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Monitoring hydrogen sulfide (H2S) in living organisms is very important because H2S acts as a regulator in many physiological and pathological processes. Upregulation of endogenous H2S concentration has been shown to be closely related to the occurrence and development of tumors, atherosclerosis, neurodegenerative diseases and diabetes. Herin, a novel fluorescent probe HND with aggregation-induced emission was designed. Impressively, HND exhibited a high selectivity, fast response (1 min) and low detection limit (0.61 µM) for H2S in PBS buffer (10 mM, pH = 7.42). Moreover, the reaction mechanism between HND and H2S was conducted by Job's plot, HR-MS, and DFT. In particular, HND was successfully employed to detect H2S in HeLa cells.
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Colorantes Fluorescentes , Sulfuro de Hidrógeno , Sulfuro de Hidrógeno/análisis , Humanos , Colorantes Fluorescentes/química , Células HeLa , Imagen Óptica/métodos , Espectrometría de Fluorescencia/métodos , Límite de DetecciónRESUMEN
OBJECTIVE: The prognostic role of the number of cycles of adjuvant chemotherapy (ACT) after total mesorectal excision in stage III and high-risk stage II rectal cancer is unknown. As a result of this, our study was designed to assess the effect of the number of cycles of ACT on the prediction of cancer-specific survival. METHODS: Four hundred patients that were diagnosed as stage III and high-risk stage II rectal cancer from January 2012 to January 2018 and who had received total mesorectal excision were enrolled in this study. A nomogram incorporating the number of cycles of ACT was also developed in this study. For internal validation, the bootstrap method was used and the consistency index was used to evaluate the accuracy of the model. The patients were stratified into risk groups according to their tumor characteristics by recursive partitioning analysis. RESULTS: We found that the risk of death was decreased by 26% (HR = 0.74, 95% CI: 0.61-0.89, P = 0.0016) with each increasing ACT cycle. The N stage, positive lymph node ratio (PLNR), carcinoembryonic antigen, neutrophil-to-lymphocyte ratio, and the number of cycles of ACT were chosen and entered into the nomogram model. Recursive partitioning analysis-based risk stratification revealed a significant difference in the prognosis in rectal cancer patients with high-risk, intermediate-risk, and low-risk (3-year cancer-specific survival: 0.246 vs. 0.795 vs. 0.968, P < 0.0001). Seven or more cycles of ACT yielded better survival in patients with PLNR ≥ 0.28 but not in patients with PLNR < 0.28. CONCLUSION: In conclusion, the nomogram prognosis model based on the number of cycles of ACT predicted individual prognosis in rectal cancer patients who had undergone total mesorectal excision. These findings further showed that in patients with PLNR ≥ 0.28, no fewer than 7 cycles of ACT are needed to significantly reduce the patient's risk of death.
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Neoplasias del Recto , Neoplasias Testiculares , Quimioterapia Adyuvante , Humanos , Masculino , Estadificación de Neoplasias , Nomogramas , Pronóstico , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/patología , Neoplasias del Recto/cirugía , Estudios Retrospectivos , Neoplasias Testiculares/patologíaRESUMEN
N(6)-methyladenosine (m(6)A) is the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes. Here we report ALKBH5 as another mammalian demethylase that oxidatively reverses m(6)A in mRNA in vitro and in vivo. This demethylation activity of ALKBH5 significantly affects mRNA export and RNA metabolism as well as the assembly of mRNA processing factors in nuclear speckles. Alkbh5-deficient male mice have increased m(6)A in mRNA and are characterized by impaired fertility resulting from apoptosis that affects meiotic metaphase-stage spermatocytes. In accordance with this defect, we have identified in mouse testes 1,551 differentially expressed genes that cover broad functional categories and include spermatogenesis-related mRNAs involved in the p53 functional interaction network. The discovery of this RNA demethylase strongly suggests that the reversible m(6)A modification has fundamental and broad functions in mammalian cells.
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Dioxigenasas/metabolismo , Proteínas de la Membrana/metabolismo , Oxidorreductasas N-Desmetilantes/metabolismo , Procesamiento Postranscripcional del ARN , ARN Mensajero/metabolismo , Desmetilasa de ARN, Homólogo 5 de AlkB , Animales , Secuencia de Bases , Núcleo Celular/metabolismo , Dioxigenasas/química , Dioxigenasas/genética , Técnicas de Silenciamiento del Gen , Células HeLa , Humanos , Infertilidad Masculina/enzimología , Masculino , Proteínas de la Membrana/química , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Tamaño de los Órganos , Oxidorreductasas N-Desmetilantes/química , Oxidorreductasas N-Desmetilantes/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Transporte de Proteínas , Interferencia de ARN , ARN Mensajero/química , Espermatogénesis/genética , Testículo/enzimología , Testículo/patología , TranscriptomaRESUMEN
PURPOSE OF THE STUDY: The incidence of acute kidney injury (AKI) with a poor prognosis in the elderly has been increasing each year. This study aimed to investigate the clinical characteristics of and risk factors for death from AKI in the elderly and help improve prognosis. STUDY DESIGN: This study was a retrospective cohort study based on data from adult patients (≥18 years old) admitted to 15 hospitals in China between 1 January 2009 and 31 December 2011. The characteristics of AKI in the elderly were compared with those in younger patients. RESULTS: In elderly patients with AKI, rates of hypertension, cardiovascular disease and multiple organ dysfunction syndrome (MODS) were higher than in younger patients (44.2% vs 31.2%, 16.1% vs 4.6% and 20.9% vs 16.9%, respectively), the length of ICU stay was longer (3.8 days vs 2.7 days, P=0.019) and renal biopsy (1.0% vs 7.13%, P<0.001) and dialysis (9.6% vs 19.2%, P<0.001) were performed less. Hospital-acquired (HA) AKI was more common than community-acquired (CA) AKI (60.3% vs 39.7%), while the most common cause of AKI was pre-renal (53.5%). Multiple logistic regression analysis showed that age (OR 1.041, 95% CI 1.023 to 1.059), cardiovascular disease (OR 1.980, 95% CI 1.402 to 2.797), cancer (OR 2.302, 95% CI 1.654 to 3.203), MODS (OR 3.023, 95% CI 1.627 to 5.620) and mechanical ventilation (OR 2.408, 95% CI 1.187 to 4.887) were significant risk factors for death. CONCLUSIONS: HA-AKI and pre-renal AKI were more common in the elderly. Age, cardiovascular disease, cancer, MODS and mechanical ventilation were independent risk factors for death in the elderly with AKI.
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Lesión Renal Aguda/mortalidad , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Biopsia , China/epidemiología , Comorbilidad , Femenino , Humanos , Tiempo de Internación/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Diálisis Renal/estadística & datos numéricos , Estudios Retrospectivos , Factores de RiesgoRESUMEN
The first imported Middle East respiratory syndrome (MERS) case in China was identified in May 2015. We determined the kinetics of antibody (IgG and IgM) and neutralizing antibodies against MERS-coronavirus (MERS-CoV) in this case before discharge. Moreover, no seroconversion was found among 53 close contacts by anti-MERS IgG antibody enzyme-linked immunosorbent assay (ELISA) of paired serum samples. These findings suggest that neither community nor nosocomial transmission of MERS-CoV occurred in China.
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Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/transmisión , Viaje , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , China/epidemiología , Trazado de Contacto , Infecciones por Coronavirus/sangre , Ensayo de Inmunoadsorción Enzimática , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Masculino , República de Corea/epidemiologíaRESUMEN
AIMS: This study aimed to develop a family-centered care survey for Chinese adult intensive care units and to establish the survey's psychometric properties. BACKGROUND: Family-centered care (FCC) is widely recognized as an ideal model of care. Few studies have explored FCC perceptions among family members of adult critical care patients in Asian countries, and no Chinese FCC measurement has been developed. METHODS: An English version of the 3-factor family-centered care survey for adult intensive care units (FCCS-AICU) was translated into Chinese using a modified back translation procedure. Based on the literature review, two additional concepts, information and empowerment, were added to the Chinese FCCS-AICU. The psychometric properties of the Chinese FCCS-AICU were determined with 249 family members from a medical center in Taiwan and were tested for construct and convergent validity, and internal consistency. RESULTS: Both the monolingual and bilingual equivalence tests of the English and Chinese versions of the 3-factor FCCS-AICU were supported. Exploratory factor analysis supported the 5-factor structure of the Chinese FCCS-AICU with a total explained variance of 58.34%. The Chinese FCCS-AICU was correlated with the Chinese Critical Care Family Needs Inventory. Internal consistency, determined by Cronbach's α, for the overall scale was .94. CONCLUSIONS: The Chinese FCCS-AICU is a valid and reliable tool for measuring perceptions of FCC by family members of adult intensive care patients within Chinese-speaking communities.
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Enfermería de Cuidados Críticos/métodos , Familia , Atención al Paciente/métodos , Adolescente , Adulto , Anciano , China , Femenino , Humanos , Masculino , Persona de Mediana Edad , Psicometría , Adulto JovenRESUMEN
Endometrial carcinoma (EC) is a common type of uterine cancer in developed countries, originating from the uterine epithelium. The incidence rate of EC in Taiwan has doubled from 2005. Cancer stem cells (CSCs) are a subpopulation of cancer cells that have high tumorigenicity and play a crucial role in the malignant processes of cancer. Targeting molecules associated with CSCs is essential for effective cancer treatments. This study delves into the role of Exosome component 5 (EXOSC5) in EC. Data from The Cancer Genome Atlas suggests a correlation between high EXOSC5 mRNA expression and unfavorable EC prognosis. EXOSC5 knockdown diminished EC-CSC self-renewal and reduced expression of key cancer stemness proteins, including c-MYC and SOX2. Intriguingly, this knockdown significantly curtailed tumorigenicity and CSC frequency in EC tumor spheres. A mechanistic examination revealed a reduction in netrin4 (NTN4) levels in EXOSC5-depleted EC cells. Moreover, NTN4 treatment amplified EC cell CSC activity and, when secreted, NTN4 partnered with integrin ß1, subsequently triggering the FAK/SRC axis to elevate c-MYC activity. A clear positive relation between EXOSC5 and NTN4 was evident in 93 EC tissues. In conclusion, EXOSC5 augments NTN4 expression, activating c-MYC via the integrin ß1/FAK/SRC pathway, offering potential avenues for EC diagnosis and treatment.
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Neoplasias Endometriales , Integrina beta1 , Humanos , Femenino , Integrina beta1/metabolismo , Transducción de Señal/genética , Neoplasias Endometriales/metabolismo , Células Madre Neoplásicas/metabolismo , Línea Celular Tumoral , Antígenos de Neoplasias/metabolismo , Proteínas de Unión al ARN/metabolismo , Complejo Multienzimático de Ribonucleasas del Exosoma/metabolismo , Netrinas/metabolismoRESUMEN
Osteoporosis is a usual bone disease in aging populations, principally in postmenopausal women. Anti-resorptive and anabolic drugs have been applied to prevent and cure osteoporosis and are associated to a different of adverse effects. Du-Zhong is usually applied in Traditional Chinese Medicine to strengthen bone, regulate bone metabolism, and treat osteoporosis. Chlorogenic acid is a major polyphenol in Du-Zhong. In the current study, chlorogenic acid was found to enhance osteoblast proliferation and differentiation. Chlorogenic acid also inhibits the RANKL-induced osteoclastogenesis. Notably, ovariectomy significantly decreased bone volume and mechanical properties in the ovariectomized (OVX) rats. Administration of chlorogenic acid antagonized OVX-induced bone loss. Taken together, chlorogenic acid seems to be a hopeful molecule for the development of novel anti-osteoporosis treatment.
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Osteoclastos , Osteoporosis , Humanos , Ratas , Femenino , Animales , Ácido Clorogénico/farmacología , Ácido Clorogénico/uso terapéutico , Ácido Clorogénico/metabolismo , Osteogénesis , Osteoporosis/metabolismo , Osteoblastos/metabolismo , Diferenciación CelularRESUMEN
PURPOSE: We undertook a multicenter epidemiological survey among hospitalized patients with chronic kidney disease (CKD), aiming to reveal the characteristics of elderly CKD by comparing it with non-elderly CKD. METHODS: Medical records were obtained from 18 military hospitals across China from 1 January 2009 to 31 December 2011. The characteristics of chronic kidney disease in the elderly were analyzed through comparing with those in younger patients with chronic kidney disease. RESULTS: A total of 380,461 hospitalized patients were included in the database, with 25,826 (6.8%) diagnosed with CKD. Unlike non-elderly, the top-three causes of chronic kidney disease among elderly patients were diabetic nephropathy (24.1%), hypertension-related renal impairment (20.9%), and primary glomerular disease (11.1%). 71.6% of the elderly patients with CKD had more than one comorbidities and the number of morbidities increased with age. In-hospital mortality of the elderly was significantly higher than those of younger patients (3.3% vs. 1.0%). Multiple logistic regression analysis showed that age, CKD 5 stage, acidosis, cardiovascular and cerebrovascular diseases, infection disease, neoplasm, and dementia were independent risk factors for death from CKD in the elderly. The median length of stay (LOS) was similar between elderly and younger CKD patients. The median cost was higher for elderly CKD patients than for younger CKD patients. Among elderly individuals with CKD, LOS, and hospitalization costs also increased with an increase in the number of coexisting diseases. CONCLUSIONS: Diabetic nephropathy, and hypertension-related kidney injury were the leading causes of chronic kidney disease in elderly patients, which is different from the non-elderly. Elderly patients with chronic kidney disease were more likely to have a higher burden of comorbidities, which were associated with worse in-hospital outcomes.
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Nefropatías Diabéticas , Hipertensión , Insuficiencia Renal Crónica , Humanos , Anciano , Persona de Mediana Edad , Estudios Transversales , Nefropatías Diabéticas/complicaciones , Tasa de Filtración Glomerular , Insuficiencia Renal Crónica/complicaciones , Hipertensión/complicaciones , Factores de RiesgoRESUMEN
Three previously undescribed and sixteen known alkaloids were bioguidedly isolated from the bulbs of Narcissus tazetta subsp. chinensis (M.Roem.) Masamura & Yanagih. The structures were elucidated by spectroscopic data, including HRESIMS, NMR, and ECD. Eleven of the isolated alkaloids exhibited immunosuppressive activity on the proliferation of human T cells. (+)-Narciclasine (18) showed the most significantly suppressive activity with an IC50 value of 14 ± 5 nM. In vitro, (+)-narciclasine (18) blocked NF-κB signal transduction, but did not affect PI3K/AKT signal transduction. What was more, (+)-narciclasine significantly reduced ALT and AST levels and alleviated liver damage induced by ConA in AIH mouse model.
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Alcaloides , Proliferación Celular , Inmunosupresores , Narcissus , Narcissus/química , Humanos , Animales , Alcaloides/farmacología , Alcaloides/química , Alcaloides/aislamiento & purificación , Inmunosupresores/farmacología , Inmunosupresores/química , Inmunosupresores/aislamiento & purificación , Ratones , Proliferación Celular/efectos de los fármacos , Linfocitos T/efectos de los fármacos , Estructura Molecular , FN-kappa B/metabolismo , FN-kappa B/antagonistas & inhibidores , Benzofenantridinas/farmacología , Benzofenantridinas/química , Benzofenantridinas/aislamiento & purificación , Relación Estructura-Actividad , Relación Dosis-Respuesta a Droga , Estereoisomerismo , Transducción de Señal/efectos de los fármacos , Fenantridinas , Alcaloides de AmaryllidaceaeRESUMEN
PURPOSE: In post-hoc analyses of phaseIII randomized controlled study(STELLAR), to analyzethe prognostic impact oflateral pelvic lymph node (LPLN)metastasis in locally advanced rectal cancer (LARC). METHODS: LPLN metastasis was defined as a short diameterâ¯>â¯7 mm on magnetic resonance imaging (MRI).The studyincluded 591 patients with LARC.All patients received neoadjuvant (chemo)radiotherapy combined withradical resection. RESULTS: Among 591 patients, 99 (16.8â¯%) were diagnosed with LPLN metastasis, mostly with unilateral metastasis (79.8â¯%), with internal iliac lymph node metastasis being more common (81.8â¯%).Significant differences were found among with and without LPLN metastasis in rectal segmentation (P=0.001),N disease (P<0.001), mesenteric LN metastasis or not (P=0.030). The median follow-up timewas 34.0â¯months, three-year disease-free survival (DFS),overall survival (OS), andmetastasis-free survival (MFS)were significantly lower in LPLN metastaticgroup than those in LPLN non-metastaticgroup (51.4â¯% vs. 68.2â¯%, P<0.001; 71.8â¯% vs. 84.2â¯%, P=0.006; 60.8â¯% vs. 80.1â¯%,P<0.001), respectively; while there were no significant differences in locoregional recurrence(11.4â¯% vs. 8.5â¯%, P=0.564). Multivariate analysis found that LPLN metastasis was an independent prognostic factor affecting DFS (P=0.005), OS (P=0.036),MFS (P=0.001).No significantly survival benefit was observed for the short-term radiotherapy based total neoadjuvant therapy compared to long-term concurrent chemoradiotherapy. CONCLUSIONS: LPLN metastasis observed byMRI should be considered in LARC patients, especially in populations with lowrectal cancer, N2 disease, and mesenteric LN metastasis. LPLN metastasis diagnosed by MRI is a significant and independent risk factor and is associated with worse DFS, OS, MFS.
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We herein report a case of slowly progressive cutaneous, rhinofacial, and pulmonary mucormycosis caused by Mucor irregularis in an immunocompetent woman who was successfully managed by combined surgical debridement and antifungal therapy. Slow progression, pulmonary involvement, occurrence in an immunocompetent patient, and good prognosis are unusual features of our case.
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Dermatosis Facial/patología , Enfermedades Pulmonares Fúngicas/patología , Mucor/aislamiento & purificación , Mucormicosis/diagnóstico , Mucormicosis/patología , Enfermedades Nasales/patología , Adulto , Antifúngicos/administración & dosificación , ADN de Hongos/química , ADN de Hongos/genética , Desbridamiento , Dermatosis Facial/complicaciones , Dermatosis Facial/tratamiento farmacológico , Dermatosis Facial/cirugía , Femenino , Humanos , Enfermedades Pulmonares Fúngicas/complicaciones , Enfermedades Pulmonares Fúngicas/tratamiento farmacológico , Datos de Secuencia Molecular , Mucormicosis/tratamiento farmacológico , Mucormicosis/cirugía , Enfermedades Nasales/complicaciones , Enfermedades Nasales/tratamiento farmacológico , Enfermedades Nasales/cirugía , Análisis de Secuencia de ADN , Resultado del TratamientoRESUMEN
Tricalcium phosphate (TCP) has gained attention due to its interconnected porous structures which promote fibrovascular invasion and bony replacement. Moreover, when gelatin is added and crosslinked with genipin (GGT), TCP exhibits robust biocompatibility and stability, making it an excellent bone substitute. In this study, we incorporated emodin and lumbrokinase (LK) into GGT to develop an antibacterial biomaterial. Emodin, derived from various plants, possesses antibacterial and anti-inflammatory properties. LK comprises proteolytic enzymes extracted from the earthworm Lumbricus rubellus and exhibits fibrinolytic activity, enabling it to dissolve biofilms. Additionally, LK stimulates osteoblast activity while inhibiting osteoclast differentiation. GGT was combined with emodin and lumbrokinase to produce the GGTELK composite. The biomedical effects of GGTELK were assessed through in vitro assays and an ex vivo bone defect model. The GGTELK composite demonstrated antibacterial properties, inhibiting the growth of S. aureus and reducing biofilm formation. Moreover, it exhibited anti-inflammatory effects by reducing the secretion of IL-6 in both in vivo cell experiments and the ex vivo model. Therefore, the GGTELK composite, with its stability, efficient degradation, biocompatibility, and anti-inflammatory function, is expected to serve as an ideal bone substitute.
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BACKGROUND: Rectal cancer is one of the most common gastrointestinal malignancies, and most cases include locally advanced cancers at the time of diagnosis (stage II/III). OBJECTIVES: The purpose of this study is to observe the dynamic changes in the nutritional status of patients with locally advanced rectal cancer during concurrent radiation therapy and chemotherapy and to evaluate the nutritional risk and incidence of malnutrition in these patients. METHODS: A total of 60 patients with locally advanced rectal cancer were enrolled in this study. The 2002 Nutritional Risk Screening and Patient-Generated Subjective Global Assessment Scales (PG-SGA) were used to assess nutritional risk and status. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ) - C30 and QLQ-CR38 scales were used for the quality of life evaluation. Toxicity was evaluated using the CTC 3.0 standard. RESULTS: The incidence of nutritional risk among these 60 patients was 38.33% (23 of 60) before and 53% (32 of 60) after concurrent chemo-radiotherapy. There were 28 patients in the well-nourished group, with a PG-SGA score of <2 points, and 17 patients in the nutrition-changed group, with a PG-SGA score of <2 points before and 2 points during and after chemo-radiotherapy. In the well-nourished group, the incidence of nausea, vomiting and diarrhea mentioned in the summary was lower and the expectations for the future (according to the QLQ-CR30 and QLQ-CR28 scales) were higher than in the undernourished group. The undernourished group required delayed treatment more often and experienced nausea, vomiting and diarrhea earlier and for longer than the well-nourished group. These results show that the quality of life of the well-nourished group was better. CONCLUSIONS: There is a degree of nutritional risk and deficiency in patients with locally advanced rectal cancer. Chemoradiotherapy increases the incidence of nutritional risk and deficiencies. KEY WORDS: Enteral nutrition, Colorectal neoplasms, Quality of life, Chemo-radiotherapy, EORTC.
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Neoplasias Primarias Secundarias , Neoplasias del Recto , Humanos , Estado Nutricional , Calidad de Vida , Neoplasias del Recto/patología , Diarrea/etiología , Quimioradioterapia/efectos adversos , Neoplasias Primarias Secundarias/complicaciones , Vómitos , Náusea/complicacionesRESUMEN
The family of Papilionidae (Lepidoptera: Papilionoidea) is a group of butterflies with high ecological and conservation value. The Hengduan Mountains (HMDs) in Southwest China is an important diversity centre for these butterflies. However, the spatial distribution pattern and the climate vulnerability of Papilionidae butterflies in the HDMs remain unknown to date. The lack of such knowledge has already become an obstacle in formulating effective butterfly conservation strategies. The present research compiled a 59-species dataset with 1938 occurrence points. The Maxent model was applied to analyse the spatial pattern of species richness in subfamilies Parnassiinae and Papilioninae, as well as to predict the response under the influence of climate change. The spatial pattern of both subfamilies in the HDMs has obvious elevation prevalence, with Parnassiinae concentrated in the subalpine to alpine areas (2500-5500 m) in western Sichuan, northwestern Yunnan and eastern Tibet, while Papilioninae is concentrated in the low- to medium-elevation areas (1500-3500 m) in the river valleys of western Yunnan and western Sichuan. Under the influence of climate change, both subfamilies would exhibit northward and upward range shifts. The majority of Parnassiinae species would experience drastic habitat contraction, resulting in lower species richness across the HDMs. In contrast, most Papilioninae species would experience habitat expansion, and the species richness would also increase significantly. The findings of this research should provide new insights and a clue for butterfly diversity and climatic vulnerability in southwestern China. Future conservation efforts should be focused on species with habitat contraction, narrow-ranged distribution and endemicity with both in situ and ex situ measures, especially in protected areas. Commercialised collecting targeting these species must also be regulated by future legislation.
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Nuclear epidermal growth factor receptor (EGFR) has been shown to be correlated with drug resistance and a poor prognosis in patients with cancer. Previously, we have identified a tripartite nuclear localization signal (NLS) within EGFR. To comprehensively determine the functions and underlying mechanism of nuclear EGFR and its clinical implications, we aimed to explore the nuclear export signal (NES) sequence of EGFR that is responsible for interacting with the exportins. We combined in silico prediction with site-directed mutagenesis approaches and identified a putative NES motif of EGFR, which is located in amino acid residues 736-749. Mutation at leucine 747 (L747) in the EGFR NES led to increased nuclear accumulation of the protein via a less efficient release of the exportin CRM1. Interestingly, L747 with serine (L747S) and with proline (L747P) mutations were found in both tyrosine kinase inhibitor (TKI)-treated and -naïve patients with lung cancer who had acquired or de novo TKI resistance and a poor outcome. Reconstituted expression of the single NES mutant EGFRL747P or EGFRL747S, but not the dual mutant along with the internalization-defective or NLS mutation, in lung cancer cells promoted malignant phenotypes, including cell migration, invasiveness, TKI resistance, and tumor initiation, supporting an oncogenic role of nuclear EGFR. Intriguingly, cells with germline expression of the NES L747 mutant developed into B cell lymphoma. Mechanistically, nuclear EGFR signaling is required for sustaining nuclear activated STAT3, but not for Erk. These findings suggest that EGFR functions are compartmentalized and that nuclear EGFR signaling plays a crucial role in tumor malignant phenotypes, leading to tumorigenesis in human cancer.
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BACKGROUND: The understanding of epidermal growth factor receptor (EGFR) deregulation in carcinogenesis remains incomplete. We investigated the implications of EGFR gene status and EGFR nuclear translocation in gallbladder carcinoma (GBCA). METHODS: Subcellular localization of EGFR and phosphorylated EGFR (pEGFR) was analyzed by fractional immunoblotting and confocal immunofluorescence in GBCA cell lines. pEGFR binding to iNOS promoter was assessed by chromatin immunoprecipitation with iNOS promoter activity evaluated by luciferase assay. EGFR, pEGFR, and iNOS were immunohistochemically assessable for localization and level in the training set of 104 GBCAs on tissue microarrays, with 76 cases analyzed for EGFR gene by chromogenic in situ hybridization (CISH) and mutant-enriched PCR targeting exons 19 and 21. The prognostic impact of nuclear pEGFR (N-pEGFR) immunoexpression was reaffirmed on whole sections of 58 GBCAs in the test set. RESULTS: Nuclear expression of EGFR and pEGFR was substantiated in vitro with augmented activity of iNOS promoter elicited by pEGFR binding upon EGF treatment. Despite no mutation, EGFR amplification, identified in 11 cases (15%) by CISH, strongly correlated with cytoplasmic EGFR expression (P < 0.001) but not with disease-specific survival (DSS). Immunoexpression of nuclear EGFR (N-EGFR), cytoplasmic pEGFR, and N-pEGFR was strongly related to that of iNOS (all ≤0.005). N-pEGFR independently predicted worse DSS in both training (P = 0.0468, HR = 2.024) and test sets (P = 0.0223, HR = 5.573). CONCLUSIONS: N-EGFR and N-pEGFR express in GBCA, conferring clinical aggressiveness partly through iNOS transactivation. Lacking response-predicting mutation, EGFR gene status, albeit amplified in 15% of GBCA, is neither related to nuclear EGFR translocation nor prognostically useful.
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Adenocarcinoma/metabolismo , Carcinoma Papilar/metabolismo , Núcleo Celular/metabolismo , Receptores ErbB/metabolismo , Neoplasias de la Vesícula Biliar/metabolismo , Regulación Neoplásica de la Expresión Génica , Óxido Nítrico Sintasa de Tipo II/genética , Transporte Activo de Núcleo Celular , Adenocarcinoma/genética , Adenocarcinoma/mortalidad , Anciano , Western Blotting , Carcinoma Papilar/genética , Carcinoma Papilar/mortalidad , Inmunoprecipitación de Cromatina , Citoplasma/metabolismo , Receptores ErbB/genética , Femenino , Técnica del Anticuerpo Fluorescente , Neoplasias de la Vesícula Biliar/genética , Neoplasias de la Vesícula Biliar/mortalidad , Humanos , Técnicas para Inmunoenzimas , Hibridación in Situ , Luciferasas/metabolismo , Masculino , Mutación/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Fosforilación , Pronóstico , Regiones Promotoras Genéticas , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Tasa de Supervivencia , Células Tumorales Cultivadas , Regulación hacia ArribaRESUMEN
BACKGROUND: The current standards for the diagnosis and treatment of patients with COPD clearly rely on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria based on post-bronchodilator spirometric values. However, clinical evidence for using the post-bronchodilator FEV1 in the severity classification has not been fully investigated. METHODS: Patients with COPD were enrolled and followed up prospectively between October 2006 and January 2011. We compared the observed 3-year risk of all causes and respiratory mortality with the risk predicted by the pre- and post-bronchodilator percent predicted FEV1. Other important phenotypes including BMI, MMRC dyspnea scale, ECOG performance status and severe AECOPD (acute exacerbation) were also compared between the two groups. The different severity classifications of COPD, measured according the GOLD guidelines by post- and pre-bronchodilator percent predicted FEV1 were compared for prediction of mortality. RESULTS: There were 35 deaths among the 300 COPD patients (11.7%). Multivariate analysis showed that the post-bronchodilator percent predicted FEV1 was a significant independent predictor of mortality but pre-bronchodilator percent predicted FEV1 was not (p = 0.008 vs 0.126) and it was more strongly correlated with all studied predictors of outcome than the pre-bronchodilator percent predicted FEV1. Kaplan-Meier analysis showed that the discrimination ability to predict mortality from the GOLD criteria using post bronchodilator percent predicted FEV1 (p = 0.009) was better than using pre-bronchodilator percent predicted FEV1 (p = 0.131). CONCLUSIONS: The post-bronchodilator percent predicted FEV1 is better than the pre-bronchodilator percent predicted FEV1 in the evaluation of the severity of disease in COPD patients and is more accurate in predicting the risk of death by the GOLD classification.
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Broncodilatadores , Volumen Espiratorio Forzado , Enfermedad Pulmonar Obstructiva Crónica , Índice de Severidad de la Enfermedad , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Enfermedad Pulmonar Obstructiva Crónica/clasificación , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/mortalidad , Medición de Riesgo , EspirometríaRESUMEN
OBJECTIVE: To explore the association between the Helicobacter pylori (H. pylori) infection and the expression and methylation of energy-related genes in gastric cancer. METHODS: Real-time fluorescence quantitative reverse transcription (RT)-PCR was performed to quantify the expressions level of lactate dehydrogenase (LDH), dihydrolipoamide dehydrogenase (DLD) and Ran-specific GTPase-activating protein (RanGAP) genes in the samples of human gastric cancer (n = 30), metastatic lymph node (n = 30) and peri-cancerous tissues (n = 30) as confirmed by pathological examinations. Those patients were chosen of Affiliated Hospital of Guiyang Medical University, from January 2005 to December 2009. The relationship between the gene expression and H. pylori infection was analyzed. The methylation of LDH, DLD and RanGAP genes at promoter CpG island was measured by bisulfite sequencing (BSP). RESULTS: The relative gene expressions of LDH, DLD and RanGAP in peri-cancerous tissues, gastric cancer and metastatic lymph nodes were 1.0, 3.1, 3.0 and 1.0, 3.1, 2.8, and 1.0, 0.4, 0.5 respectively (all P < 0.05). The expression levels of LDH and DLD genes in H. pylori-positive gastric cancer was high than those in the negative group (2.3 vs 1.0, 3.0 vs 1.0, 2.6 vs 1.0, all P < 0.05). The demethylation of LDH and DLD genes at promoter -2325 and -1885 site as well as the over methylation of RanGAP gene at the promoter -570 and -170 sites respectively were detected in H. pylori infection and cagA-overexpressed cells. CONCLUSION: H. pylori infection may promote the development and progression of gastric cancer by inducing the aberrant methylation of LDH, DLD and RanGAP genes to up-regulate the gene expressions of LDH and DLD and down-regulate the gene expression of RanGAP.
Asunto(s)
Infecciones por Helicobacter/genética , Interacciones Huésped-Patógeno , Neoplasias Gástricas/genética , Neoplasias Gástricas/microbiología , Adulto , Anciano , Islas de CpG , Metilación de ADN , Dihidrolipoamida Deshidrogenasa/genética , Dihidrolipoamida Deshidrogenasa/metabolismo , Femenino , Proteínas Activadoras de GTPasa/genética , Proteínas Activadoras de GTPasa/metabolismo , Regulación Neoplásica de la Expresión Génica , Infecciones por Helicobacter/metabolismo , Helicobacter pylori , Humanos , Lactato Deshidrogenasas/genética , Lactato Deshidrogenasas/metabolismo , Masculino , Persona de Mediana Edad , Neoplasias Gástricas/metabolismo , Sitio de Iniciación de la TranscripciónRESUMEN
It's worth noting that detect effective methods for tracking ClO- could help us uncover the function of ClO- in living systems. Here, two coumarin-based probes, named (E)-3-(1-hydrazonoethyl)-2H-chromen-2-one (1A) and 3-((E)-1-(((E)-(2,3-dihydro-1H-imidazol-4-yl)methylene)-hydrazono)ethyl)- 2H-chromen-2-one (1B) with aggregation-induced emission (AIE) effect in Tris-HCl (pH = 7.2) buffer solution were synthesized and used for sensing ClO- selectivity. 1A and 1B responded to ClO- through the oxidation hydrolysis effect. The mechanism was further verified by HR-MS and DFT calculation. Cell imaging indicated that 1A and 1B were good membrane permeability with low toxicity to HEK293T, and expected to be used to detect ClO- in cells.