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BACKGROUND: Infectious diseases are still one of the greatest threats to human health, and the etiology of 20% of cases of clinical fever is unknown; therefore, rapid identification of pathogens is highly important. Traditional culture methods are only able to detect a limited number of pathogens and are time-consuming; serologic detection has window periods, false-positive and false-negative problems; and nucleic acid molecular detection methods can detect several known pathogens only once. Three-generation nanopore sequencing technology provides new options for identifying pathogens. CASE SUMMARY: Case 1: The patient was admitted to the hospital with abdominal pain for three days and cessation of defecation for five days, accompanied by cough and sputum. Nanopore sequencing of the drainage fluid revealed the presence of oral-like bacteria, leading to a clinical diagnosis of bronchopleural fistula. Cefoperazone sodium sulbactam treatment was effective. Case 2: The patient was admitted to the hospital with fever and headache, and CT revealed lung inflammation. Antibiotic treatment for Streptococcus pneumoniae, identified through nanopore sequencing of cerebrospinal fluid, was effective. Case 3: The patient was admitted to our hospital with intermittent fever and an enlarged neck mass that had persisted for more than six months. Despite antibacterial treatment, her symptoms worsened. The nanopore sequencing results indicate that voriconazole treatment is effective for Aspergillus brookii. The patient was diagnosed with mixed cell type classical Hodgkin's lymphoma with infection. CONCLUSION: Three-generation nanopore sequencing technology allows for rapid and accurate detection of pathogens in human infectious diseases.
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PURPOSE: To investigate whether prognosis of patients with hepatocellular carcinoma (HCC) is affected by the abundance and subgroups of myeloid-derived suppressor cells (MDSCs) as well as subtypes and expression of apolipoprotein E (apoE). METHODS: 31 HCC patients were divided into three groups according to blood total apoE level for detecting the abundance of immunoregulatory cells by flow cytometry. Tumour tissue microarrays from 360 HCC patients were evaluated about the abundance and subgroups of MDSCs and the expression of apoE2, apoE3, apoE4 by immunofluorescence staining and immunohistochemistry staining. Survival analysis by means of univariate, multivariate COX regression and Kaplan-Meier methods of the 360 patients was performed based on clinical and pathological examinations along with 10 years' follow-up data. RESULTS: The lower apoE group presented higher abundance of MDSCs in the peripheral blood of HCC patients than higher apoE group. The abundance of monocyte-like MDSCs (M-MDSCs) was higher in the apoE low level group than high level group (p = 0.0399). Lower H-score of apoE2 (HR = 6.140, p = 0.00005) and higher H-score of apoE4 (HR = 7.001, p = 0.009) in tumour tissue were significantly associated with shorter overall survival (OS). The higher infiltration of polymorphonuclear granulocyte-like MDSCs (PMN-MDSCs, HR = 3.762, p = 0.000009) and smaller proportion of M-MDSCs of total cells (HR = 0.454, p = 0.006) in tumour tissue were independent risk factors for shorter recurrence-free survival (RFS). CONCLUSION: The abundance of MDSCs in HCC patients' plasma negatively correlates with the level of apoE. The expression of apoE4 in HCC tissue indicated a poor prognosis while apoE2 might be a potential protective factor.
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Apolipoproteínas E , Carcinoma Hepatocelular , Neoplasias Hepáticas , Células Supressoras Mieloides , Humanos , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/metabolismo , Masculino , Prognóstico , Feminino , Pessoa de Meia-Idade , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Apolipoproteínas E/genética , Idoso , AdultoRESUMO
BACKGROUND & AIMS: Patients with intrahepatic cholangiocarcinoma (iCCA) respond poorly to immune checkpoint blockades (ICBs). In this study, we aimed to dissect the potential mechanisms underlying poor response to ICBs and explore a rational ICB-based combination therapy in iCCA. METHODS: scRNA-seq dataset GSE151530 was analyzed to investigate the differentially expressed genes in malignant cells following ICBs therapy. RNA-seq analysis and western blot assays were performed to examine the upstream and downstream signaling pathways of CD73. Subcutaneous tumor xenograft models were utilized to investigate the impact of CD73 on iCCA growth. Plasmid AKT/NICD-induced spontaneous murine iCCAs were used to explore the therapeutic efficacy of CD73 enzymatic inhibitor AB680 combined with PD-1 blockade. Time-of-flight mass cytometry (CyTOF) was conducted to identify the tumor-infiltrating immune cell populations and their functional changes in murine iCCAs treated with AB680 in combination with PD-1 antibody. RESULTS: scRNA-seq analysis identified elevated CD73 expression in malignant cells in response to ICBs therapy. Mechanistically, ICBs therapy upregulated CD73 expression in malignant cells via TNF-α/NF-κB signaling pathway. In vivo studies revealed that CD73 inhibition suppressed the growth of subcutaneous tumors, and achieved synergistic depression effects with gemcitabine and cisplatin (GC). Adenosine produced by CD73 activates AKT/GSK3ß/ß-catenin signaling axis in iCCA cells. CD73 inhibitor AB680 potentiates anti-tumor efficacy of PD-1 antibody in murine iCCAs. CyTOF analysis showed that AB680 combined with anti-PD-1 therapy promoted the infiltration of CD8+ T, CD4+ T cells, and NK cells in murine iCCAs, while simultaneously decreased the proportions of macrophages and neutrophils. Moreover, AB680 combined with anti-PD-1 significantly upregulated the expression of Granzyme B, Tbet and co-stimulatory molecule ICOS in infiltrating CD8+ T cells. CONCLUSIONS: CD73 inhibitor AB680 limits tumor progression and potentiates therapeutic efficacy of GC chemotherapy or anti-PD-1 treatment in iCCA. AB680 combined with anti-PD-1 therapy effectively elicits anti-tumor immune response.
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5'-Nucleotidase , Neoplasias dos Ductos Biliares , Colangiocarcinoma , Inibidores de Checkpoint Imunológico , Receptor de Morte Celular Programada 1 , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , Colangiocarcinoma/imunologia , Animais , 5'-Nucleotidase/antagonistas & inibidores , 5'-Nucleotidase/metabolismo , Camundongos , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/imunologia , Neoplasias dos Ductos Biliares/metabolismo , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Linhagem Celular Tumoral , Progressão da DoençaRESUMO
PURPOSE: Hepatocellular carcinoma (HCC) is a critical global health concern, with existing treatments benefiting only a minority of patients. Recent findings implicate the chemokine ligand 17 (CCL17) and its receptor CCR4 as pivotal players in the tumor microenvironment (TME) of various cancers. This investigation aims to delineate the roles of CCL17 and CCR4 in modulating the tumor's immune landscape, assessing their potential as therapeutic interventions and prognostic markers in HCC. METHODS: 873 HCC patients post-radical surgery from 2008 to 2012 at Zhongshan Hospital, Fudan University were retrospectively examined. These individuals were stratified into a training cohort (n = 354) and a validation cohort (n = 519). Through immunohistochemical analysis on HCC tissue arrays, the expressions of CCL17, CCR4, CD73, CD47, HHLA2, and PD-L1 were quantified. Survival metrics were analyzed using the Cox model, and a prognostic nomogram was devised via R software. RESULTS: The investigation confirmed the presence of CCL17 and CCR4 within the cancerous and stromal compartments of HCC tissues, associating their heightened expression with adverse clinical markers and survival outcomes. Notably, the interplay between CD73 and CCR4 expression in tumor stroma highlighted a novel cellular entity, CCR4 + CD73 + stromal cells, impacting overall and relapse-free survival. A prognostic nomogram amalgamating these immunological markers and clinical variables was established, offering refined prognostic insights and aiding in the management of HCC. The findings suggest that reduced CCR4 and CCR4 + CD73 + cell prevalence may forecast improved outcomes post-TACE. CONCLUSION: This comprehensive evaluation of CCR4, CCL17, and associated markers introduces a nuanced understanding of the HCC immunological milieu, proposing CCR4 + CD73 + stromal cells as critical to HCC pathogenesis and patient stratification.
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5'-Nucleotidase , Biomarcadores Tumorais , Carcinoma Hepatocelular , Quimiocina CCL17 , Proteínas Ligadas por GPI , Neoplasias Hepáticas , Receptores CCR4 , Microambiente Tumoral , Humanos , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/imunologia , Quimiocina CCL17/metabolismo , Feminino , Masculino , Prognóstico , Receptores CCR4/metabolismo , Pessoa de Meia-Idade , Biomarcadores Tumorais/metabolismo , 5'-Nucleotidase/metabolismo , Estudos Retrospectivos , Microambiente Tumoral/imunologia , Proteínas Ligadas por GPI/metabolismo , Idoso , AdultoRESUMO
Lymph node metastasis (LNM) facilitates distant tumor colonization and leads to the high mortality in patients with intrahepatic cholangiocarcinoma (ICC). However, it remains elusive how ICC cells subvert immune surveillance within the primary tumor immune microenvironment (TIME) and subsequently metastasize to lymph nodes (LNs). In this study, scRNA-seq and bulk RNA-seq analyses identified decreased infiltration of dendritic cells (DCs) into primary tumor sites of ICC with LNM, which was further validated via dual-color immunofluorescence staining of 219 surgically resected ICC samples. Tumor-infiltrating DCs correlated with increased CD8+ T cell infiltration and better prognoses in ICC patients. Mechanistically, ß-catenin-mediated CXCL12 suppression accounted for the impaired DC recruitment in ICC with LNM. Two mouse ICC cell lines MuCCA1 and mIC-23 cells were established from AKT/NICD or AKT/YAP-induced murine ICCs respectively and were utilized to construct the footpad tumor LNM model. We found that expansion and activation of conventional DCs (cDCs) by combined Flt3L and poly(I:C) (FL-pIC) therapy markedly suppressed the metastasis of mIC-23 cells to popliteal LNs. Moreover, ß-catenin inhibition restored the defective DC infiltration into primary tumor sites and reduced the incidence of LNM in ICC. Collectively, our findings identify tumor cell intrinsic ß-catenin activation as a key mechanism for subverting DC-mediated anti-tumor immunity in ICC with LNM. FL-pIC therapy or ß-catenin inhibitor could merit exploration as a potential regimen for mitigating ICC cell metastasis to LNs and achieving effective tumor immune control.
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OBJECTIVE: We aim to determine the effect of region of residence (urban vs. rural) on the odds of receiving standard of care treatment for locally advanced BCa in Louisiana and its impact on survival outcomes. METHODS: Using the Louisiana Tumor Registry, we identified American Joint Committee on Cancer (AJCC) stage II or III, BCa diagnoses in Louisiana residents between 2010 and 2020. Treatment received was classified as standard or non-standard of care according to American Urological Association (AUA) guidelines and location of residence was determined using Rural Urban Commuting Area-Tract-level 2010 (RUCA). Multivariable logistic regression analyses and multivariate cox proportional hazard analyses were performed. RESULTS: Of 983 eligible patients, 85.6% (841/983) lived in urban areas. Overall, only 37.5% received standard-of-care (SOC) for the definitive management of locally advanced bladder cancer. Individuals living in rural areas (OR 0.53, 95% CI: 0.31-0.91, p = 0.02) were less likely to receive standard of care treatment. Both rural residence and receipt of non-standard of care therapy were associated with an increased risk of bladder cancer-specific (adj HR 1.53, 95% CI: 1.09-2.14, p = 0.01 and adj HR: 1.85, 95% CI: 1.43-2.39, <0.0001) and overall mortality (adj HR: 1.28, 95% CI: 1.01-1.61, p = 0.04 and adj HR: 1.73 95% CI: 1.44-2.07, p < 0.0001). CONCLUSIONS: Most patients with locally advanced bladder cancer in Louisiana do not receive SOC therapy. Individuals living in rural locations are more likely to receive non-standard of care therapy than individuals in urban areas. Nonstandard of care treatment and rural residence are both associated with worse survival outcomes for Louisiana residents with locally advanced bladder cancer.
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População Rural , Padrão de Cuidado , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/terapia , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia , Louisiana/epidemiologia , Feminino , Masculino , Idoso , População Rural/estatística & dados numéricos , Pessoa de Meia-Idade , Sistema de Registros , Idoso de 80 Anos ou mais , Estadiamento de Neoplasias , População Urbana/estatística & dados numéricosRESUMO
Calcium-ion batteries (CIBs) are considered as potential next-generation energy storage systems due to their abundant reserves and relatively low cost. However, irreversible structural changes and weak conductivity still hinder in current CIBs cathode materials. Herein, an organic molecular intercalation strategy is proposed, in which V2O5 regulated with quinoline, pyridine, and water molecules are studied as cathode material to provide fast ion diffusion channels, large storage host, and high conductivity for Ca ions. Among them, V2O5-quinoline (QVO) owns the largest interplanar spacing of 1.25 nm and the V-O chains are connected with organic molecular by hydrogen bond, which stabilizes the crystal structure. As a result, QVO exhibits a specific capacity of 168 mAh g-1 at 1 A g-1 and capacity retention of 80% after 500 cycles at 5 A g-1 than the other materials. Furthermore, X-Ray diffraction and X-ray absorption spectroscopy results reveal a reversible order-disorder transformation mechanism of Ca2+ for QVO, which can make full use of the abundant active sites for high capacity and simultaneously achieve fast reaction kinetics for excellent rate performance. These results demonstrate that QVO is a promising cathode material for CIBs, providing more choices for the development of high-performance CIBs.
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BACKGROUND Simultaneous bilateral basal ganglia hemorrhage is an infrequent occurrence in medical literature. The etiology of bilateral basal ganglia intracerebral hemorrhage remains elusive, in contrast to that of unilateral basal ganglia hypertensive intracerebral hemorrhage, resulting in lack of consensus among scholars. Importantly, patients with uremia and cerebral hemorrhage, especially patients with large hematoma volumes, exhibit a markedly elevated mortality rate. Patients can benefit from implementation of positive and efficacious therapeutic approaches. CASE REPORT We present a clinical case involving a 42-year-old male patient who was admitted to the hospital in a comatose state. The initial head computed tomography scan revealed the presence of simultaneous basal ganglia hemorrhage; this phenomenon could potentially be attributed to the occurrence of cerebral hemorrhage induced by severe renal hypertension in individuals with uremia. The patient underwent emergency surgical intervention to evacuate the hematoma, followed by continuous blood purification treatment. Ultimately, these interventions have the potential to improve patient outcomes. CONCLUSIONS Incidence of bilateral basal ganglia hemorrhage is exceptionally rare and associated with an unfavorable prognosis, often resulting in mortality among individuals with severe underlying conditions or complications. The hematoma was successfully eliminated through the use of skull resection and neuroendoscopy techniques, resulting in favorable outcomes. The implementation of bedside continuous hemodialysis in patients with uremic cerebral hemorrhage can enhance therapeutic efficacy, thus warranting its recommendation for similar cases. Based on our observations, it is plausible that severe hypertension plays a contributory role in the development of simultaneous bilateral basal ganglia bleeding.
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Hemorragia dos Gânglios da Base , Humanos , Masculino , Adulto , Hemorragia dos Gânglios da Base/complicações , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVE: We aimed to assess the impact of integrated nursing and psychological intervention on pain intensity and patient satisfaction in individuals with urinary calculi. METHODS: This retrospective study included 94 urological patients from the Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, between January 2020 and June 2022. Participants were divided into a control group (n=48), receiving routine nursing and psychological intervention, and a study group (n=46), receiving integrated nursing and psychological intervention. We compared pain intensity, pain relief rate, patient satisfaction, Numeric Rating Scale (NRS) score, Pittsburgh Sleep Quality Index (PSQI) score, Self-rating Depression Scale (SDS) score, Self-rating Anxiety Scale (SAS) score, and quality of life scores between the groups. RESULTS: The study group had shorter hospital stays and lower hospitalization costs than the control group (both P < 0.05). Pain relief and satisfaction rates were higher in the study group (both P < 0.05). Post-intervention, both groups showed significant reductions in NRS, PSQI, SDS, and SAS scores, with greater reductions in the study group (all P < 0.05). Quality of life scores increased in both groups, more so in the SG (P < 0.05). The study group also had fewer adverse events (P < 0.05). Both groups showed decreased serum creatinine and blood urea nitrogen levels post-intervention, with a more significant decline in the study group (P < 0.05). Education, marital status, and occupation were major factors influencing outcomes in urinary calculi patients. CONCLUSION: Integrated nursing and psychological intervention significantly alleviates pain, improves emotional well-being, enhances sleep quality, increases overall life quality, and contributes to high patient satisfaction among urinary calculi patients.
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Photobiomodulation (PBM) is a well-established medical technology that employs diverse light sources like lasers or light-emitting diodes to generate diverse photochemical and photophysical reactions in cells, thereby producing beneficial clinical outcomes. In this study, we introduced an 830 nm near-infrared (NIR) laser irradiation system combined with a microscope objective to precisely and controllably investigate the impact of PBM on the migration and viability of human adipose mesenchymal stem cells (hADSCs). We observed a biphasic dose-response in hADSCs' viability and migration after PBM exposure (0-10 J/cm2), with the 5 J/cm2 group showing significantly higher cell viability and migration ability than other groups. Additionally, at the optimal dose of 5 J/cm2, we used nanoparticle tracking analysis (NTA) and found a 6.25-fold increase in the concentration of extracellular vesicles (EVs) derived from hADSCs (PBM/ADSC-EVs) compared to untreated cells (ADSC-EVs). Both PBM/ADSC-EVs and ADSC-EVs remained the same size, with an average diameter of 56 nm measured by the ExoView R200 system, which falls within the typical size range for exosomes. These findings demonstrate that PBM not only improves the viability and migration of hADSCs but also significantly increases the EV yield.
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Movimento Celular , Sobrevivência Celular , Vesículas Extracelulares , Células-Tronco Mesenquimais , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/efeitos da radiação , Sobrevivência Celular/efeitos da radiação , Movimento Celular/efeitos da radiação , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/efeitos da radiação , Tecido Adiposo/citologia , Tecido Adiposo/efeitos da radiação , Terapia com Luz de Baixa Intensidade , Relação Dose-Resposta à Radiação , Células Cultivadas , Raios InfravermelhosRESUMO
Understanding and further regulating the degradation of mandrel materials is a key aspect of target fabrication in inertial confinement fusion (ICF). Here, a quasi-one-dimensional confinement model is developed using a series of single-walled carbon nanotubes with varying diameters (Dm), and the degradation of poly-α-methylstyrene (PAMS) as a typical mandrel material is investigated under such confined conditions by using the combined method of quantum mechanics and molecular mechanics. In comparison to the isolated system, the calculations show that confinement can decrease or increase the energy barriers of PAMS degradation, which directly depends on Dm. Following which a clear exponential relationship between the degradation rate of PAMS and its own density is derived, indicating that the density of PAMS can be used to regulate mandrel degradation. This work highlights the important effects of confinement on degradation and provides a valuable reference for further development of polymer degradation technologies in ICF target fabrication and other fields.
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OBJECTIVE: To evaluate the occurrence of aortic dilatation and its associated predictors with coarctation of the aorta (CoA) in infants using multi-slice computed tomography (MSCT). METHODS: The clinical data of 47 infantile patients with CoA diagnosed by MSCT and 28 infantile patients with simple ventricular septal defect were analyzed retrospectively. Aortic diameters were measured at six different levels, and aortic sizes were compared by z score. The coarctation site-diaphragm ratio was used to describe the degree of narrowing. Relevant clinical data were collated and analyzed. RESULTS: The dilation rate and z score of the ascending aorta in the severe CoA group were significantly higher than those in the mild CoA group (11 [52.38%] vs. 21 [80.77%], P=0.038 and 2.00 ± 0.48 vs. 2.36 ± 0.43, P=0.010). Pearson's correlation analysis found that the z score of the ascending aorta was negatively correlated with the coarctation site-diaphragm ratio value (r=-0.410, P=0.004). A logistic retrospective analysis found that an increased degree of coarctation was an independent predictor of aortic dilatation (adjusted odds ratio 0.002; 95% confidence interval 0.00-0.819; P=0.043). The z score of the ascending aorta in the severe CoA group was significantly higher than that in the ventricular septal defect group (P<0.05). CONCLUSION: Most infants with CoA can also have significant dilatation of the ascending aorta, and the degree of this dilatation is related to the degree of coarctation. Assessment of aortic diameter and related malformations by MSCT can predict the risk of aortic dilatation in infants with CoA.
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Coartação Aórtica , Comunicação Interventricular , Lactente , Humanos , Angiografia por Tomografia Computadorizada , Dilatação , Estudos Retrospectivos , Coartação Aórtica/diagnóstico por imagemRESUMO
INTRODUCTION: A survival paradox between T4N0 (Stage IIB/IIC) and Stage IIIA colon cancer exists, even after adjusting for adequate lymph node (LN) retrieval and receipt of adjuvant chemotherapy (C). We conducted a large hospital-based study to re-evaluate this survival paradox based on the newest 8th edition staging system. METHODS: The National Cancer Data Base was queried to evaluate 35,606 patients diagnosed with Stage IIB, IIC, and IIIA colon cancer between 2010 and 2017. The Kaplan-Meier method and log-rank test were used to compare unadjusted overall survival (OS). Multivariable Cox proportional hazards model was used to determine the association of stage with hazard ratios adjusted for relevant demographic and clinical variables including ≥ 12 LNs retrieved and receipt of adjuvant chemotherapy. P value < 0.05 was considered statistically significant. RESULTS: The 5-year OS for optimally treated stage IIIA colon cancer (receipt of C) was 84.3%, which was significantly higher than stage IIB/C (≥ 12 LNs retrieved + C) (72.8%; P < 0.0001). Stage was an independent predictor of OS. Among optimally treated Stage IIIA patients, T1N1 had the best survival (90.6%) while stage T4bN0 (stage IIC) had the worst (70.9%) (P < 0.0001). Compared to stage IIB, stage IIC had a 17% increased risk of overall death while stage IIIA had a 21% reduction in death (P < 0.0001). CONCLUSION: Stage IIB/C and Stage IIIA survival paradox persists even after accounting for receipt of adjuvant chemotherapy and adequate lymph node retrieval. Future iteration of the TNM system should take this paradox into consideration.
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Neoplasias do Colo , Estadiamento de Neoplasias , Humanos , Neoplasias do Colo/patologia , Neoplasias do Colo/mortalidade , Neoplasias do Colo/terapia , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Quimioterapia Adjuvante , Estados Unidos/epidemiologia , Estudos Retrospectivos , Taxa de Sobrevida , Colectomia , Idoso de 80 Anos ou mais , Excisão de Linfonodo , Estimativa de Kaplan-MeierRESUMO
The trivalent phosphine-catalyzed [4+1] spiro-annulation reaction of allenyl imide and activated methylene cyclocompounds has been developed for the construction of various spiro-2-cyclopenten-1-ones. Oxindoles, 3-isochromanones, and 2-indanones are selected as 1C synthons to capture the in situ-generated bis-electrophilic α,ß-unsaturated ketenyl phosphonium intermediate, affording the corresponding monospiro- and bispiro-cyclopentenones in good to excellent yields (≤91%) under mild conditions. The primary attempt at asymmetric catalysis using monophosphine (R)-SITCP provides promising enantioselectivity (45% ee). A plausible reaction mechanism is also proposed.
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OBJECTIVES: The APC2 gene, encoding adenomatous polyposis coli protein-2, is involved in cytoskeletal regulation in neurons responding to endogenous extracellular signals and plays an important role in brain development. Previously, the APC2 variants have been reported to be associated with cortical dysplasia and intellectual disability. This study aims to explore the association between APC2 variants and epilepsy. METHODS: Whole-exome sequencing (WES) was performed in cases (trios) with epilepsies of unknown causes. The damaging effects of variants were predicted by protein modeling and in silico tools. Previously reported APC2 variants were reviewed to analyze the genotype-phenotype correlations. RESULTS: Four pairs of compound heterozygous missense variants were identified in four unrelated patients with epilepsy without brain malformation/intellectual disability. All variants presented no or low allele frequencies in the controls. The missense variants were predicted to be damaging by silico tools, and affect hydrogen bonding with surrounding amino acids or decreased protein stability. Patients with variants that resulted in significant changes in protein stability exhibited more severe and intractable epilepsy, whereas patients with variants that had minor effect on protein stability exhibited relatively mild phenotypes. The previously reported APC2 variants in patients with complex cortical dysplasia with other brain malformations-10 (CDCBM10; MIM: 618677) were all truncating variants; in contrast, the variants identified in epilepsy in this study were all missense variants, suggesting a potential genotype-phenotype correlation. SIGNIFICANCE: This study suggests that APC2 is potentially associated with epilepsy without brain malformation/intellectual disability. The genotype-phenotype correlation helps to understand the underlying mechanisms of phenotypic heterogeneity.
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Epilepsia , Deficiência Intelectual , Malformações do Desenvolvimento Cortical , Transtornos do Neurodesenvolvimento , Humanos , Deficiência Intelectual/genética , Epilepsia/genética , Transtornos do Neurodesenvolvimento/genética , Mutação de Sentido Incorreto , Fenótipo , Proteínas do Citoesqueleto/genéticaRESUMO
Polyamide 66 was extensively utilized in various applications contributed by its excellent mechanical performance and outstanding durability. However, its high crystallinity renders it to have low transparency, which seriously limits its application in optical devices. Herein, a highly transparent polyamide (PA) 66-based copolymer was reported using 4,4'-diaminodicyclohexylmethane (PACM), adipic acid, and polyamide 66 salt as the reaction monomers. Wide-angle X-ray diffraction (WAXD) analysis revealed that the crystal phase of the synthesized PA66/PACM6 displayed a clear transition from α to γ as the PACM6 increased accompanied by a decreased intensity in the diffraction peak of the copolymer, whose transmittance was successfully adjusted reaching as high as 92.5% (at 550 nm) when the PACM6 was 40 wt%. Moreover, the copolymer with a higher content of PACM6 exhibited larger toughness. On the other hand, the biaxially oriented films of PA66/PACM6 (20 wt%) were also prepared, and it was found that the transparency of the PA66/PACM6 copolymer could be further enhanced via adjusting the stretching ratio of the film. Furthermore, the mechanical strength of the biaxially oriented PA66/PACM6 was also improved with the increase in the orientation degree in the stretching process, indicating that the physical properties of the transparent PA66 were significantly influenced by its alicyclic structure, and the introduction of PACM into PA66 was capable of effectively improving the optical and crystalline characteristics of PA66, revealing that the synthetic strategy has great potential for guiding the design and development of transparent polyamide materials.
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BACKGROUND: The ZFHX3 gene plays vital roles in embryonic development, cell proliferation, neuronal differentiation and neuronal death. This study aims to explore the relationship between ZFHX3 variants and epilepsy. METHODS: Whole-exome sequencing was performed in a cohort of 378 patients with partial (focal) epilepsy. A Drosophila Zfh2 knockdown model was used to validate the association between ZFHX3 and epilepsy. RESULTS: Compound heterozygous ZFHX3 variants were identified in eight unrelated cases. The burden of ZFHX3 variants was significantly higher in the case cohort, shown by multiple/specific statistical analyses. In Zfh2 knockdown flies, the incidence and duration of seizure-like behaviour were significantly greater than those in the controls. The Zfh2 knockdown flies exhibited more firing in excitatory neurons. All patients presented partial seizures. The five patients with variants in the C-terminus/N-terminus presented mild partial epilepsy. The other three patients included one who experienced frequent non-convulsive status epilepticus and two who had early spasms. These three patients had also neurodevelopmental abnormalities and were diagnosed as developmental epileptic encephalopathy (DEE), but achieved seizure-free after antiepileptic-drug treatment without adrenocorticotropic-hormone/steroids. The analyses of temporal expression (genetic dependent stages) indicated that ZFHX3 orthologous were highly expressed in the embryonic stage and decreased dramatically after birth. CONCLUSION: ZFHX3 is a novel causative gene of childhood partial epilepsy and DEE. The patients of infantile spasms achieved seizure-free after treatment without adrenocorticotropic-hormone/steroids implies a significance of genetic diagnosis in precise treatment. The genetic dependent stage provided an insight into the underlying mechanism of the evolutional course of illness.
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Epilepsias Parciais , Proteínas de Homeodomínio , Espasmos Infantis , Animais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Epilepsias Parciais/genética , Epilepsias Parciais/tratamento farmacológico , Sequenciamento do Exoma , Predisposição Genética para Doença , Proteínas de Homeodomínio/genética , Mutação , Espasmos Infantis/genética , DrosophilaRESUMO
BACKGROUND: The effectiveness of renal denervation (RDN) in reducing blood pressure and systemic sympathetic activity in hypertensive patients has been established. However, the underlying central mechanism remains unknown. This study aimed to investigate the role of RDN in regulating cardiovascular function via the central renin-angiotensin system (RAS) pathway. METHODS: Ten-week-old spontaneously hypertensive rats (SHR) were subjected to selective afferent renal denervation (ADN) using capsaicin solution. We hypothesized that ADN would effectively reduce blood pressure and rebalance the RAS component of the paraventricular nucleus (PVN) in SHR. RESULTS: The experimental results show that the ADN group exhibited significantly lower blood pressure, reduced systemic sympathetic activity, decreased chronic neuronal activation marker C-FOS expression in the PVN, and improved arterial baroreflex function, compared with the Sham group. Furthermore, ACE and AT1 protein expression was reduced while ACE2 and MAS protein expression was increased in the PVN of SHR after ADN. CONCLUSIONS: These findings suggest that RDN may exert these beneficial effects through modulating the central RAS pathway.
Assuntos
Barorreflexo , Pressão Sanguínea , Hipertensão , Rim , Núcleo Hipotalâmico Paraventricular , Ratos Endogâmicos SHR , Sistema Renina-Angiotensina , Sistema Nervoso Simpático , Animais , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Rim/inervação , Rim/metabolismo , Hipertensão/fisiopatologia , Hipertensão/cirurgia , Hipertensão/metabolismo , Sistema Nervoso Simpático/fisiopatologia , Sistema Nervoso Simpático/cirurgia , Sistema Nervoso Simpático/metabolismo , Masculino , Enzima de Conversão de Angiotensina 2/metabolismo , Modelos Animais de Doenças , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proto-Oncogene Mas , Peptidil Dipeptidase A/metabolismo , Simpatectomia/métodos , Receptor Tipo 1 de Angiotensina/metabolismo , Capsaicina/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , RatosRESUMO
PURPOSE: We sought to summarize the value of contrast-enhanced computed tomography (CECT) in the differential diagnosis of bladder paraganglioma (BPG) and bladder cancer. METHODS: The medical records of 19 patients with BPG (13 males, 6 females) and 56 patients with bladder cancer (49 males, 7 females) between November 2007 and June 2023 were retrospectively reviewed. All patients underwent unenhanced and contrast-enhanced CT scanning. RESULTS: Patient age (46.4 ± 11.1 years vs. 58.6 ± 16.0 years), tumor calcification (1/19 vs. 18/56), stalk (0/19 vs. 10/56), internal vessels (15/19 vs. 19/56) and the enlarged adjacent supplying artery (14/19 vs. 10/56) were significantly different between BPG and bladder cancer (P < 0.05). The CT value in the corticomedullary phase (92.4 ± 16.6 HU vs. 64.0 ± 14.5 HU) and the contrast-enhanced value in the corticomedullary phase (54.5 ± 17.4 HU vs. 28.5 ± 12.8 HU) were significantly greater in BPG patients than in bladder cancer patients (P < 0.001), with corresponding area under the curve values of 0.930 and 0.912, respectively. The optimal cutoff values were 83.2 HU and 38.5 HU, respectively. A CT value > 83.2 HU in the corticomedullary phase and a contrast-enhanced CT value > 38.5 HU in the corticomedullary phase were used to indicate BPG with sensitivities of 78.9% and 89.5%, respectively, and specificities of 94.6% and 75.0%, respectively. CONCLUSION: The corticomedullary phase of CECT plays an important role in the preoperative differential diagnosis of BPG and bladder cancer.