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Patients with Philadelphia chromosome-like acute lymphoblastic leukaemia (Ph-like ALL) often face a grim prognosis, with PDGFRB gene fusions being commonly detected in this subgroup. Our study has unveiled a newfound fusion gene, TERF2::PDGFRB, and we have found that patients carrying this fusion gene exhibit sensitivity to dasatinib. Ba/F3 cells harbouring the TERF2::PDGFRB fusion display IL-3-independent cell proliferation through activation of the p-PDGFRB and p-STAT5 signalling pathways. These cells exhibit reduced apoptosis and demonstrate sensitivity to imatinib in vitro. When transfused into mice, Ba/F3 cells with the TERF2::PDGFRB fusion gene induce tumorigenesis and a shortened lifespan in cell-derived graft models, but this outcome can be improved with imatinib treatment. In summary, we have identified the novel TERF2::PDGFRB fusion gene, which exhibits oncogenic potential both in vitro and in vivo, making it a potential therapeutic target for tyrosine kinase inhibitors (TKIs).
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Proteínas de Fusión Oncogénica , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptor beta de Factor de Crecimiento Derivado de Plaquetas , Proteína 2 de Unión a Repeticiones Teloméricas , Animales , Humanos , Ratones , Carcinogénesis , Transformación Celular Neoplásica , Mesilato de Imatinib , Inhibidores de Proteínas Quinasas/farmacología , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Transducción de Señal , Factor de Transcripción STAT5/genética , Proteína 2 de Unión a Repeticiones Teloméricas/genética , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genéticaRESUMEN
Cardiac myosin-binding protein C (cMyBP-C) is a novel cardiac marker of acute myocardial infarction (AMI) and acute cardiac injuries (ACI). Construction of point-of-care testing techniques capable of sensing cMyBP-C with high sensitivity and precision is urgently needed. Herein, we synthesized an Au@NGQDs@Au/Ag multi-shell nanoUrchins (MSNUs), and then applied it in a colorimetric/SERS dual-mode immunoassay for detection of cMyBP-C. The MSNUs displayed superior stability, colorimetric brightness, and SERS enhancement ability with an enhanced factor of 5.4 × 109, which were beneficial to improve the detection capability of test strips. The developed MSNU-based test strips can achieve an ultrasensitive immunochromatographic assay of cMyBP-C in both colorimetric and SERS modes with the limits of detection as low as 19.3 and 0.77 pg/mL, respectively. Strikingly, this strip was successfully applied to analyze actual plasma samples with significantly better sensitivity, negative predictive value, and accuracy than commercially available gold test strips. Notably, this method possessed a wide range of application scenarios via combining with a color recognizer application named Color Grab on the smartphone, which can meet various needs of different users. Overall, our MSNU-based test strip as a mobile health monitoring tool shows excellent sensitivity, reproducibility, and rapid detection of the cMyBP-C, which holds great potential for the early clinic diagnosis of AMI and ACI.
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Proteínas Portadoras , Oro , Humanos , Inmunoensayo/métodos , Proteínas Portadoras/sangre , Oro/química , Límite de Detección , Colorimetría/métodos , Nanopartículas del Metal/química , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/sangre , Espectrometría Raman/métodosRESUMEN
Intrauterine adhesion (IUA) is manifestations of endometrial fibrosis and excessive extracellular matrix deposition. C1q/tumor necrosis factor-related protein-6 (CTRP6) is a newly identified adiponectin paralog which has been reported to modulate the fibrosis process of several diseases; however, the endometrial fibrosis function of CTRP6 remains unknown. Our study aimed to assess the role of CTRP6 in endometrial fibrosis and further explore the underlying mechanism. Here, we found that the expression of CTRP6 was downregulated in the endometrial tissues of IUA. In vitro experiments demonstrated the reduced level of CTRP6 in facilitated transforming growth factor-ß1 (TGF-ß1)-induced human endometrial stromal cells (HESCs). In addition, CTRP6 inhibited the expression of α-smooth muscle actin (α-SMA) and collagen I in TGF-ß1-treated HESCs. Mechanistically, CTRP6 activated the AMP-activated protein kinase (AMPK) and protein kinase B (AKT) pathway in HESCs, and AMPK inhibitor (AraA) or PI3K inhibitor (LY294002) pretreatment abolished the protective effect of CTRP6 on TGF-ß1-induced fibrosis. CTRP6 markedly decreased TGF-ß1-induced Smad3 phosphorylation and nuclear translocation, and AMPK or AKT inhibition reversed these effects. Notably, CTRP6-overexpressing treatment alleviated the fibrosis of endometrium in vivo. Therefore, CTRP6 ameliorates endometrial fibrosis, among which AMPK and AKT are essential for the anti-fibrotic effect of CTRP6 via the Smad3 pathway. Taken together, CTRP6 may be a potential therapeutic target for the treatment of intrauterine adhesion.
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Endometrio , Fibrosis , Transducción de Señal , Proteína smad3 , Animales , Femenino , Humanos , Ratones , Adipoquinas/metabolismo , Colágeno , Endometrio/metabolismo , Endometrio/efectos de los fármacos , Endometrio/patología , Transducción de Señal/efectos de los fármacos , Proteína smad3/metabolismo , Proteína smad3/genética , Adherencias Tisulares/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Factores de Necrosis Tumoral/metabolismo , Factores de Necrosis Tumoral/genética , Enfermedades Uterinas/metabolismo , Enfermedades Uterinas/patologíaRESUMEN
BACKGROUND: Radioresistance and immune escape are crucial reasons for unsatisfactory therapeutic effects of glioblastoma (GBM). Although triggering receptor expressed on myeloid cells-2 (TREM2) involved in forming immunosuppressive microenvironment, but the underlying mechanism and its roles in mediating cancer radioresistance remain unclear, moreover, the efficient delivery of drugs targeting TREM2 to GBM encounters serious challenges. Hence, this study aimed to elucidate the effect and mechanisms of targeted TREM2 silencing on reversing the radioresistance and immune escape of GBM aided by a glutathione-responsive biomimetic nanoparticle (NP) platform. METHODS: Radioresistant GBM cell lines and TREM2 stable knockdown GBM cell lines were firstly established. RNA sequencing, colony formation assay, western blot, enzyme-linked immunosorbent assay and co-immunoprecipitation assay were used to detect the molecular mechanisms of TREM2 in regulating the radioresistance and immune escape of GBM. The glutathione-responsive biomimetic NP, angiopep-2 (A2)- cell membrane (CM)-NP/siTREM2/spam1, was then constructed to triply and targeted inhibit TREM2 for in vivo study. Orthotopic GBM-bearing mouse models were established to evaluate the anti-GBM effect of TREM2 inhibition, multiplex immunofluorescence assay was conducted to detect the infiltration of immune cells. RESULTS: TREM2 was a regulator in accelerating the radioresistance and immune escape of GBM through participating in DNA damage repair and forming a positive feedback loop with high mobility group box 1 (HMGB1) to cascade the activation of Toll-like receptor 4 (TLR4)/protein kinase B (Akt) signaling. A2-CM-NP/siTREM2/spam1 was successfully synthesized with excellent passive targeting, active targeting and homologous targeting, and the in vivo results exhibited its remarkable anti-GBM therapeutic effect through promoting the infiltration of type 1 helper T cells and CD8+T cells, reducing the infiltration of type 2 helper T cells and regulatory T cells, repolarizing macrophages to M1-type, and decreasing the secretion of pro-tumor and immunosuppressive cytokines. CONCLUSIONS: Targeting TREM2 therapy is a promising avenue for optimizing radiotherapy and immunotherapy to improve the prognosis of GBM patients.
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Glioblastoma , Proteína HMGB1 , Glicoproteínas de Membrana , Proteínas Proto-Oncogénicas c-akt , Tolerancia a Radiación , Receptores Inmunológicos , Transducción de Señal , Receptor Toll-Like 4 , Glioblastoma/radioterapia , Glioblastoma/metabolismo , Glioblastoma/patología , Glioblastoma/inmunología , Glioblastoma/genética , Receptores Inmunológicos/metabolismo , Humanos , Animales , Línea Celular Tumoral , Glicoproteínas de Membrana/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor Toll-Like 4/metabolismo , Proteína HMGB1/metabolismo , Escape del Tumor , Ratones , Retroalimentación Fisiológica , Ratones Desnudos , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patologíaRESUMEN
ETV6::ABL1 is a rare fusion gene that found in MPN, ALL, and AML. It has a complex and diverse formation mechanism due to the reciprocal orientations of the ETV6 and ABL1 genes relative to the centromeres. NPM1 is frequently mutated in adult AML, often accompanied by FLT3-ITD, which suggests molecular synergisms in AML pathogenesis. Previous reports on ETV6::ABL1 mostly focus on FLT3-ITD. In this study, we present a case of AML with ETV6::ABL1, along with NPM1 and FLT3-ITD. The patient showed a rapid increase in primitive cells at the initial stage, along with the presence of immature granulocytes and erythrocytes. Through cytogenetic analysis, fluorescence in situ hybridization (FISH), and RNA-seq, we elucidated the mechanism behind the formation of the ETV6::ABL1 fusion gene. Despite conventional chemotherapy failure and rapid tumor proliferation, we attempted to add FLT3 inhibitor sorafenib to the treatment, along with chemotherapy bridging to haploidentical transplantation. After haplo-HSCT, a combination of sorafenib and dasatinib was administered as maintenance therapy. The patient achieved complete remission (CR) and maintained it for 11 months. The intricate genetic landscape observed in this case presents diagnostic dilemmas and therapeutic challenges, emphasizing the importance of a comprehensive understanding of its implications for disease classification, risk stratification, and treatment selection.
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BACKGROUND: Sesterterpenoids are rare species among the terpenoids family. Ophiobolins are sesterterpenes with a 5-8-5 tricyclic skeleton. The oxidized ophiobolins exhibit significant cytotoxic activity and potential medicinal value. There is an urgent need for large amounts of ophiobolins supplication for drug development. The synthetic biology approach has been successfully employed in lots of terpene compound production and inspired us to develop a cell factory for ophiobolin biosynthesis. RESULTS: We developed a systematic metabolic engineering strategy to construct an ophiobolin biosynthesis chassis based on Saccharomyces cerevisiae. The whole-cell biotransformation methods were further combined with metabolic engineering to enhance the expression of key ophiobolin biosynthetic genes and improve the supply of precursors and cofactors. A high yield of 5.1 g/L of ophiobolin F was reached using ethanol and fatty acids as substrates. To accumulate oxidized ophiobolins, we optimized the sources and expression conditions for P450-CPR and alleviated the toxicity of bioactive compounds to cells through PDR engineering. We unexpectedly obtained a novel ophiobolin intermediate with potent cytotoxicity, 5-hydroxy-21-formyl-ophiobolin F, and the known bioactive compound ophiobolin U. Finally, we achieved the ophiobolin U titer of 128.9 mg/L. CONCLUSIONS: We established efficient cell factories based on S. cerevisiae, enabling de novo biosynthesis of the ophiobolin skeleton ophiobolin F and oxidized ophiobolins derivatives. This work has filled the gap in the heterologous biosynthesis of sesterterpenoids in S. cerevisiae and provided valuable solutions for new drug development based on sesterterpenoids.
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Ingeniería Metabólica , Saccharomyces cerevisiae , Sesterterpenos , Sesterterpenos/metabolismo , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genéticaRESUMEN
ABSTRACT: Studies have examined the therapeutic effect of levosimendan on cardiovascular diseases such as heart failure, perioperative cardiac surgery, and septic shock, but the specific mechanism in mice remains largely unknown. This study aimed to investigate the relaxation mechanism of levosimendan in the thoracic aorta smooth muscle of mice. Levosimendan-induced relaxation of isolated thoracic aortic rings that were precontracted with norepinephrine or KCl was recorded in an endothelium-independent manner. Vasodilatation by levosimendan was not associated with the production of the endothelial relaxation factors nitric oxide and prostaglandins. The voltage-dependent K + channel (K V ) blocker (4-aminopyridine) and selective K Ca blocker (tetraethylammonium) had no effect on thoracic aortas treated with levosimendan, indicating that K V and K Ca channels may not be involved in the levosimendan-induced relaxation mechanism. Although the inwardly rectifying K + channel (K ir ) blocker (barium chloride) and the K ATP channel blocker (glibenclamide) significantly inhibited levosimendan-induced vasodilation in the isolated thoracic aorta, barium chloride had a much stronger inhibitory effect on levosimendan-induced vasodilation than glibenclamide, suggesting that levosimendan-induced vasodilation may be mediated by K ir channels. The vasodilation effect and expression of K ir 2.1 induced by levosimendan were further enhanced by the PKC inhibitor staurosporine. Extracellular calcium influx was inhibited by levosimendan without affecting intracellular Ca 2+ levels in the isolated thoracic aorta. These results suggest that K ir channels play a more important role than K ATP channels in regulating vascular tone in larger arteries and that the activity of the K ir channel is enhanced by the PKC pathway.
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Aorta Torácica , Músculo Liso Vascular , Proteína Quinasa C , Simendán , Vasodilatación , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/metabolismo , Simendán/farmacología , Masculino , Vasodilatación/efectos de los fármacos , Proteína Quinasa C/metabolismo , Proteína Quinasa C/antagonistas & inhibidores , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Ratones , Canales de Potasio de Rectificación Interna/metabolismo , Canales de Potasio de Rectificación Interna/antagonistas & inhibidores , Canales de Potasio de Rectificación Interna/efectos de los fármacos , Vasodilatadores/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Bloqueadores de los Canales de Potasio/farmacologíaRESUMEN
BACKGROUND: Multivisceral en bloc resection with the ipsilateral kidney is commonly performed in patients with retroperitoneal liposarcoma (RLPS). We evaluated the effect of nephrectomy on short- and long-term outcomes in patients with RLPS. METHODS: Data from a prospectively maintained database of the Peking University Cancer Hospital Sarcoma Center between April 2011 and August 2022 were analyzed. We classified the RLPS patients who underwent surgery into nephrectomy group (NP) and non-nephrectomy group (non-NP). Patients were matched using a 1:1 propensity score to eliminate baseline differences between groups. Postoperative renal function outcomes, major morbidity, and mortality were analyzed to compare short-term outcomes after nephrectomy. Differences in local recurrence-free survival (LRFS) and overall survival (OS) were compared by Kaplan-Meier analysis with respect to oncological benefits. RESULTS: In the matched cohort, patients in the NP group had significantly higher postoperative eGFR and CKD stages, but none required dialysis. Patients between NP and non-NP had a comparable major morbidity (p = 0.820) and 60-day mortality (p = 0.475). Patients in the NP group had a higher 5-year LRFS rates than those in the non-NP group (34.5 vs. 17.8%, p = 0.015), and similar 5-year OS rates (52.4 vs. 47.1%, p = 0.401). Nephrectomy was an independent risk factor for LRFS, but not for major morbidity or OS. CONCLUSIONS: RLPS resection with nephrectomy is related to a mild progression of renal impairment; however, dialysis is rare. En bloc nephrectomy for complete resection of RLPS is safe and improves local control.
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Liposarcoma , Nefrectomía , Puntaje de Propensión , Neoplasias Retroperitoneales , Humanos , Masculino , Femenino , Nefrectomía/métodos , Liposarcoma/cirugía , Liposarcoma/patología , Liposarcoma/mortalidad , Persona de Mediana Edad , Neoplasias Retroperitoneales/cirugía , Neoplasias Retroperitoneales/patología , Neoplasias Retroperitoneales/mortalidad , Anciano , Adulto , Estudios Retrospectivos , Hospitales de Alto Volumen , Estimación de Kaplan-Meier , Resultado del TratamientoRESUMEN
Small-cell neuroendocrine carcinoma of the cervix (SCNCC) is a rare and aggressive tumor with a poor prognosis. Surgical resection followed by adjuvant therapy is the standard treatment for early-stage disease but the influence of different neo/adjuvant treatment approaches remains unclear. Retrospectively, we collected patients' characteristics and treatments in two medical centers. Disease status and survival outcomes were renewed through follow-up. Statistics analysis mainly included Kaplan-Meier methods for survival curve estimation, log-rank test for survival curve comparison, and Cox proportional hazards models for independent prognostic factors prediction. Finally, 51 patients treated by radical surgery between January 2010 and April 2020 were enrolled with a median age of 50 years (range: 32-68). 12 (23.5%) patients were at stage IIIC1 according to the International Federation of Gynecology and Obstetrics (FIGO) 2018 staging systems and the rest were at the early stage. The mean tumor size was 3.6±1.3 cm. Pathological examination found 24 cases with pure SCNCC and 27 cases with admixed SCCC. 29 (56.9%) patients had deep stromal infiltration and 19 (37.3%) patients had lymphovascular space invasion. 34 (66.7%) patients received neo/adjuvant chemotherapy and pelvic radiation was conducted in 41 (80.39%) patients with a median dose of 46 Gy (range: 40-50.4 Gy). The median follow-up time was 25.0 months. The median disease-free survival (DFS) time was 23.0 months. 27 (52.9%) patients developed distant metastasis and 14 (27.5%) experienced local failure. The median overall survival (OS) was 32.0 months. Univariate and multivariate analysis showed neoadjuvant chemotherapy as negative (HR=2.081, 95% CI 1.030-4.203, p=0.041) and adjuvant chemotherapy (HR=0.409, 95% CI 0.213-0.784, p=0.020) as positive independent prognostic factor for DFS. For OS, only lymph node metastasis was confirmed as an independent prognostic factor in both univariate analysis (HR=1.528, 95% CI 1.011-2.308, p=0.044) and multivariate analysis (HR=1.697, 95% CI 1.041-2.768, p=0.034). In conclusion, for surgically treated SCNCC, adjuvant chemotherapy showed a positive influence on DFS while neoadjuvant chemotherapy harmed DFS. OS was unaffected by either treatment choice.
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Carcinoma Neuroendocrino , Carcinoma de Células Pequeñas , Neoplasias del Cuello Uterino , Femenino , Humanos , Adulto , Persona de Mediana Edad , Anciano , Resultado del Tratamiento , Cuello del Útero/patología , Estudios Retrospectivos , Estadificación de Neoplasias , Pronóstico , Carcinoma de Células Pequeñas/cirugía , Carcinoma de Células Pequeñas/tratamiento farmacológico , Neoplasias del Cuello Uterino/cirugía , Neoplasias del Cuello Uterino/tratamiento farmacológico , Quimioterapia Adyuvante , Carcinoma Neuroendocrino/cirugía , Carcinoma Neuroendocrino/tratamiento farmacológicoRESUMEN
BACKGROUND: As a chronic metabolic disease, diabetes poses a serious threat to human health and has become a major public health problem in China and worldwide. In 2020, 30% of Chinese people (aged ≥ 60 years) reported having diabetes mellitus. Moreover, individuals with diabetes living in rural areas face a significantly higher mortality risk compared to those in urban areas. In this study, we explored the inner experience of self-management behaviors in elderly patients with type 2 diabetes in rural areas to inform targeted interventions. METHODS: A phenomenological research design was used to explore the inner experience of self-management in rural elderly diabetes. Ten elderly diabetic patients were sampled from December 2022 to March 2023 in rural areas of Yangcheng County, Jincheng City, ShanXi Province, China. The seven-step Colaizzi phenomenological was used to analyze the interview data and generate themes. RESULTS: Four themes emerged: "Insufficient self-management cognition", "Negative self-management attitude", "Slack self-management behavior", and "No time for self-management". CONCLUSION: The level of self-management among elderly patients with type 2 diabetes in rural areas is low. Healthcare professionals should develop targeted interventions aimed at enhancing their cognitive levels, modifying their coping styles, and improving their self-management abilities to improve their quality of life.
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Diabetes Mellitus Tipo 2 , Investigación Cualitativa , Población Rural , Automanejo , Humanos , Diabetes Mellitus Tipo 2/terapia , Diabetes Mellitus Tipo 2/psicología , Anciano , Masculino , Femenino , Automanejo/psicología , Población Rural/estadística & datos numéricos , China/epidemiología , Persona de Mediana Edad , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Hospice care professionals often experience trauma patient deaths and multiple patient deaths in a short period of time (more so than other nurses). This repeated exposure to the death process and the death of patients leads to greater psychological pressure on hospice care professionals. But at present, people pay more attention to the feelings and care burden of the family members of dying patients but pay less attention to medical staff. Thus, this study aimed to develop a scale on the burden of care for hospice care providers and assess the coping capacity of hospice professionals. Raising awareness of the psychological burden of hospice professionals. METHODS: Through a literature review, research group discussion, Delphi method and a pre-survey of professional coping skills among nurses, 200 hospice professionals who had received training in hospice care from pilot institutions engaged in or providing hospice care were selected for investigation. Cronbach's α coefficient and split-half reliability were used to test the internal consistency of the scale, and content validity and explore factor analysis (EFA) were used to test the construct validity of the scale. RESULTS: Two rounds of Delphi methods were carried out, and the effective recovery rate was 100%. The expert authority coefficients of the two rounds were 0.838 and 0.833, respectively. The Kendall's W coefficient of experts in the first round was 0.121 ~ 0.200 (P < 0.05), and the Kendall's W coefficient of the second round was 0.115-0.136 (P < 0.05), indicating a good level of expert coordination. The final survey scale for the care burden of hospice professionals included four dimensions-working environment (9 items), professional roles (8 items), clinical nursing (9 items) and psychological burden (7 items)-with a total of 33 items. The total Cronbach's α coefficient of the scale was 0.963, and the Cronbach's α coefficients of the working environment, professional roles, clinical nursing and psychological burden dimensions were 0.920, 0.889, 0.936 and 0.910, respectively. The total split-half reliability of the scale was 0.927, and the split-half reliability of each dimension was 0.846, 0.817, 0.891, and 0.832. The content validity of the scale items ranged from 0.90 to 1.00. Exploratory factor analysis revealed 5 common factors, with a total cumulative contribution rate of 68.878%. The common degree of each item in the scale was > 0.4, and the factor loading of each item was also > 0.4. CONCLUSION: The scale is an open-access, short, easy-to-administer scale. And which for assessing hospice care burden among hospice professionals developed in this study demonstrated strong reliability and validity. This tool can serve as a dependable instrument for evaluating the burden of hospice care for terminally ill patients by professionals in the hospice setting.
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Cuidados Paliativos al Final de la Vida , Hospitales para Enfermos Terminales , Humanos , Adaptación Psicológica , China , Psicometría , Reproducibilidad de los Resultados , Encuestas y CuestionariosRESUMEN
Boscalid, a widely used SDHI fungicide, has been employed in plant disease control for over two decades. However, there is currently no available information regarding its antifungal activity against Sclerotium rolfsii and the potential risk of resistance development in this pathogen. In this study, we evaluated the sensitivity of 100 S. rolfsii strains collected from five different regions in China during 2018-2019 to boscalid using mycelial growth inhibition method and assessed the risk of resistance development. The EC50 values for boscalid ranged from 0.2994 µg/mL to 1.0766 µg/mL against the tested strains, with an average EC50 value of 0.7052 ± 0.1473 µg/mL. Notably, a single peak sensitivity baseline was curved, indicating the absence of any detected resistant strains. Furtherly, 10 randomly selected strains of S. rolfsii were subjected to chemical taming to evaluate its resistance risk to boscalid, resulting in the successful generation of six stable and inheritable resistant mutants. These mutants exhibited significantly reduced mycelial growth, sclerotia production, and virulence compared to their respective parental strains. Cross-resistance tests revealed a correlation between boscalid and flutolanil, benzovindiflupyr, pydiflumetofen, fluindapyr, and thifluzamide; however, no cross-resistance was observed between boscalid and azoxystrobin. Thus, we conclude that the development risk of resistance in S. rolfsii to boscalid is low. Boscalid can be used as an alternative fungicide for controlling peanut sclerotium blight when combined with other fungicides that have different mechanisms of action. Finally, the target genes SDHB, SDHC, and SDHD in S. rolfsii were initially identified, cloned and sequenced to elucidate the mechanism of S. rolfsii resistance to boscalid. Two mutation genotypes were found in the mutants: SDHD-D111H and SDHD-H121Y. The mutants carrying SDHD-H121Y exhibited moderate resistance, while the mutants with SDHD-D111H showed low resistance. These findings contribute to our comprehensive understanding of molecular mechanisms underlying plant pathogens resistance to SDHI fungicides.
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Basidiomycota , Compuestos de Bifenilo , Fungicidas Industriales , Niacinamida/análogos & derivados , Fungicidas Industriales/farmacología , Succinato Deshidrogenasa , Medición de Riesgo , Enfermedades de las Plantas/microbiologíaRESUMEN
OBJECTIVE: To assess the correlation between lesion location and swallowing function characteristics in post-stroke dysphagia (PSD) patients. MATERIALS AND METHODS: We enrolled 133 PSD. The patients were divided into supratentorial and infratentorial stroke groups. We compared the measurements in the videofluoroscopic swallowing study (VFSS) with 3ml and 5 ml of diluted and thickened barium liquid data between supratentorial and brainstem stroke groups. We further compared the difference of VFSS measurements between patients with left hemispheric or right hemispheric lesions (further divided into unilateral hemispheric cortical and subcortical subgroups) and brianstem leison stroke group.To explore the lesion location's effect on different bolus volume, the VFSS measurements of 3ml and 5ml in each subgroups were compared respectively. The measurements of VFSS included the oral transit time, soft palate elevation duration, hyoid bone movement duration (HMD), UES opening duration, pharyngeal transit duration (PTD), stage of ansition duration, and laryngeal closure duration (LCD), the upper esophageal sphincter opening (UESO), hyoid bone superior horizontal displacement, and hyoid bone anterior horizontal displacement. General swallowing function was assessed using the Penetration Aspiration Scale (PAS) and Functional Oral Intake Scale (FOIS). We performed the paired t-test, Spearman's correlation, and Kruskal-Wallis test analysis to characterize the parameters among the groups. RESULTS: Fifty-eight patients were assessed in the final analysis. The HMD (p = 0.019), PTD (p = 0.048) and LCD (p = 0.013) were significantly different between the supratentorial and brainstem lesion groups in 5ml volume. The HMD was significantly different (p = 0.045) between the left cortical and brainstem lesion groups. Significant differences in the HMD (p = 0.037) and LCD (p = 0.032) between the left subcortical and brainstem lesion groups were found in 5ml volume bolus. There was no group different when taking the 3ml volume bolus. Regarding the relationship between food bolus volume and swallowing functions, only the UESO demonstrated a significant difference in the subcortical lesion of the right hemisphere (p = 0.0032) compared the 3 ml and 5 ml volume bolus. The PTD demonstrated a moderate correlation with the PAS scores (r = 0.38, p = 0.0044). The HMD (r = 0.32, p = 0.018) and LCD (r = 0.29, p = 0.039) demonstrated weak correlations with the PAS scores. We did not identify any correlation between the VFSS parameters and FOIS scores in each subgroup level. CONCLUSION: The PSD with brainstem lesion shows more sever dysfunction in the pharyngeal phases. The left hemisphere was engaged in both the oral and pharyngeal phases. Lesions in the bilateral cortical, subcortical, and brainstem regions may impair sensory input.
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Trastornos de Deglución , Deglución , Accidente Cerebrovascular , Grabación en Video , Humanos , Trastornos de Deglución/fisiopatología , Trastornos de Deglución/etiología , Trastornos de Deglución/diagnóstico , Trastornos de Deglución/diagnóstico por imagen , Masculino , Femenino , Anciano , Persona de Mediana Edad , Accidente Cerebrovascular/fisiopatología , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/diagnóstico , Fluoroscopía , Valor Predictivo de las Pruebas , Anciano de 80 o más Años , Factores de Tiempo , Factores de Riesgo , Estudios RetrospectivosRESUMEN
Osteoarthritis (OA) is a prevalent degenerative joint disorder caused by the progressive destruction of cartilage and inflammation in the articular cavity. Studies have proved that the inhibition of articular cartilage destruction and generation of inflammatory factors can be effective strategies for treating OA. Notopterol (NOT) is a quality control index of Notopterygium incisum Ting ex H. T. Chang (N. incisum) with anti-inflammatory, antioxidant, and analgesic activities. Moreover, NOT has been used for many years to treat joint diseases. A study using human C28/I2 cells suggested that NOT down-regulated the hypersecretion of inflammatory mediators and alleviated the degradation of the extracellular matrix (ECM). In addition, NOT decreased the overproduction of reactive oxygen species (ROS) and chondrocyte apoptosis through the nuclear factor erythroid-2-related factor 2 (Nrf2) signaling pathway. NOT exerted a chondroprotective effect by partly inhibiting the Janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3) and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathways and regulating the nuclear factor Nrf2/heme oxygenase-1(HO-1) signaling pathway. In vivo, NOT improved the destruction of articular cartilage in a rat OA model, which may be related to the inhibition of tumor necrosis factor α (TNF-α), interleukin (IL)-1ß, IL-6, and IL-12 expressions in synovial fluid. In summary, these results showed that NOT alleviated the progression of OA and is expected to become a new therapy for treating OA clinically.
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Cartílago Articular , Osteoartritis , Humanos , Ratas , Animales , Fosfatidilinositol 3-Quinasas/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Osteoartritis/metabolismo , Inflamación/metabolismo , Condrocitos/metabolismo , Cartílago Articular/metabolismo , Interleucina-1beta/metabolismoRESUMEN
Mixed phenotype acute leukemia (MPAL) is a subtype of leukemia in which lymphoid and myeloid markers are co-expressed. Knowledge regarding the genetic features of MPAL is lacking due to its rarity and heterogeneity. Here, we applied an integrated genomic and transcriptomic approach to explore the molecular characteristics of 176 adult patients with MPAL, including 86 patients with T-lymphoid/myeloid MPAL (T/My MPAL-NOS), 42 with Ph+ MPAL, 36 with B-lymphoid/myeloid MPAL (B/My MPAL-NOS), 4 with t(v;11q23), and 8 with MPAL, NOS, rare types. Genetically, T/My MPAL-NOS was similar to B/T MPAL-NOS but differed from Ph+ MPAL and B/My MPAL-NOS. T/My MPAL-NOS exhibited higher CEBPA, DNMT3A, and NOTCH1 mutations. Ph+ MPAL demonstrated higher RUNX1 mutations. B/T MPAL-NOS showed higher NOTCH1 mutations. By integrating next-generation sequencing and RNA sequencing data of 89 MPAL patients, we defined eight molecular subgroups (G1-G8) with distinct mutational and gene expression characteristics. G1 was associated with CEBPA mutations, G2 and G3 with NOTCH1 mutations, G4 with BCL11B rearrangement and FLT3 mutations, G5 and G8 with BCR::ABL1 fusion, G6 with KMT2A rearrangement/KMT2A rearrangement-like features, and G7 with ZNF384 rearrangement/ZNF384 rearrangement-like characteristics. Subsequently, we analyzed single-cell RNA sequencing data from five patients. Groups G1, G2, G3, and G4 exhibited overexpression of hematopoietic stem cell disease-like and common myeloid progenitor disease-like signatures, G5 and G6 had high expression of granulocyte-monocyte progenitor disease-like and monocyte disease-like signatures, and G7 and G8 had common lymphoid progenitor disease-like signatures. Collectively, our findings indicate that integrative genomic and transcriptomic profiling may facilitate more precise diagnosis and develop better treatment options for MPAL.
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Leucemia Mieloide Aguda , Transcriptoma , Humanos , Enfermedad Aguda , Fenotipo , GenómicaRESUMEN
A simple and efficient electrochemical sulfonylation of organoboronic acids with sodium arylsulfinate salts has been reported for the first time. A variety of aryl, heteroaryl, and alkenylsulfones were obtained in good to excellent yields via a simple electrochemical sulfonylation of various arylboronic acids, heterocyclic boronic acids, or alkenylboronic acids with sodium arylsulfinate at room temperature in 5 h under the catalyst-free and additive-free conditions. A plausible mechanism has been proposed based on various radical-trapping and CV control experiments.
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BACKGROUND: Manual measurement of endobronchial optical coherence tomography (EB-OCT) images means a heavy workload in the clinical practice, which can also introduce bias if the subjective opinions of doctors are involved. OBJECTIVE: We aim to develop a convolutional neural network (CNN)-based EB-OCT image analysis algorithm to automatically identify and measure EB-OCT parameters of airway morphology. METHODS: The ResUNet, MultiResUNet, and Siamese network were used for analyzing airway inner area (Ai), airway wall area (Aw), airway wall area percentage (Aw%), and airway bifurcate segmentation obtained from EB-OCT imaging, respectively. The accuracy of the automatic segmentations was verified by comparing with manual measurements. RESULTS: Thirty-three patients who were diagnosed with asthma (n = 13), chronic obstructive pulmonary disease (COPD, n = 13), and normal airway (n = 7) were enrolled. EB-OCT was performed in RB9 segment (lateral basal segment of the right lower lobe), and a total of 17,820 OCT images were collected for CNN training, validation, and testing. After training, the Ai, Aw, and airway bifurcate were readily identified in both normal airway and airways of asthma and COPD. The ResUNet and the MultiResUNet resulted in a mean dice similarity coefficient of 0.97 and 0.95 for Ai and Aw segmentation. The accuracy Siamese network in identifying airway bifurcate was 96.6%. Bland-Altman analysis indicated there was a negligible bias between manual and CNN measurements for Ai (bias = -0.02 to 0.01, 95% CI = -0.12 to 0.14) and Aw% (bias = -0.06 to 0.12, 95% CI = -1.98 to 2.14). CONCLUSION: EB-OCT imaging in conjunction with ResUNet, MultiResUNet, and Siamese network could automatically measure normal and diseased airway structure with an accurate performance.
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Asma , Aprendizaje Profundo , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Tomografía de Coherencia Óptica , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico por imagen , Pulmón , Asma/diagnóstico por imagenRESUMEN
PURPOSE: This study investigated the mediating role of resilience in the association between moderate-to-vigorous physical activity (MVPA) and psychological ill-being, as well as the moderating role of age in the direct and indirect relationship between MVPA and psychological ill-being in children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Eighty-five children aged 6-12 years (Mage = 8.41 ± 1.44 years) diagnosed with ADHD were recruited. Participants wore an accelerometer on their non-dominant wrist for seven consecutive days to record MVPA. Resilience and psychological ill-being were assessed using self-reported questionnaires. RESULTS: MVPA was positively associated with resilience but negatively related to depression and stress. Resilience was negatively correlated with depression and stress. Using the bootstrapping method, the indirect effect of resilience was found between MVPA and depression (-0.006%, 95% confidence interval [CI] = [-0.060, -0.020]) in children with ADHD, supporting partial mediation. Moderated mediation analysis further demonstrated that the indirect effect of MVPA on depression via resilience was stronger in older children (-0.008, 95% CI = [-0.023, -0.001]) than in younger children with ADHD. CONCLUSION: The findings may inform future empirical studies on designing exercise interventions with MVPA levels that help to improve resilience and depression in children with ADHD.
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Trastorno por Déficit de Atención con Hiperactividad , Resiliencia Psicológica , Humanos , Niño , Bienestar Psicológico , Encuestas y Cuestionarios , AutoinformeRESUMEN
PURPOSE OF REVIEW: This review aims to comprehensively explore the clinical characteristics of COVID-19-related cardiac injury and examine the potential mechanisms underlying cardiac injury in patients affected by COVID-19. RECENT FINDINGS: The COVID-19 pandemic has primarily been associated with severe respiratory symptoms. However, emerging evidence has indicated that a significant number of COVID-19 patients also experience myocardial injury, leading to conditions such as acute myocarditis, heart failure, acute coronary syndrome, and arrhythmias. The incidence of myocardial injury is notably higher in patients with preexisting cardiovascular diseases. Myocardial injury often manifests with elevated levels of inflammation biomarkers, as well as abnormalities observed on electrocardiograms and echocardiograms. COVID-19 infection has been found to be associated with myocardial injury, which can be attributed to several pathophysiological mechanisms. These mechanisms include injury caused by hypoxia, resulting from respiratory compromise, a systemic inflammatory response triggered by the infection, and direct attack on the myocardium by the virus itself. Furthermore, the angiotensin-converting enzyme 2 (ACE2) receptor plays a crucial role in this process. Early recognition, prompt diagnosis, and a comprehensive understanding of the underlying mechanisms are essential for effectively managing and reducing the mortality associated with myocardial injury in COVID-19 patients.
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COVID-19 , Lesiones Cardíacas , Miocarditis , Humanos , COVID-19/complicaciones , SARS-CoV-2 , Pandemias , Miocarditis/diagnóstico , Miocarditis/terapia , Biomarcadores , Miocardio , Prueba de COVID-19RESUMEN
Alterations in resting-state functional connectivity (rsFC) of hippocampus and orbitofrontal cortex (OFC) have been highly implicated in major depressive disorder (MDD) and the researches have penetrated to the subregional level. However, relatively little is known about the intrinsic connectivity patterns of these two regions in adolescent MDD (aMDD), especially that of their functional subregions. Therefore, in the current study, we recruited 68 first-episode drug-naive aMDD patients and 43 matched typically developing controls (TDC) to characterize the alterations of whole-brain rsFC patterns in hippocampus and OFC at both regional and subregional levels in aMDD. The definition of specific functional subregions in hippocampus and OFC were based on the prior functional clustering-analysis results. Furthermore, the relationship between rsFC alterations and clinical features was also explored. Compared to TDC group, aMDD patients showed decreased connectivity of the left whole hippocampus with bilateral OFC and right inferior temporal gyrus at the regional level and increased connectivity between one of the right hippocampal subregions and right posterior insula at the subregional level. Reduced connectivity of OFC was only found in the subregion of left OFC with left anterior insula extending to lenticula in aMDD patients relative to TDC group. Our study identifies that the aberrant hippocampal and orbitofrontal rsFC was predominantly located in the insular cortex and could be summarized as an altered hippo-orbitofrontal-insular circuit in aMDD, which may be the unique features of brain network dysfunction in depression at this particular age stage. Moreover, we observed the distinct rsFC alterations in adolescent depression at the subregional level, especially the medial and lateral OFC.