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1.
Mod Pathol ; : 100616, 2024 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-39326497

RESUMEN

Gain-of-function isocitrate dehydrogenase (IDH) mutations are pathogenically significant in many tumor types and are actionable in cholangiocarcinoma, low-grade glioma, and acute myeloid leukemia. Rare IDH mutations have been described in prostatic adenocarcinoma (PCa). Recent publications suggested that psammomatous calcifications in PCa are associated with IDH1 mutation. In this retrospective study, we queried our institutional clinical sequencing database (Cohort 1), and previously published PCa datasets in cBioPortal (Cohort 2). Samples were stratified by oncogenic hotspot IDH mutations at IDH1 R132 and IDH2 R140/R172, and other non-hotspot IDH mutations. Seventeen (0.4%) cases were identified from 4033 PCa in Cohort 1 harboring mutually exclusive oncogenic hotspot IDH1 (N=15, one of which was subclonal) or IDH2 (N=2) mutations, and 20 (0.5%) cases had non-hotspot IDH1/2 mutations. Histologic review of 13 cases with IDH1 hotspot mutation and available material showed Grade Group 3 or higher disease. Immunohistochemistry was performed on cases with IDH1 hotspot mutation when possible, and showed AR, PSA, PSMA and NKX3.1 positive in all four cases stained. In Cohort 2, nine cases (0.3%) harboring IDH1 hotspot mutations were identified from 2749 patients, and nine cases carried non-hotspot IDH1/2 mutations. The combined cohorts of 23 PCa with clonal IDH1 hotspot mutations had no ETS fusions, SPOP hotspot mutations, somatic or germline alterations in BRCA1/2, ATM, RB1 or AR; 19 cases with successful microsatellite instability (MSI) testing were all microsatellite stable. Conversely, among 29 cases with non-hotspot IDH mutations, there were four with TMPRSS2::ERG fusion, six with SPOP hotspot mutations, and 10 with AR amplifications/hotspot mutations; eight were MSI-high. Notably, only two cases with IDH1 hotspot mutation had psammomatous calcifications. Our findings provide evidence that IDH1 hotspot mutations serve as driver alterations in this rare yet distinct molecular subset of PCa. Further studies are warranted to correlate response to androgen deprivation and IDH inhibitors.

2.
Mod Pathol ; 37(5): 100467, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38460672

RESUMEN

Renal low-grade oncocytic tumor (LOT) is a recently recognized renal cell neoplasm designated within the "other oncocytic tumors" category in the 2022 World Health Organization classification system. Although the clinicopathologic, immunohistochemical, and molecular features reported for LOT have been largely consistent, the data are relatively limited. The morphologic overlap between LOT and other low-grade oncocytic neoplasms, particularly eosinophilic chromophobe renal cell carcinoma (E-chRCC), remains a controversial area in renal tumor classification. To address this uncertainty, we characterized and compared large cohorts of LOT (n = 67) and E-chRCC (n = 69) and revealed notable differences between the 2 entities. Clinically, LOT predominantly affected women, whereas E-chRCC showed a male predilection. Histologically, although almost all LOTs were dominated by a small-nested pattern, E-chRCC mainly showed solid and tubular architectures. Molecular analysis revealed that 87% of LOT cases harbored mutations in the tuberous sclerosis complex (TSC)-mTOR complex 1 (mTORC1) pathway, most frequently in MTOR and RHEB genes; a subset of LOT cases had chromosomal 7 and 19q gains. In contrast, E-chRCC lacked mTORC1 mutations, and 60% of cases displayed chromosomal losses characteristic of chRCC. We also explored the cell of origin for LOT and identified L1 cell adhesion molecule (L1CAM), a collecting duct and connecting tubule principal cell marker, as a highly sensitive and specific ancillary test for differentiating LOT from E-chRCC. This distinctive L1CAM immunohistochemical labeling suggests the principal cells as the cell of origin for LOT, unlike the intercalated cell origin of E-chRCC and oncocytoma. The ultrastructural analysis of LOT showed normal-appearing mitochondria and intracytoplasmic lumina with microvilli, different from what has been described for chRCC. Our study further supports LOT as a unique entity with a benign clinical course. Based on the likely cell of origin and its clinicopathologic characteristics, we propose that changing the nomenclature of LOT to "Oncocytic Principal Cell Adenoma of the Kidney" may be a better way to define and describe this entity.


Asunto(s)
Adenoma Oxifílico , Biomarcadores de Tumor , Carcinoma de Células Renales , Neoplasias Renales , Molécula L1 de Adhesión de Célula Nerviosa , Humanos , Neoplasias Renales/patología , Neoplasias Renales/genética , Neoplasias Renales/química , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/química , Femenino , Masculino , Persona de Mediana Edad , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Molécula L1 de Adhesión de Célula Nerviosa/genética , Molécula L1 de Adhesión de Célula Nerviosa/análisis , Molécula L1 de Adhesión de Célula Nerviosa/metabolismo , Anciano , Adulto , Adenoma Oxifílico/patología , Adenoma Oxifílico/genética , Diagnóstico Diferencial , Anciano de 80 o más Años , Inmunohistoquímica , Clasificación del Tumor , Mutación
3.
Mod Pathol ; 37(10): 100557, 2024 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-38964503

RESUMEN

Small cell carcinomas (SMC) of the lung are now molecularly classified based on the expression of transcriptional regulators (NEUROD1, ASCL1, POU2F3, and YAP1) and DLL3, which has emerged as an investigational therapeutic target. PLCG2 has been shown to identify a distinct subpopulation of lung SMC with stem cell-like and prometastasis features and poor prognosis. We analyzed the expression of these novel neuroendocrine markers and their association with traditional neuroendocrine markers and patient outcomes in a cohort of bladder neuroendocrine carcinoma (NEC) consisting of 103 SMC and 19 large cell NEC (LCNEC) assembled in tissue microarrays. Coexpression patterns were assessed and integrated with detailed clinical annotation including overall (OS) and recurrence-free survival (RFS) and response to neoadjuvant/adjuvant chemotherapy. We identified 5 distinct molecular subtypes in bladder SMC based on the expression of ASCL1, NEUROD1, and POU2F3: ASCL1+/NEUROD1- (n = 33; 34%), ASCL1- /NEUROD1+ (n = 21; 21%), ASCL1+/NEUROD1+ (n = 17; 17%), POU2F3+ (n = 22, 22%), and ASCL1- /NEUROD1- /POU2F3- (n = 5, 5%). POU2F3+ tumors were mutually exclusive with those expressing ASCL1 and NEUROD1 and exhibited lower expression of traditional neuroendocrine markers. PLCG2 expression was noted in 33 tumors (32%) and was highly correlated with POU2F3 expression (P < .001). DLL3 expression was high in both SMC (n = 72, 82%) and LCNEC (n = 11, 85%). YAP1 expression was enriched in nonneuroendocrine components and negatively correlated with all neuroendocrine markers. In patients without metastatic disease who underwent radical cystectomy, PLCG2+ or POU2F3+ tumors had shorter RFS and OS (P < .05), but their expression was not associated with metastasis status or response to neoadjuvant/adjuvant chemotherapy. In conclusion, the NEC of the bladder can be divided into distinct molecular subtypes based on the expression of ASCL1, NEUROD1, and POU2F3. POU2F3-expressing tumors represent an ASCL1/NEUROD1-negative subset of bladder NEC characterized by lower expression of traditional neuroendocrine markers. Marker expression patterns were similar in SMC and LCNEC. Expression of PLCG2 and POU2F3 was associated with shorter RFS and OS. DLL3 was expressed at high levels in both SMC and LCNEC of the bladder, nominating it as a potential therapeutic target.

4.
Molecules ; 29(17)2024 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-39274975

RESUMEN

The electrocatalytic performance of a Fe65Co10Si12.5B12.5 Fe-based compounds toward alkaline hydrogen evolution reaction (HER) is enhanced by dealloying. The dealloying process produced a large number of nanosheets on the surface of NS-Fe65Co10Si12.5B12.5, which greatly increased the specific surface area of the electrode. When the dealloying time is 3 h, the overpotential of NS-Fe65Co10Si12.5B12.5 is only 175.1 mV at 1.0 M KOH and 10 mA cm-2, while under the same conditions, the overpotential of Fe65Co10Si12.5B12.5 is 215 mV, which is reduced. In addition, dealloying treated electrodes also show better HER performance than un-dealloying treated electrodes. With the increase in Co doping amount, the overpotential of the hydrogen evolution reaction decreases, and the hydrogen evolution activity is the best when the addition amount of Co is 10%. This work not only provides a basic understanding of the relationship between surface activity and the dealloying of HER catalysts, but also paves a new way for doping transition metal elements in Fe-based electrocatalysts working in alkaline media.

5.
Metab Eng ; 79: 38-48, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37392985

RESUMEN

Microbial overproduction of aromatic chemicals has gained considerable industrial interest and various metabolic engineering approaches have been employed in recent years to address the associated challenges. So far, most studies have used sugars (mostly glucose) or glycerol as the primary carbon source. In this study, we used ethylene glycol (EG) as the main carbon substrate. EG could be obtained from the degradation of plastic and cellulosic wastes. As a proof of concept, Escherichia coli was engineered to transform EG into L-tyrosine, a valuable aromatic amino acid. Under the best fermentation condition, the strain produced 2 g/L L-tyrosine from 10 g/L EG, outperforming glucose (the most common sugar feedstock) in the same experimental conditions. To prove the concept that EG can be converted into different aromatic chemicals, E. coli was further engineered with a similar approach to synthesize other valuable aromatic chemicals, L-phenylalanine and p-coumaric acid. Finally, waste polyethylene terephthalate (PET) bottles were degraded using acid hydrolysis and the resulting monomer EG was transformed into L-tyrosine using the engineered E. coli, yielding a comparable titer to that obtained using commercial EG. The strains developed in this study should be valuable to the community for producing valuable aromatics from EG.


Asunto(s)
Escherichia coli , Glicol de Etileno , Escherichia coli/genética , Escherichia coli/metabolismo , Glicol de Etileno/metabolismo , Ingeniería Metabólica/métodos , Glucosa/metabolismo , Tirosina/genética , Tirosina/metabolismo , Carbono/metabolismo , Fermentación
6.
Curr Cardiol Rep ; 25(7): 747-759, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37233923

RESUMEN

PURPOSE OF REVIEW: Heart failure is a severe clinical syndrome with complex and unclarified mechanisms, and it poses a serious threat to human health. MicroRNA, a non-coding RNA, can directly bind to target genes and regulate their expression. The important role of microRNAs in the development of HF has become a hot topic of research in recent years. This paper summarizes and prospects the mechanisms of microRNAs in regulating cardiac remodeling during heart failure to provide reference ideas for further research and clinical treatment. RECENT FINDINGS: With extensive research, more target genes for microRNAs have been clarified. By modulating various molecules, microRNAs affect the contractile function of the myocardium and alter the process of myocardial hypertrophy, myocyte loss, and fibrosis, thereby interfering with the process of cardiac remodeling and exerting an important effect in the process of heart failure. Based on the above mechanism, microRNAs have promising applications in the diagnosis and treatment of heart failure. MicroRNAs form a complex post-transcriptional control mechanism of gene expression, and the increase or decrease of their content during heart failure largely alters the course of cardiac remodeling. By continuously identifying their target genes, it is expected to achieve more precise diagnosis and treatment of this important topic of heart failure.


Asunto(s)
Insuficiencia Cardíaca , MicroARNs , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Remodelación Ventricular/genética , Miocardio/metabolismo , Regulación de la Expresión Génica
7.
Genes Chromosomes Cancer ; 61(9): 542-550, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35430756

RESUMEN

Tumors with NUTM1 fusions occur predominantly in the thoracic cavity and head and neck region. However, recent literature expanded the location of NUTM1-translocated malignancy to soft tissue, brain, and visceral organs. In this study, we describe the first series of six NUTM1-translocated carcinomas and sarcomas occurring in the genitourinary tract. The sites of origin were kidney (n = 2), bladder (n = 3), and penis (n = 1). All tumors occurred in adulthood (range: 30-78 years). The histologic features were heterogeneous, showing epithelial, spindle cell, or primitive small blue round cell morphology. Glandular architecture, keratinization, rhabdoid cells, or myxoid-to-edematous stromal component were also noted. In three cases, features were in keeping with a carcinoma (two from kidney and one from bladder), whereas the remaining three were classified as malignant undifferentiated neoplasm (MUN)/sarcoma. Fusion partners detected in four cases tested by either FISH and/or RNA sequencing were BRD4 in two kidney tumors, MXD1 in a bladder sarcoma, and MXD4 in a penile sarcoma. NUT immunostain showed diffuse spiculated positivity in five cases. Immunopositivity for various cytokeratins was noted in two tumors. The outcome of NUTM1-rearranged genitourinary malignancy was dismal: four of five cases with follow-up developed distant metastasis, and three suffered disease-specific death. In conclusion, NUTM1-rearranged carcinoma and sarcoma can affect the genitourinary tract, including kidney, bladder, and penis. Histologic features and keratin immunoexpression are highly variable. A NUTM1-fusion positive malignancy may be included in the differential diagnosis of a MUN of the genitourinary tract given the dismal outcome and the existing BET-targeted therapy for tumors with BRD3/4::NUTM1 fusion.


Asunto(s)
Carcinoma , Sarcoma , Neoplasias de los Tejidos Blandos , Adulto , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Biomarcadores de Tumor/genética , Carcinoma/genética , Proteínas de Ciclo Celular , Humanos , Masculino , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Proteínas de Fusión Oncogénica/genética , Proteínas Represoras/genética , Sarcoma/genética , Neoplasias de los Tejidos Blandos/genética , Factores de Transcripción/genética
8.
BMC Microbiol ; 21(1): 299, 2021 10 29.
Artículo en Inglés | MEDLINE | ID: mdl-34715786

RESUMEN

BACKGROUND: Peanut (Arachis hypogaea L.) is an important oil and economic crop. Calcium modulates plants in response to abiotic stresses and improves plant resistance to pathogens. Enrichment of beneficial microorganisms in the rhizosphere is associated with plant disease resistance and soil development. The purpose of this study was to analyze the differences in peanut rhizosphere microbial community structure between the calcium treatment and the control during two growth stages and to explain why calcium application could improve the resistance of peanuts to soil-borne pathogens. RESULTS: The 16S rDNA amplicon sequencing of rhizosphere microbiome showed that calcium application significantly enriched Serratia marcescens and other three dominant strains at the seedling stage. At the pod filling stage, ten dominant stains such as Sphingomonas changbaiensis and Novosphingobium panipatense were enriched by calcium. Serratia marcescens aseptic fermentation filtrate was mixed with PDA medium and inoculated with the main soil-borne pathogens in the seedling stage, which could inhibit the growth of Fusarium solani and Aspergillus flavus. The aseptic fermentation filtrate of Novosphingobium panipatense was mixed with PDA medium and inoculated with the main soil-borne pathogens in the pod filling stage, which could inhibit the growth of Sclerotium rolfsii and Leptosphaerulina arachidicola. CONCLUSIONS: Calcium application increases the resistance of peanuts to soil-borne pathogens by enriching them with specific dominant bacteria.


Asunto(s)
Arachis/efectos de los fármacos , Calcio/farmacología , Resistencia a la Enfermedad/efectos de los fármacos , Enfermedades de las Plantas/prevención & control , Probióticos/farmacología , Rizosfera , Antibiosis , Arachis/crecimiento & desarrollo , Arachis/microbiología , Bacterias/clasificación , Bacterias/efectos de los fármacos , Bacterias/genética , Bacterias/metabolismo , Frutas/efectos de los fármacos , Frutas/crecimiento & desarrollo , Frutas/microbiología , Microbiota/efectos de los fármacos , Enfermedades de las Plantas/microbiología , Probióticos/metabolismo , ARN Ribosómico 16S/genética , Plantones/efectos de los fármacos , Plantones/crecimiento & desarrollo , Plantones/microbiología , Suelo/química , Microbiología del Suelo
9.
Langmuir ; 37(23): 7176-7184, 2021 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-34096304

RESUMEN

Magnetorheological fluid (MRF) is an intelligent material, which can be controlled by an external magnetic field. It is widely used in damping, finishing, mechanical transmission, sealing, and other engineering fields due to its magnetorheological (MR) effect. However, despite decades of research and experimental development, the wide application of MRF is still restricted by its serious settlement problem owing to the density difference between the magnetic particles and carrier liquid. Here, using the coprecipitation method, a kind of Fe3O4-modified nanolignocellulose (Fe3O4/NLC) composite fiber was characterized by its unique advantages such as low density, soft magnetism property, and high specific surface. These Fe3O4/NLCs were used as a kind of reinforcing particle with carbonyl iron powder in the new bidisperse MRF system. The performances of MRF samples were enhanced by these superior properties. We found that all MRF samples with composite fibers exhibited excellent antisettlement and dynamic mechanical characteristics and cooperativity between Fe3O4 and NLCs. Furthermore, redispersibility of MRF is qualitatively evaluated by a shearing test in this paper, explaining the high property of antihardening. This composite fiber improves the comprehensive performance of MRF and has the potential to be repeatedly used in engineering applications.

10.
BMC Geriatr ; 21(1): 125, 2021 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-33593292

RESUMEN

BACKGROUND: Frailty increases the adverse outcomes of clinical heart failure; however, the relationship between frailty and stage-B heart failure (SBHF) remains unknown. We aimed to explore the epidemiology and predictive value of frailty in older adults with SBHF. METHODS: A prospective cohort of SBHF inpatients aged 65 years or older who were hospitalized between September 2018 and February 2019 and were followed up for 6 months were included. SBHF was defined as systolic abnormality, structural abnormality (left ventricular enlargement, left ventricular hypertrophy, wall motion abnormalities, valvular heart disease), or prior myocardial infarction. Frailty was assessed by the Fried frailty phenotype. Multivariable Cox proportional hazards regression was used to explore the independent risk and prognostic factors. RESULTS: Data of 443 participants (age: 76.1 ± 6.79 years, LVEF: 62.8 ± 4.92%, men: 225 [50.8%], frailty: 109 [24.6%]) were analyzed. During the 6-month follow-up, 83 (18.7%) older SBHF inpatients experienced all-cause mortality or readmission, and 29 (6.5%) of them developed clinical HF. Frail individuals had a 1.78-fold (95%CI: 1.02-3.10, P = 0.041) higher risk of 6-month mortality or readmission and a 2.83-fold (95%CI 1.24-6.47, P = 0.014) higher risk of developing clinical HF, independent of age, sex, left ventricular ejection fraction, and N-terminal pro-B-type natriuretic peptide level. CONCLUSIONS: Frailty is common in older SBHF inpatients and should be considered to help identify individuals with an increased risk of mortality or readmission, and developing clinical HF. TRIAL REGISTRATION: ChiCTR1800017204 .


Asunto(s)
Fragilidad , Insuficiencia Cardíaca , Anciano , Anciano de 80 o más Años , Femenino , Fragilidad/diagnóstico , Fragilidad/epidemiología , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/terapia , Humanos , Pacientes Internos , Masculino , Readmisión del Paciente , Pronóstico , Estudios Prospectivos , Volumen Sistólico , Función Ventricular Izquierda
11.
J Clin Ultrasound ; 49(6): 527-532, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-33786835

RESUMEN

PURPOSE: A Killian-Jamieson diverticulum (KJD) may be mistaken for a thyroid nodule on ultrasound (US). The purpose of this retrospective study was to search for specific US features that would help differentiate between KJD and thyroid nodules. METHODS: A total of 12 patients with KJD who had undergone an US examination of the neck were identified. The size, shape, boundary, echopattern, location, color flow signals on color Doppler US of KJD and the relationship between the lesion and esophageal wall were analyzed. The change of size, shape and internal echotexture were also observed when the lesion was compressed with the probe and when the patient was asked to drink water. RESULTS: All KJD were confirmed by barium esophagography. All KJD were posterior to the left thyroid lobe on US, and were associated with a semicircular hypoechoic anterior wall. The internal echotexture was heterogeneous. In eight cases, the connection to the esophageal wall was seen. When compressing with the US probe or when the patients swallowed water, the size, shape or internal echotexture of the lesion changed. CONCLUSION: The specific criteria for US diagnosis of KJD included the connection to the esophageal wall and the fact that the internal echotexture, shape and size of KJD changed in real-time when the patient swallowed water or when the lesion was compressed with the transducer.


Asunto(s)
Divertículo de Zenker/diagnóstico por imagen , Adulto , Diagnóstico Diferencial , Esófago/diagnóstico por imagen , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Nódulo Tiroideo/diagnóstico por imagen , Ultrasonografía
12.
Cytokine ; 125: 154801, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31442680

RESUMEN

BACKGROUND: HIV rapid progressors (RPs) present with a rapid decline of CD4+ T cells within a few years of infection. Determining the underlying mechanisms throughout this decline is important to identify prognostic biomarkers and intervention strategies. Determining the numbers of CD4+ and CD8+ T cells is essential for monitoring the immune status of HIV infected patients. There are additional kinds of cell subtypes in T cells, but their relationship to the rapid progression of HIV disease is not well defined. METHODS: Nineteen RPs and twenty-one chronic progressors (CPs) were enrolled in this study. Based on the intensity of CD4 and CD8 expression, different T cell subtypes were identified, including CD4+CD8+T cells, CD4-CD8- T cells, CD4+CD8low T cells and CD4-CD8low T cells. Alterations in these T cell subtypes in early HIV infection (within 120 days of infection) between RPs and CPs were measured, and the relationships between these subtypes and HIV disease progression were investigated. In addition, expression of IFN-γ in T cell subtypes after PMA stimulation was analyzed by flow cytometry. RESULTS: We found that during early HIV infection, CD4+CD8low T cells both significantly decreased in numbers and percentages in RPs compared to CPs. Furthermore, baseline CD4+CD8low T cells positively correlated not only with baseline CD4+T cells but also with CD4+T cells 12 months after infection. Moreover, survival analysis indicated that low levels of baseline CD4+CD8low T cells significantly accelerated the decline in CD4+ T cells as well as increased viral loads. CD4+CD8low T cells secreted significantly more IFN-γ after PMA stimulation compared to CD4+CD8-T cells and CD4-CD8+T cells, which may be beneficial for the prevention of disease progression. CONCLUSIONS: Our results identified that in early stage HIV-1 infection, a subtype of T cells, CD4+CD8low, are associated with subsequent disease progression.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Adulto , Biomarcadores/sangre , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/metabolismo , Enfermedad Crónica , Correlación de Datos , Progresión de la Enfermedad , Humanos , Interferón gamma/metabolismo , Masculino , Acetato de Tetradecanoilforbol/análogos & derivados , Acetato de Tetradecanoilforbol/farmacología , Carga Viral/inmunología
13.
J Inherit Metab Dis ; 43(3): 529-539, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-31774565

RESUMEN

Classic Galactosaemia is a genetic disorder, characterised by galactose intolerance in newborns. It occurs due to recessive mutations in the galactose-1-phosphate uridylyltransferase (GALT) gene. One of the main alterations caused by GALT deficiency is the accumulation of galactose 1-phosphate (Gal-1P) in cells. Studies have suggested that Gal-1P exerts cellular toxicity, possibly by inhibiting cellular metabolism. However, the exact significance of Gal-1P in disease pathogenesis remains unclear. In this study, we tested the hypothesis that Gal-1P inhibits cellular glucose utilisation by competing with substrates in the glycolytic pathway. We also investigated the metabolism of both galactose and glucose in GALT-expressing HEK293T and 143B cells to identify critical reactions steps contributing to the metabolic toxicity of galactose. Notably, we found that galactose-treated HEK293T and 143B cells, which express endogenous GALT, accumulate markedly high intracellular Gal-1P concentrations. Despite very high intracellular Gal-1P concentrations, no inhibition of cellular glucose uptake and no significant changes in the intracellular concentrations of glycolytic metabolites were observed. This indicates that Gal-1P does not exert an inhibitory effect on glycolysis in cells and rules out one potential hypothesis for cellular Gal-1P toxicity. We also investigated the mechanism responsible for the observed Gal-1P accumulation. Our results suggest that Gal-1P accumulation is a result of both low GALT activity and the absence of product inhibition by Gal-1P on galactokinase (GALK1), the enzyme responsible for phosphorylating galactose to Gal-1P. These findings provide a better understanding of the disease mechanisms underlying Classic Galactoaemia.


Asunto(s)
Galactosa/metabolismo , Galactosemias/metabolismo , Galactosafosfatos/metabolismo , UTP-Hexosa-1-Fosfato Uridililtransferasa/metabolismo , Células HEK293 , Humanos , UTP-Hexosa-1-Fosfato Uridililtransferasa/genética
14.
Cost Eff Resour Alloc ; 18: 12, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32140079

RESUMEN

BACKGROUND: To investigate the long-term economic outcome of dapagliflozin versus metformin in Chinese patients with type 2 diabetes mellitus (T2DM) whose diet and exercise have not provided sufficient glycemic control. METHODS: An economic analysis of dapagliflozin versus metformin was conducted by using the Chinese Outcomes Model for T2DM with a time horizon of lifetime, which was developed and validated based on the Chinese population. The efficacy data of lowering HbA1c of dapagliflozin and metformin was derived from a network meta-analysis. Other clinical, cost and utility inputs were obtained from published sources. Lifetime discounted quality-adjusted life-years, cost, and incremental cost-effectiveness ratio were measured. The uncertainty was facilitated by one-way and probabilistic sensitivity analyses. RESULTS: The comparison of metformin and dapagliflozin in Chinese patients with insufficient glycemic control by diet and exercise showed that dapagliflozin was more costly and produced fewer health benefits in our simulated cohort. The sensitivity analyses indicated that the results were robust. CONCLUSIONS: Dapagliflozin is not likely to be cost-effective compared with metformin for Chinese patients with T2DM inadequately controlled with diet and exercise.

15.
BMC Geriatr ; 20(1): 218, 2020 06 22.
Artículo en Inglés | MEDLINE | ID: mdl-32571237

RESUMEN

BACKGROUND: We aimed to assess the utility of the combination of the mini-mental state examination (MMSE) + clock drawing test (CDT) and the Fried phenotype for predicting non-elective hospital readmission or death within 6 months in elderly inpatients with cardiovascular disease (CVD). METHODS: A single-center prospective cohort was conducted from September 2018 to February 2019. Inpatients ≥65 years old were recruited. Predictive validity was tested using a Cox proportional hazards regression model analysis, and the discriminative ability was evaluated by the receiver operating characteristic (ROC) curve. RESULTS: A total of 542 patients were included. Overall, 12% (64/542) screened positive for cognitive impairment, 16% (86/542) were physically frail and 8% (44/542) had cognitive impairment combined with physical frailty, showing an older age (P < 0.001) and a lower education level (P < 0.001) than physically frail patients. A total of 113 patients (20.9%) died or were readmitted at 6 months. Frail participants with a normal (hazard ratio [HR]: 1.73, 95% confidence interval [CI]: 1.06-2.82, P = 0.028) or impaired cognition (HR: 2.50, 95% CI: 1.27-4.91, P = 0.008) had a higher risk of non-elective hospital readmission or death than robust patients after adjusting for the age, sex, education level, marital status, the presence of diabetes mellitus, heart failure, and history of stroke. The area under the ROC curve (AUC) showed that the discriminative ability in relation to 6 months readmission and death for the MMSE + CDT + Fried phenotype was 0.65 (95% CI: 0.60-0.71), and the AUC for men was 0.71 (95% CI: 0.63-0.78), while that for women was 0.60 (95% CI: 0.51-0.69). CONCLUSIONS: Accounting for cognitive impairment in the frailty phenotype may allow for the better prediction of non-elective hospital readmission or death in elderly inpatients with CVD in the short term. TRIAL REGISTRATION: ChiCTR1800017204; date of registration: 07/18/2018.


Asunto(s)
Enfermedades Cardiovasculares , Fragilidad , Anciano , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/terapia , Cognición , Femenino , Anciano Frágil , Fragilidad/diagnóstico , Evaluación Geriátrica , Humanos , Pacientes Internos , Masculino , Readmisión del Paciente , Estudios Prospectivos
16.
BMC Musculoskelet Disord ; 21(1): 556, 2020 Aug 18.
Artículo en Inglés | MEDLINE | ID: mdl-32811509

RESUMEN

BACKGROUND: Combined anterior and posterior ankle impingement has seldom been reported. Cedell fracture, fracture of posteromedial tubercle of talus, is an uncommon and easily missed injury which may elicit posteromedial ankle impingement. The injury mechanisms and management strategies of these two lesions have been reported individually. But the concurrent lesion of both of them has not been reported. CASE PRESENTATION: We reported a 58-year-old female with combined anterior and posterior ankle impingement syndrome with nonunion of Cedell fracture in whom open osteophytes debridement, fracture internal fixation and posterior talotibial ligament reconstruction were performed. The AOFAS hindfoot score was 90 at 1 year follow-up. To our knowledge, this was the first reported case with anterior, posterior and posteromedial impingement which was treated operatively with an excellent short-term outcome. CONCLUSIONS: To fully recognize this occult lesion and avoid missing is imperative for reducing the morbidities. We suggest CT and MRI as excellent imaging modalities that can help the timely diagnosis and appropriate treatment for this combined impingement with circumferential lesions.


Asunto(s)
Traumatismos del Tobillo , Fracturas Óseas , Astrágalo , Tobillo , Traumatismos del Tobillo/diagnóstico por imagen , Traumatismos del Tobillo/cirugía , Articulación del Tobillo/diagnóstico por imagen , Articulación del Tobillo/cirugía , Femenino , Humanos , Persona de Mediana Edad , Astrágalo/diagnóstico por imagen , Astrágalo/cirugía , Resultado del Tratamiento
17.
Dement Geriatr Cogn Disord ; 47(4-6): 375-384, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31466053

RESUMEN

BACKGROUND: An increasing number of studies suggest the importance of prospective memory (ProM) due to its functional relevance and sensitivity to neuropathology. However, its relevant neural substrates have not been sufficiently explored. OBJECTIVES: The present study aimed to investigate the relationship between structural connectivity and both objective and subjective ProM measures in a group of non-demented people with subjective memory complaints, and to examine the potential of ProM measures to detect the difference between subjective cognitive decline (SCD) and mild cognitive impairment (MCI) in the pre-dementia stage. METHOD: Thirty-sevennon-dementedparticipants aged above 50 years were recruited from an outpatient Neurology Clinic; 13 of them fulfilled the criteria of MCI and 24 of SCD. All subjects received comprehensive neuropsychological tests, including the adapted version of the Cambridge Prospective Memory Test, as well as the Taiwan version of the Prospective and Retrospective Memory Questionnaire. The diffusion tensor imaging technique with tract-based spatial statistics was applied to measure cerebral microstructural changes. RESULTS: Time-based ProM performance was significantly correlated with microstructural integrity of the right superior longitudinal fasciculus, while the event-based one was associated with that of the left superior longitudinal fasciculus and the genu of the corpus callosum among all participants and in the SCD group. After controlling for age, the correlation remained significant between event-based ProM performance and the left superior longitudinal fasciculus among all participants and in the MCI group, as well as between event-based ProM performance and the genu among all participants. Although self-reported ProM failures in real life was associated with fiber disruption of the left superior longitudinal fasciculus among all participants and within the MCI group, an inverse relationship was also observed with that of the corpus callosum in the SCD group even after controlling for age. As compared to the SCD group, people with MCI performed significantly worse on time-based ProM tasks and reported more ProM failures in daily life. CONCLUSIONS: ProM was related to the integrity of interhemispheric commissural fibers and association fibers that connect the frontal lobe with posterior regions, with a task-specific laterality effect. Time-based ProM tasks and self-reported ProM questionnaire may be sensitive to early pathological cognitive deterioration, while the concomitant aging process and individual awareness level may respectively confound the results of evaluation.


Asunto(s)
Lateralidad Funcional , Trastornos de la Memoria/diagnóstico por imagen , Anciano , Anciano de 80 o más Años , Cuerpo Calloso/diagnóstico por imagen , Imagen de Difusión Tensora , Femenino , Lóbulo Frontal/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Trastornos de la Memoria/psicología , Persona de Mediana Edad , Fibras Nerviosas , Pruebas Neuropsicológicas , Estudios Retrospectivos , Encuestas y Cuestionarios , Taiwán
18.
J Hepatol ; 69(5): 1037-1046, 2018 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-30031886

RESUMEN

BACKGROUND & AIMS: Radical resection is the best treatment for patients with advanced hepatic alveolar echinococcosis (AE). Liver transplantation is considered for selected advanced cases; however, a shortage of organ donors and the risk of postoperative recurrence are major challenges. The aim of this study was to assess the clinical outcomes of ex vivo liver resection and autotransplantation for end-stage AE. METHODS: In this prospective study, 69 consecutive patients with end-stage hepatic AE were treated with ex vivo resection and liver autotransplantation between January 2010 and February 2017. The feasibility, safety and long-term clinical outcome of this technique were assessed. RESULTS: Ex vivo extended hepatectomy with autotransplantation was successful in all patients without intraoperative mortality. The median weight of the graft and AE lesion were 850 (370-1,600) g and 1,650 (375-5,000) g, respectively. The median duration of the operation and anhepatic phase were 15.9 (8-24) h and 360 (104-879) min, respectively. Six patients did not need any blood transfusion. Complications higher than IIIa according to Clavien classification were observed in 10 patients. The 30-day-mortality and overall mortality (>90 days) were 7.24% (5/69) and 11.5% (8/69), respectively. The mean hospital stay was 34.5 (12-128) days. Patients were followed-up systematically for a median of 22.5 months (14-89) without recurrence. CONCLUSION: This is the largest series assessing ex vivo liver resection and autotransplantation in end-stage hepatic AE. This technique could be an effective alternative to liver transplantation in patients with end-stage hepatic AE, with the advantage that it does not require an organ nor immunosuppressive agents. LAY SUMMARY: Ex vivo liver resection and autotransplantation were performed in a large series of patients with end-stage hepatic alveolar echinococcosis. The results showed that this surgical option was feasible, with acceptable postoperative mortality, but 100% disease-free survival in survivors. Careful patient selection, as well as precise assessment for size and quality of the remnant liver are key to successful surgery.


Asunto(s)
Equinococosis Hepática/cirugía , Hepatectomía/métodos , Trasplante de Hígado/métodos , Adolescente , Adulto , Femenino , Hepatectomía/efectos adversos , Humanos , Trasplante de Hígado/efectos adversos , Masculino , Persona de Mediana Edad , Trasplante Autólogo , Trasplante Homólogo , Adulto Joven
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