of LMM cases (4/7) were positive for FISH. Nine of 10 tumours harboured activating hotspot mutations in GNAQ, GNA11, or PLCB4. Additional mutations of EIF1AX, SF3B1, or BAP1 were found in 40%, 30%, and 10% of tumours, respectively. During the follow-up (median = 43 months), 5 LMM patients experienced recurrence and/or metastasis, 3 of them died of the disease and the other 2 are alive with the tumour. Our study is by far the first cohort of LMN cases tested by FISH. In addition to morphological indicators including necrosis and mitotic figures, using a combination of Ki-67 and FISH helps to differentiate between IMC and LMM, especially in LMM cases with less pleomorphic features. SF3B1 mutation is first described in 2 cases of plaque-type blue nevus associated with LMM. Patients with SF3B1 mutation might be related to poor prognosis in LMN.
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Biomarcadores de Tumor , Inmunohistoquímica , Hibridación Fluorescente in Situ , Melanoma , Neoplasias Meníngeas , Mutación , Humanos , Masculino , Femenino , Persona de Mediana Edad , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/patología , Adulto , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Melanoma/genética , Melanoma/patología , Estudios Retrospectivos , Anciano , Secuenciación de Nucleótidos de Alto Rendimiento , Adulto Joven , Adolescente , Análisis Mutacional de ADNRESUMEN
OBJECTIVE: The study aims to evaluate the accuracy of an MRI-based artificial intelligence (AI) segmentation cartilage model by comparing it to the natural tibial plateau cartilage. METHODS: This study included 33 patients (41 knees) with severe knee osteoarthritis scheduled to undergo total knee arthroplasty (TKA). All patients had a thin-section MRI before TKA. Our study is mainly divided into two parts: (i) In order to evaluate the MRI-based AI segmentation cartilage model's 2D accuracy, the natural tibial plateau was used as gold standard. The MRI-based AI segmentation cartilage model and the natural tibial plateau were represented in binary visualization (black and white) simulated photographed images by the application of Simulation Photography Technology. Both simulated photographed images were compared to evaluate the 2D Dice similarity coefficients (DSC). (ii) In order to evaluate the MRI-based AI segmentation cartilage model's 3D accuracy. Hand-crafted cartilage model based on knee CT was established. We used these hand-crafted CT-based knee cartilage model as gold standard to evaluate 2D and 3D consistency of between the MRI-based AI segmentation cartilage model and hand-crafted CT-based cartilage model. 3D registration technology was used for both models. Correlations between the MRI-based AI knee cartilage model and CT-based knee cartilage model were also assessed with the Pearson correlation coefficient. RESULTS: The AI segmentation cartilage model produced reasonably high two-dimensional DSC. The average 2D DSC between MRI-based AI cartilage model and the tibial plateau cartilage is 0.83. The average 2D DSC between the AI segmentation cartilage model and the CT-based cartilage model is 0.82. As for 3D consistency, the average 3D DSC between MRI-based AI cartilage model and CT-based cartilage model is 0.52. However, the quantification of cartilage segmentation with the AI and CT-based models showed excellent correlation (r = 0.725; P values < 0.05). CONCLUSION: Our study demonstrated that our MRI-based AI cartilage model can reliably extract morphologic features such as cartilage shape and defect location of the tibial plateau cartilage. This approach could potentially benefit clinical practices such as diagnosing osteoarthritis. However, in terms of cartilage thickness and three-dimensional accuracy, MRI-based AI cartilage model underestimate the actual cartilage volume. The previous AI verification methods may not be completely accurate and should be verified with natural cartilage images. Combining multiple verification methods will improve the accuracy of the AI model.
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Cartílago Articular , Osteoartritis de la Rodilla , Humanos , Inteligencia Artificial , Cartílago Articular/anatomía & histología , Articulación de la Rodilla/anatomía & histología , Imagen por Resonancia Magnética/métodosRESUMEN
Stimuli-responsive aggregation-induced emission (AIE) materials are highly sensitive and rapidly responsive to external signals, making them ideal solid materials for anti-counterfeiting encryption. However, the limited conformational and packing variations resulting from regio-isomerization with a single substituent restricts the stimuli-responsive behavior of these materials. In this work, several AIE-active regio-structural isomers based on the salicylaldehyde Schiff base scaffold have been straightforwardly obtained through multiple substitutions with bromide and triphenylamine moieties. Solvent-effect experiments demonstrate their different orders of charge-transfer and excited-state intramolecular proton transfer upon photoexcitation, indicating the regulation of excited-state processes via multi-site isomerization. These isomers also demonstrate mechanochromism and acidichromism, allowing for adjustable stimuli-responsive effects. As a demonstration, p-Br-TPA with both mechanochromism and acidichromism can be synergistically utilized for multi-level decryption. This study successfully regulates the evolution of excited states through multi-site isomerization, offering a general approach for achieving tunable stimuli-responsive properties in AIE-active salicylaldehyde Schiff bases toward multi-level decryption.
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As one of the important paths for China to achieve the "dual carbon" strategyï¼ developing hydrogen fuel cell vehicles is currently being promoted in various regions across the countryï¼ including passenger carsï¼ coachesï¼ and heavy-duty trucks. Quantifying the carbon reduction potential of hydrogen fuel cell vehicles for different vehicle types and regions has become a hot research topic. Using a life cycle assessment method that considers future vehicle fuel economyï¼ power generation carbon emission factorsï¼ hydrogen production carbon emission factorsï¼ and regional differences in the scale and hydrogen production methodsï¼ this study quantitatively evaluated the life cycle carbon emissions of different types of vehiclesï¼ including fuel cell vehicles ï¼FCVï¼ï¼ traditional fuel vehicles ï¼ICEVï¼ï¼ and battery electric vehicles ï¼BEVï¼. We compared and analyzed the carbon reduction potential of hydrogen fuel cell vehicles at different times and in different regions and conducted an uncertainty analysis on hydrogen consumption per hundred kilometers. The results showed that by 2025ï¼ the life cycle carbon emissions of hydrogen fuel cell coaches would decrease by 36.0% compared to that of traditional fuel coachesï¼ but the reduction in carbon emissions for hydrogen fuel cell heavy-duty trucks was not significant. By 2035ï¼ as the hydrogen energy source structure in China continues to improveï¼ the life cycle carbon emissions of hydrogen fuel cell heavy-duty trucks were predicted to decrease by 36.5% compared to that of traditional fuel heavy-duty trucks. The decarbonization potential was most significant for heavy-duty trucks compared to that of passenger cars and coaches. Taking the Beijing-Tianjin-Hebei demonstration group as an example in 2035ï¼ as the hydrogen consumption per hundred kilometers decreases by 20%ï¼ the carbon reduction potential of FCV passenger carsï¼ coachesï¼ and heavy-duty trucks would increase by 7.29%ï¼ 9.93%ï¼ and 19.57%ï¼ respectively. Thereforeï¼ it is recommended to prioritize the promotion of hydrogen fuel cell coaches in the short termï¼ heavy-duty trucks in the long termï¼ and passenger cars as a supplement. Promoting hydrogen fuel cell vehicles in different regions and stages will help advance the low-carbon development of the automotive industry in China.
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High-throughput Chromatin Conformation Capture (Hi-C) technologies can be used to investigate the three-dimensional genomic structure of plants. However, the practical utility of these technologies is impeded by significant background noise, hindering their capability in detecting fine 3D genomic structures. In this study, we optimized the Bridge Linker Hi-C technology (BL-Hi-C) to comprehensively investigate the 3D chromatin landscape of Brassica rapa and Brassica oleracea. The Bouquet configuration of both B. rapa and B. oleracea was elucidated through the construction of a 3D genome simulation. The optimized BL-Hi-C exhibited lower background noise compared to conventional Hi-C methods. Taking this advantage, we used BL-Hi-C to identify FLC gene loops in Arabidopsis, B. rapa, and B. oleracea. We observed that gene loops of FLC2 exhibited conservation across Arabidopsis, B. rapa, and B. oleracea. While gene loops of syntenic FLCs exhibited conservation across B. rapa and B. oleracea, variations in gene loops were evident among multiple paralogs FLCs within the same species. Collectively, our findings highlight the high sensitivity of optimized BL-Hi-C as a powerful tool for investigating the fine 3D genomic organization.
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Feature selection (FS) is recognized for its role in enhancing the performance of learning algorithms, especially for high-dimensional datasets. In recent times, FS has been framed as a multi-objective optimization problem, leading to the application of various multi-objective evolutionary algorithms (MOEAs) to address it. However, the solution space expands exponentially with the dataset's dimensionality. Simultaneously, the extensive search space often results in numerous local optimal solutions due to a large proportion of unrelated and redundant features [H. Adeli and H. S. Park, Fully automated design of super-high-rise building structures by a hybrid ai model on a massively parallel machine, AI Mag. 17 (1996) 87-93]. Consequently, existing MOEAs struggle with local optima stagnation, particularly in large-scale multi-objective FS problems (LSMOFSPs). Different LSMOFSPs generally exhibit unique characteristics, yet most existing MOEAs rely on a single candidate solution generation strategy (CSGS), which may be less efficient for diverse LSMOFSPs [H. S. Park and H. Adeli, Distributed neural dynamics algorithms for optimization of large steel structures, J. Struct. Eng. ASCE 123 (1997) 880-888; M. Aldwaik and H. Adeli, Advances in optimization of highrise building structures, Struct. Multidiscip. Optim. 50 (2014) 899-919; E. G. González, J. R. Villar, Q. Tan, J. Sedano and C. Chira, An efficient multi-robot path planning solution using a* and coevolutionary algorithms, Integr. Comput. Aided Eng. 30 (2022) 41-52]. Moreover, selecting an appropriate MOEA and determining its corresponding parameter values for a specified LSMOFSP is time-consuming. To address these challenges, a multi-objective self-adaptive particle swarm optimization (MOSaPSO) algorithm is proposed, combined with a rapid nondominated sorting approach. MOSaPSO employs a self-adaptive mechanism, along with five modified efficient CSGSs, to generate new solutions. Experiments were conducted on ten datasets, and the results demonstrate that the number of features is effectively reduced by MOSaPSO while lowering the classification error rate. Furthermore, superior performance is observed in comparison to its counterparts on both the training and test sets, with advantages becoming increasingly evident as the dimensionality increases.
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Background: Bilateral deep thalamic nucleus brain stimulation (STN-DBS) surgery is often used to treat the motor symptoms of patients with Parkinson's disease. The change of neurocognitive symptoms in patients is, however, still unclear. Objective: We aimed at analyzing the deterioration of neurocognitive symptoms in patients with Parkinson's disease after deep brain stimulation surgery under different follow-up times. Methods: A comprehensive literature review was conducted using Pubmed, Cochrane Library, and Web of Science to screen eligible study records, the meta-analysis was performed using an inverse variance method and a random-effects model. Additionally, the areas of analysis include five: cognition, executive function, memory capacity, and verbal fluency (phonetic fluency and semantic fluency). They were analyzed for changes at six and twelve months postoperatively compared to baseline. The Meta-analysis has been registered with PROSPERO under the registration number: CRD42022308786. Results: In terms of overall cognitive performance, executive function, and memory capacity, the original studies show a trend of improvement in these areas at 12 months postoperatively compared with 6 months, at variance, patients did not improve or deteriorated in phonetic fluency(d = -0.42 at both 6-month and 12-month follow-up) and semantic fluency from 6 to 12 months postoperatively. Conclusion: In terms of most neurocognitive symptoms, including cognitive ability, executive function, and learning memory capacity, bilateral STN-DBS surgery appears to be safe at relatively long follow-up times. However, postoperative phonetic and semantic fluency changes should still not be underestimated, and clinicians should pay more attention to patients' changes in both.
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The World Health Organization has updated their classification system for the diagnosis of gliomas, combining histological features with molecular data including isocitrate dehydrogenase 1 and codeletion of chromosomal arms 1p and 19q. 1p/19q codeletion analysis is commonly performed by fluorescence in situ hybridization (FISH). In this study, we developed a 57-gene targeted next-generation sequencing (NGS) panel including 1p/19q codeletion detection mainly to assess diagnosis and potential treatment response in melanoma, gastrointestinal stromal tumor, and glioma patients. Loss of heterozygosity analysis was performed using the NGS method on 37 formalin-fixed paraffin-embedded glioma tissues that showed 1p and/or 19q loss determined by FISH. Conventional methods were applied for the validation of some glioma-related gene mutations. In 81.1% (30 of 37) and 94.6% (35 of 37) of cases, 1p and 19q were found to be in agreement whereas concordance for 1p/19q codeletion and no 1p/19q codeletion was found in 94.7% (18 of 19) and 94.4% (17 of 18) of cases, respectively. Overall, comparing NGS results with those of conventional methods showed high concordance. In conclusion, the NGS panel allows reliable analysis of 1p/19q codeletion and mutation at the same time.