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Establishment of B-lineage-specific gene expression requires the binding of transcription factors to inaccessible chromatin of progenitors. The transcription factor EBF1 can bind genomic regions prior to the detection of chromatin accessibility in a manner dependent on EBF1's C-terminal domain (CTD) and independent of cooperating transcription factors. Here, we studied the mechanism whereby the CTD enables this pioneering function. The CTD of EBF1 was dispensable for initial chromatin targeting but stabilized occupancy via recruitment of the chromatin remodeler Brg1. We found that the CTD harbors a prion-like domain (PLD) with an ability of liquid-liquid phase separation, which was enhanced by interaction of EBF1 with the RNA-binding protein FUS. Brg1 also partitioned into phase-separated FUS condensates and coincided with EBF1 and FUS foci in pro-B cells. Heterologous PLDs conferred pioneering function on EBF1ΔCTD. Thus, the phase separation ability of EBF1 facilitates Brg1-mediated chromatin opening and the transition of naive progenitor chromatin to B-lineage-committed chromatin.
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Linfócitos B/metabolismo , Cromatina/metabolismo , Príons/química , Transativadores/metabolismo , Sequência de Aminoácidos , Linfócitos B/citologia , DNA Helicases/metabolismo , Humanos , Proteínas Nucleares/metabolismo , Transição de Fase , Células Precursoras de Linfócitos B/citologia , Células Precursoras de Linfócitos B/metabolismo , Domínios Proteicos , Proteína FUS de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/metabolismo , Transativadores/química , Fatores de Transcrição/metabolismoRESUMO
Owing to its remarkable ease of use, ultrasound has recently been explored for stimulating or amplifying immune responses during cancer therapy, termed 'sono-immunotherapy'. Ultrasound can cause immunogenic cell death in cancer cells via thermal and nonthermal effects to regulate the tumor microenvironment, thereby priming anticancer immunity; by integrating well-designed biomaterials, novel sono-immunotherapy approaches with augmented efficacy can also be developed. Here, we review the advances in sono-immunotherapy for cancer treatment and summarize existing limitations along with potential trends. We offer emerging insights into this realm, which might prompt breakthroughs and expand its potential applications to other diseases.
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Imunoterapia , Neoplasias , Microambiente Tumoral , Humanos , Neoplasias/terapia , Neoplasias/imunologia , Imunoterapia/métodos , Animais , Microambiente Tumoral/imunologia , Terapia por Ultrassom/métodosRESUMO
BACKGROUND AND AIMS: A single-nation study reported that pretreatment HBV viral load is associated with on-treatment risk of HCC in patients who are HBeAg-positive without cirrhosis and with chronic hepatitis B initiating antiviral treatment. We aimed to validate the association between baseline HBV viral load and on-treatment HCC risk in a larger, multinational cohort. APPROACH AND RESULTS: Using a multinational cohort from Korea, Hong Kong, and Taiwan involving 7545 adult patients with HBeAg-positive, without cirrhosis and with chronic hepatitis B who started entecavir or tenofovir treatment with baseline HBV viral load ≥5.00 log 10 IU/mL, HCC risk was estimated by baseline viral load. HBV viral load was analyzed as a categorical variable. During continuous antiviral treatment (median, 4.28 y), HCC developed in 200 patients (incidence rate, 0.61 per 100 person-years). Baseline HBV DNA level was independently associated with on-treatment HCC risk in a nonlinear pattern. HCC risk was lowest with the highest baseline viral load (≥8.00 log 10 IU/mL; incidence rate, 0.10 per 100 person-years), but increased sharply as baseline viral load decreased. The adjusted HCC risk was 8.05 times higher (95% CI, 3.34-19.35) with baseline viral load ≥6.00 and <7.00 log 10 IU/mL (incidence rate, 1.38 per 100 person-years) compared with high (≥8.00 log 10 IU/mL) baseline viral load ( p <0.001). CONCLUSIONS: In a multinational cohort of adult patients with HBeAg-positive without cirrhosis and with chronic hepatitis B, baseline HBV viral load was significantly associated with HCC risk despite antiviral treatment. Patients with the highest viral load who initiated treatment had the lowest long-term risk of HCC development.
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Antivirais , Carcinoma Hepatocelular , Antígenos E da Hepatite B , Hepatite B Crônica , Neoplasias Hepáticas , Carga Viral , Humanos , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/complicações , Hepatite B Crônica/virologia , Masculino , Neoplasias Hepáticas/virologia , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/etiologia , Feminino , Pessoa de Meia-Idade , Antígenos E da Hepatite B/sangue , Antivirais/uso terapêutico , Carcinoma Hepatocelular/virologia , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/etiologia , Adulto , Taiwan/epidemiologia , Vírus da Hepatite B , Hong Kong/epidemiologia , República da Coreia/epidemiologia , Estudos de Coortes , Tenofovir/uso terapêutico , Guanina/análogos & derivados , Guanina/uso terapêutico , DNA Viral/sangue , Incidência , Fatores de RiscoRESUMO
Plant viruses with densely packed genomes employ noncanonical translational strategies to increase the coding capacity for viral function. However, the diverse translational strategies used make it challenging to define the full set of viral genes. Here, using tomato yellow leaf curl Thailand virus (TYLCTHV, genus Begomovirus) as a model system, we identified genes beyond the annotated gene sets by experimentally profiling in vivo translation initiation sites (TISs). We found that unanticipated AUG TISs were prevalent and determined that their usage involves alternative transcriptional and/or translational start sites and is associated with flanking mRNA sequences. Specifically, two downstream in-frame TISs were identified in the viral gene AV2. These TISs were conserved in the begomovirus lineage and led to the translation of different protein isoforms localized to cytoplasmic puncta and at the cell periphery, respectively. In addition, we found translational evidence of an unexplored gene, BV2. BV2 is conserved among TYLCTHV isolates and localizes to the endoplasmic reticulum and plasmodesmata. Mutations of AV2 isoforms and BV2 significantly attenuated disease symptoms in tomato (Solanum lycopersicum). In conclusion, our study pinpointing in vivo TISs untangles the coding complexity of a plant viral genome and, more importantly, illustrates the biological significance of the hidden open-reading frames encoding viral factors for pathogenicity.
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Begomovirus , Solanum lycopersicum , Begomovirus/genética , Genoma Viral , Solanum lycopersicum/genética , Fases de Leitura Aberta/genética , Filogenia , Doenças das Plantas/genéticaRESUMO
The expression of large conductance calcium-activated potassium channels (BK channels) in adipose tissue has been identified for years. BK channel deletion can improve metabolism in vivo, but the relative mechanisms remain unclear. Here, we examined the effects of BK channels on the differentiation of adipose-derived stem cells (ADSCs) and the related mechanisms. BKα and ß1 subunits were expressed on adipocytes. We found that both deletion of the KCNMA1 gene, encoding the pore forming α subunit of BK channels, and the BK channel inhibitor paxilline increased the expression of key genes in the peroxisome proliferator activated receptor (PPAR) pathway and promoted adipogenetic differentiation of ADSCs. We also observed that the MAPK-ERK pathway participates in BK channel deficiency-promoted adipogenic differentiation of ADSCs and that ERK inhibitors blocked the differentiation-promoting effect of BK channel deficiency. Hyperplasia of adipocytes is considered beneficial for metabolic health. These results indicate that BK channels play an important role in adipose hyperplasia by regulating the differentiation of ADSCs and may become an important target for studying the pathogenesis and treatment strategies of metabolic disorder-related diseases.
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Canais de Potássio Ativados por Cálcio de Condutância Alta , Sistema de Sinalização das MAP Quinases , Humanos , Canais de Potássio Ativados por Cálcio de Condutância Alta/genética , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Hiperplasia , Diferenciação Celular , Adipócitos/metabolismoRESUMO
Antidepressants, while effective in treating depression and anxiety disorders, also induce deficits in sensory (particularly auditory) processing, which in turn may exacerbate psychiatric symptoms. How antidepressants cause auditory signature deficits remains largely unknown. Here, we found that fluoxetine-treated adult female rats were significantly less accurate when performing a tone-frequency discrimination task compared with age-matched control rats. Their cortical neurons also responded less selectively to sound frequencies. The degraded behavioral and cortical processing was accompanied by decreased cortical perineuronal nets, particularly those wrapped around parvalbumin-expressing inhibitory interneurons. Furthermore, fluoxetine induced critical period-like plasticity in their already mature auditory cortices; therefore, a brief rearing of these drug-treated rats under an enriched acoustic environment renormalized auditory processing degraded by fluoxetine. The altered cortical expression of perineuronal nets was also reversed as a result of enriched sound exposure. These findings suggest that the adverse effects of antidepressants on auditory processing, possibly because of a reduction in intracortical inhibition, can be substantially alleviated by simply pairing drug treatment with passive, enriched sound exposure. They have important implications for understanding the neurobiological basis of antidepressant effects on hearing and for designing novel pharmacological treatment strategies for psychiatric disorders.SIGNIFICANCE STATEMENT Clinical experience suggests that antidepressants adversely affect sensory (particularly auditory) processing, which can exacerbate patients' psychiatric symptoms. Here, we show that the antidepressant fluoxetine reduces cortical inhibition in adult rats, leading to degraded behavioral and cortical spectral processing of sound. Importantly, fluoxetine induces a critical period-like state of plasticity in the mature cortex; therefore, a brief rearing under an enriched acoustic environment is sufficient to reverse the changes in auditory processing caused by the administration of fluoxetine. These results provide a putative neurobiological basis for the effects of antidepressants on hearing and indicate that antidepressant treatment combined with enriched sensory experiences could optimize clinical outcomes.
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Córtex Auditivo , Fluoxetina , Ratos , Feminino , Animais , Fluoxetina/farmacologia , Percepção Auditiva/fisiologia , Som , Córtex Auditivo/fisiologia , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Estimulação Acústica/métodosRESUMO
Glioblastoma (GBM) represents a prevalent form of primary malignant tumours in the central nervous system, but the options for effective treatment are extremely limited. Ferroptosis, as the most enriched programmed cell death process in glioma, makes a critical difference in glioma progression. Consequently, inducing ferroptosis has become an appealing strategy for tackling gliomas. Through the utilization of multi-omics sequencing data analysis, flow cytometry, MDA detection and transmission electron microscopy, the impact of orexin-A on ferroptosis in GBM was assessed. In this report, we provide the first evidence that orexin-A exerts inhibitory effects on GBM proliferation via the induction of ferroptosis. This induction is achieved by instigating an unsustainable increase in iron levels and depletion of GPX4. Moreover, the regulation of TFRC, FTH1 and GPX4 expression through the targeting of NFE2L2 appears to be one of the potential mechanisms underlying orexin-A-induced ferroptosis.
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Proliferação de Células , Ferroptose , Glioblastoma , Ferro , Orexinas , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Animais , Humanos , Camundongos , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/metabolismo , Glioblastoma/patologia , Glioblastoma/genética , Ferro/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Orexinas/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genéticaRESUMO
Nanomedicines often rely on noncovalent self-assembly and encapsulation for drug loading and delivery. However, challenges such as reproducibility issues due to the multicomponent nature, off-target activation caused by premature drug release, and complex pharmacokinetics arising from assembly dissociation have hindered their clinical translation. In this study, we introduce an innovative design concept termed single molecular nanomedicine (SMNM) based on macrocyclic carrier-drug conjugates. Through the covalent linkage of two chemotherapy drugs to a hypoxia-cleavable macrocyclic carrier, azocalix[4]arene, we obtained two self-included complexes to serve as SMNMs. The intramolecular inclusion feature of the SMNMs has not only demonstrated comprehensive shielding and protection for the drugs but also effectively prevented off-target drug leakage, thereby significantly reducing their side effects and enhancing their antitumor therapeutic efficacy. Additionally, the attributes of being a single component and molecularly dispersed confer advantages such as ease of preparation and good reproducibility for SMNMs, which is desirable for clinical applications.
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Antineoplásicos , Calixarenos , Portadores de Fármacos , Nanomedicina , Humanos , Portadores de Fármacos/química , Nanomedicina/métodos , Calixarenos/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Animais , Compostos Macrocíclicos/química , Camundongos , Linhagem Celular Tumoral , Liberação Controlada de FármacosRESUMO
Catalytic asymmetric dearomatization (CADA) reactions have evolved into an efficient strategy for accessing chiral polycyclic and spirocyclic scaffolds from readily available planar aromatics. Despite the significant developments, the CADA reaction of naphthalenes remains underdeveloped. Herein, we report a Gd(III)-catalyzed asymmetric dearomatization reaction of naphthalene with a chiral PyBox ligand via visible-light-enabled [4 + 2] cycloaddition. This reaction features application of a chiral Gd/PyBox complex, which regulates the reactivity and selectivity simultaneously, in excited-state catalysis. A wide range of functional groups is compatible with this protocol, giving the highly enantioenriched bridged polycycles in excellent yields (up to 96%) and selectivity (up to >20:1 chemoselectivity, >20:1 dr, >99% ee). The synthetic utility is demonstrated by a 2 mmol scale reaction, removal of directing group, and diversifications of products. Preliminary mechanistic experiments are performed to elucidate the reaction mechanism.
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The vinylene-linked covalent organic frameworks (viCOFs) have been generally synthesized in the presence of homogeneous catalysts such as KOH or trifluoroacetic acid. However, highly ordered viCOFs cannot always be obtained due to the uncommitted growth of viCOF layers in the homogeneous system with ubiquitous catalysts. Here, we propose a scalable protocol to restrict the growth of viCOFs along the two-dimensional (2D) plane by introducing a heterogeneous catalyst, polyoxometalates (POMs). With the unique Brønsted alkalinity and catalytic surface, POMs induce the growth of 2D viCOF layers along the surface of the catalytic substrate and restrain the generation of out-of-plane branches. Based on this protocol, six typical 2D viCOFs with high crystallinity and porosity were synthesized within a shorter reaction time as compared with the reported works using the common homogeneous catalysts for viCOF synthesis. On the basis of the density functional theory calculations and experimental results, a bottom intercalation growth pattern of viCOFs was revealed during the heterogeneous reaction. The unique growth pattern greatly promotes the orderly assembly of monomers, thus shortening the reaction time and improving the crystallinity of viCOFs. Furthermore, this heterogeneous catalysis strategy is suitable for the gram-scale preparation of 2D viCOFs. These results provide a novel avenue for the synthesis of high-quality viCOFs and may bring new insights into the synthetic methodology of COFs.
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BACKGROUND: Gastric cancer is one of the global health concerns. A series of studies on the stomach have confirmed the role of the microbiome in shaping gastrointestinal diseases. Delineation of microbiome signatures to distinguish chronic gastritis from gastric cancer will provide a non-invasive preventative and treatment strategy. In this study, we performed whole metagenome shotgun sequencing of fecal samples to enhance the detection of rare bacterial species and increase genome sequence coverage. Additionally, we employed multiple bioinformatics approaches to investigate the potential targets of the microbiome as an indicator of differentiating gastric cancer from chronic gastritis. RESULTS: A total of 65 patients were enrolled, comprising 33 individuals with chronic gastritis and 32 with gastric cancer. Within each group, the chronic gastritis group was sub-grouped into intestinal metaplasia (n = 15) and non-intestinal metaplasia (n = 18); the gastric cancer group, early stage (stages 1 and 2, n = 13) and late stage (stages 3 and 4, n = 19) cancer. No significant differences in alpha and beta diversities were detected among the patient groups. However, in a two-group univariate comparison, higher Fusobacteria abundance was identified in phylum; Fusobacteria presented higher abundance in gastric cancer (LDA scored 4.27, q = 0.041 in LEfSe). Age and sex-adjusted MaAsLin and Random Forest variable of importance (VIMP) analysis in species provided meaningful features; Bacteria_caccae was the most contributing species toward gastric cancer and late-stage cancer (beta:2.43, se:0.891, p:0.008, VIMP score:2.543). In contrast, Bifidobacterium_longum significantly contributed to chronic gastritis (beta:-1.8, se:0.699, p:0.009, VIMP score:1.988). Age, sex, and BMI-adjusted MasAsLin on metabolic pathway analysis showed that GLCMANNANAUT-PWY degradation was higher in gastric cancer and one of the contributing species was Fusobacterium_varium. CONCLUSION: Microbiomes belonging to the pathogenic phylum Fusobacteria and species Bacteroides_caccae and Streptococcus_anginosus can be significant targets for monitoring the progression of gastric cancer. Whereas Bifidobacterium_longum and Lachnospiraceae_bacterium_5_1_63FAA might be protection biomarkers against gastric cancer.
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Bactérias , Fezes , Gastrite , Metagenoma , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/microbiologia , Masculino , Feminino , Pessoa de Meia-Idade , Gastrite/microbiologia , Fezes/microbiologia , Bactérias/genética , Bactérias/classificação , Bactérias/isolamento & purificação , Idoso , Microbioma Gastrointestinal/genética , AdultoRESUMO
Early confirmation of sustained virologic response (SVR) or viral relapse after direct-acting antivirals (DAAs) for hepatitis C virus (HCV) infection is essential based on public health perspectives, particularly for patients with high risk of nonadherence to posttreatment follow-ups. A total of 1011 patients who achieved end-of-treatment virologic response, including 526 receiving fixed-dose pangenotypic DAAs, and 485 receiving other types of DAAs, who had available off-treatment weeks 4 and 12 serum HCV RNA data to confirm SVR at off-treatment week 12 (SVR12) or viral relapse were included. The positive predictive value (PPV) and negative predictive value (NPV) of SVR4 to predict patients with SVR12 or viral relapse were reported. Furthermore, we analyzed the proportion of concordance between SVR12 and SVR24 in 943 patients with available SVR24 data. The PPV and NPV of SVR4 to predict SVR12 were 98.5% (95% confidence interval [CI]: 98.0-98.9) and 100% (95% CI: 66.4-100) in the entire population. The PPV of SVR4 to predict SVR12 in patients receiving fixed-dose pangenotypic DAAs was higher than those receiving other types of DAAs (99.8% [95% CI: 98.9-100] vs. 97.1% [95% CI: 96.2-97.8], p < 0.001). The NPVs of SVR4 to predict viral relapse were 100%, regardless of the type of DAAs. Moreover, the concordance between SVR12 and SVR24 was 100%. In conclusion, an off-treatment week 4 serum HCV RNA testing is sufficient to provide an excellent prediction power of SVR or viral relapse at off-treatment week 12 among patients with HCV who are treated with fixed-dose pangenotypic DAAs.
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Antivirais , Hepacivirus , Hepatite C Crônica , RNA Viral , Resposta Viral Sustentada , Humanos , Antivirais/uso terapêutico , Antivirais/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , Hepacivirus/genética , Hepacivirus/efeitos dos fármacos , Idoso , Adulto , RNA Viral/sangue , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Recidiva , Seguimentos , Resultado do Tratamento , Hepatite C/tratamento farmacológico , Hepatite C/virologiaRESUMO
What we believe to be a novel low-cost broadband continuous-wave water vapor differential absorption lidar (CW-DIAL) technique has been proposed and implemented by combing the Scheimpflug principle and the differential absorption method. The broadband CW-DIAL technique utilizes an 830-nm high-power multimode laser diode with 3-W output power as a tunable light source and a CMOS image sensor tilted at 45° as the detector. A retrieval algorithm dedicated for the broadband CW-DIAL technique has been developed to obtain range-resolved water vapor concentration from the DIAL signal. Atmospheric remote sensing of water vapor has been carried out on a near-horizontal water vapor path to validate the performance of the broadband CW-DIAL system. The retrieved water vapor concentration showed a good consistency with those measured by an air quality monitoring station, with a correlation coefficient of 0.9669. The fitting error of the water vapor concentration is found to be less than 10%. Numerical simulation studies have revealed that the aerosol-induced error on the water vapor concentration is below 5% with a background water vapor concentration of 5â g/m3 for most atmospheric conditions. The experimental results have successfully demonstrated the feasibility of the present broadband CW-DIAL technique for range-resolved water vapor remote sensing.
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Despite the emergence of various treatment strategies for rectal cancer based on neoadjuvant chemoradiotherapy, there is currently a lack of reliable biomarkers to determine which patients will respond well to neoadjuvant chemoradiotherapy. Through collecting hematological and biochemical parameters data of patients prior to receiving neoadjuvant chemoradiotherapy, we evaluated the predictive value of systemic inflammatory indices for pathological response and prognosis in rectal cancer patients. We found that baseline GRIm-Score was an independent predictor for MPR in rectal cancer patients. However, no association was observed between several commonly systemic inflammation indices and long-term outcome.
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Terapia Neoadjuvante , Neoplasias Retais , Humanos , Neoplasias Retais/patologia , Neoplasias Retais/terapia , Neoplasias Retais/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Idoso , Quimioembolização Terapêutica/métodos , Prognóstico , Resultado do Tratamento , Adulto , Quimiorradioterapia/métodosRESUMO
Cross-dehydrogenative couplings (CDC) present an efficient strategy for the assembly of biorelevant heterocycles, but are thus far largely limited to toxic transition metals and rather harsh reaction conditions. In sharp contrast, we, herein report on a mild photoelectrocatalyzed CDC-[4+2] annulation enabling the synthesis of functionalized isothiochromenes enabled by a proton-coupled electron transfer (PCET) strategy. The transformative photoelectrocatalysis obviated toxic transition-metal, high reaction temperatures, and stoichiometric chemical redox reagents. This approach was characterized by exceedingly mild conditions, ample substrate scope, and a commercially available catalyst. Gram-scale reactions and a telescoped synthesis route reflected the unique potential in the green synthesis of important S-heterocycles.
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BACKGROUND: Pure uterine serous carcinoma (p-USC) and mixed tumors with serous component (m-USC) are aggressive subtypes of endometrial cancer associated with high mortality rates. This retrospective study aimed to compare clinicopathologic features and outcomes of p-USC and m-USC in a single center. METHODS: This study retrospectively reviewed patients diagnosed with USC at Peking University People's Hospital between 2008 and 2022. T-tests and chi-square tests were used to compare clinicopathological characteristics between p-USC and m-USC. Kaplan-Meier survival curve and Cox regression analysis were used to analyze the impact of clinical and pathological variables on OS and PFS. RESULTS: Among the 91 patients who underwent surgery, 65.9% (n = 60) were p-USC, and 34.1% (n = 31) were m-USC. Patients with p-USC had earlier menopause (P = 0.0217), a lower rate of progesterone receptor(PR) expression (P < 0.001), and were more likely to have positive peritoneal cytology (P = 0.0464). After a median follow-up time of 40 months, 28 (46.7%) p-USC and 9 (29%) m-USC patients had progression disease, 18 (30%) and 8 (25.8%) patients died of their disease. 5-year PFSR were 51.2% and 75.3%, respectively, and 5-year OS rates were 66% and 67.4%. Kaplan-Meier survival analysis showed that p-USC was more likely to relapse than m-USC (P = 0.034), but there was no significant difference in OS. Cox regression analysis showed that lymph node metastasis and surgical approach were risk factors for OS, and myoinvasion depth ≥ 1/2 was an independent risk factor for PFS. CONCLUSIONS: p-USC was more likely to relapse than m-USC, but there was no significant difference in OS between the two subtypes.
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Cistadenocarcinoma Seroso , Neoplasias Uterinas , Feminino , Humanos , Estudos Retrospectivos , Recidiva Local de Neoplasia/patologia , Neoplasias Uterinas/patologia , Cistadenocarcinoma Seroso/patologia , Recidiva , Estadiamento de NeoplasiasRESUMO
BACKGROUND: Radiomics has been applied for assessing lymphovascular invasion (LVI) in patients with breast cancer. However, associations between features from peritumoral regions and the LVI status were not investigated. PURPOSE: To investigate the value of intra- and peritumoral radiomics for assessing LVI, and to develop a nomogram to assist in making treatment decisions. STUDY TYPE: Retrospective. POPULATION: Three hundred and sixteen patients were enrolled from two centers and divided into training (N = 165), internal validation (N = 83), and external validation (N = 68) cohorts. FIELD STRENGTH/SEQUENCE: 1.5 T and 3.0 T/dynamic contrast-enhanced (DCE) and diffusion-weighted imaging (DWI). ASSESSMENT: Radiomics features were extracted and selected based on intra- and peritumoral breast regions in two magnetic resonance imaging (MRI) sequences to create the multiparametric MRI combined radiomics signature (RS-DCE plus DWI). The clinical model was built with MRI-axillary lymph nodes (MRI ALN), MRI-reported peritumoral edema (MPE), and apparent diffusion coefficient (ADC). The nomogram was constructed with RS-DCE plus DWI, MRI ALN, MPE, and ADC. STATISTICAL TESTS: Intra- and interclass correlation coefficient analysis, Mann-Whitney U test, and least absolute shrinkage and selection operator regression were used for feature selection. Receiver operating characteristic and decision curve analyses were applied to compare performance of the RS-DCE plus DWI, clinical model, and nomogram. RESULTS: A total of 10 features were found to be associated with LVI, 3 from intra- and 7 from peritumoral areas. The nomogram showed good performance in the training (AUCs, nomogram vs. clinical model vs. RS-DCE plus DWI, 0.884 vs. 0.695 vs. 0.870), internal validation (AUCs, nomogram vs. clinical model vs. RS-DCE plus DWI, 0.813 vs. 0.695 vs. 0.794), and external validation (AUCs, nomogram vs. clinical model vs. RS-DCE plus DWI, 0.862 vs. 0.601 vs. 0.849) cohorts. DATA CONCLUSION: The constructed preoperative nomogram might effectively assess LVI. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/diagnóstico por imagem , Radiômica , Estudos Retrospectivos , Imagem de Difusão por Ressonância Magnética , Mama , Imageamento por Ressonância MagnéticaRESUMO
Gigaxonin is an adaptor protein for E3 ubiquitin ligase substrates. It is necessary for ubiquitination and degradation of intermediate filament (IF) proteins. Giant axonal neuropathy is a pathological condition caused by mutations in the GAN gene that encodes gigaxonin. This condition is characterized by abnormal accumulation of IFs in both neuronal and non-neuronal cells; however, it is unclear what causes IF aggregation. In this work, we studied the dynamics of IFs using their subunits tagged with a photoconvertible protein mEOS 3.2. We have demonstrated that the loss of gigaxonin dramatically inhibited transport of IFs along microtubules by the microtubule motor kinesin-1. This inhibition was specific for IFs, as other kinesin-1 cargoes, with the exception of mitochondria, were transported normally. Abnormal distribution of IFs in the cytoplasm can be rescued by direct binding of kinesin-1 to IFs, demonstrating that transport inhibition is the primary cause for the abnormal IF distribution. Another effect of gigaxonin loss was a more than 20-fold increase in the amount of soluble vimentin oligomers in the cytosol of gigaxonin knock-out cells. We speculate that these oligomers saturate a yet unidentified adapter that is required for kinesin-1 binding to IFs, which might inhibit IF transport along microtubules causing their abnormal accumulation.
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Proteínas do Citoesqueleto , Neuropatia Axonal Gigante , Humanos , Proteínas do Citoesqueleto/metabolismo , Filamentos Intermediários/metabolismo , Cinesinas/genética , Cinesinas/metabolismo , Proteínas de Filamentos Intermediários/metabolismo , Neuropatia Axonal Gigante/genética , Neuropatia Axonal Gigante/metabolismo , Neuropatia Axonal Gigante/patologia , Microtúbulos/metabolismoRESUMO
BACKGROUND: Parental care benefits offspring but comes with costs. To optimize the trade-off of costs and benefits, parents should adjust care based on intrinsic and/or extrinsic conditions. The harm to offspring hypothesis suggests that parents should invest more in younger offspring than older offspring because younger offspring are more vulnerable. However, this hypothesis has rarely been comprehensively tested, as many studies only reveal an inverse correlation between parental care and offspring age, without directly testing the effects of offspring age on their vulnerability. To test this hypothesis, we studied Kurixalus eiffingeri, an arboreal treefrog with paternal care. We first performed a field survey by monitoring paternal care during embryonic development. Subsequently, we conducted a field experiment to assess the prevalence of egg predators (a semi-slug, Parmarion martensi) and the plasticity of male care. Finally, we conducted a laboratory experiment to assess how embryo age affects predation by P. martensi. RESULTS: Our results showed that (1) male attendance and brooding frequency affected embryo survival, and (2) males attended and brooded eggs more frequently in the early stage than in the late stage. The experimental results showed that (3) males increased attendance frequency when the predators were present, and (4) the embryonic predation by the semi-slug during the early was significantly higher than in the late stage. CONCLUSIONS: Our findings highlight the importance of paternal care to embryo survival, and the care behavior is plastic. Moreover, our results provide evidence consistent with the predictions of the harm to offspring hypothesis, as males tend to care more for younger offspring which are more vulnerable.
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Hepatocellular carcinoma (HCC) is a primary liver cancer with a high mortality rate. The search for a new biomarker could help the prognosis of HCC patients. We identified the glycolytic gene set associated with HCC and the glycolytic lncRNA based on TCGA and MsigDB databases. According to these lncRNAs, K-means clustering, and regression analysis were performed on the patients. Two groups of HCC patients with different lncRNA expression levels were obtained based on K-means clustering results. The results of difference analysis and enrichment analysis showed that DEmRNA in the two HCC populations with significant survival differences was mainly enriched in transmembrane transporter complex, RNA polymerase II specificity, cAMP signaling pathway, and calcium signaling pathway. In addition, a prognostic model of HCC with 4 DElncRNAs was constructed based on regression analysis. ROC curve analysis showed that the model had good predictive performance. Drug predictionresults showed that the efficacy of JQ1, niraparib, and teniposide was higher in the low-risk group than in the high-risk group. In conclusion, this study preliminarily identified glycolytic-related prognostic features of lncRNAs in HCC and constructed a risk assessment model. The results of this study are expected to guide the prognosis assessment of clinical HCC patients.