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Chemotherapies are commonly used in cancer therapy, their applications are limited to low specificity, severe adverse reactions, and long-term medication-induced drug resistance. Poly(ADP-ribose) polymerase (PARP) inhibitors are a novel class of antitumor drugs developed to solve these intractable problems based on the mechanism of DNA damage repair, which have been widely applied in the treatment of ovarian cancer, breast cancer, and other cancers through inducing synthetic lethal effect and trapping PARP-DNA complex in BRCA gene mutated cancer cells. In recent years, PARP inhibitors have been widely used in combination with various first-line chemotherapy drugs, targeted drugs and immune checkpoint inhibitors to expand the scope of clinical application. However, the intricate mechanisms underlying the drug resistance to PARP inhibitors, including the restoration of homologous recombination, stabilization of DNA replication forks, overexpression of drug efflux protein, and epigenetic modifications pose great challenges and desirability in the development of novel PARP inhibitors. In this review, we will focus on the mechanism, structure-activity relationship, and multidrug resistance associated with the representative PARP inhibitors. Furthermore, we aim to provide insights into the development prospects and emerging trends to offer guidance for the clinical application and inspiration for the development of novel PARP inhibitors and degraders.
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BACKGROUND/AIM: X-linked hypophosphatemia (XLH), the most common form of hereditary rickets, results from loss-of-function mutations in the phosphate-regulating PHEX gene. Elevated fibroblast growth factor 23 (FGF23) contributes to hypophosphatemia in XLH. This study aimed to characterize PHEX variants and serum FGF23 profiles in Taiwanese patients with XLH. PATIENTS AND METHODS: We retrospectively reviewed the records of 102 patients clinically suspected of having hypophosphatemic rickets from 2006 to 2022. Serum intact Fibroblast growth factor-23 (iFGF23) levels were measured on clinic visit days. PHEX mutations were identified using Sanger sequencing, and negative cases were analyzed using whole-exome sequencing. RESULTS: The majority (92.1%) of patients exhibited elevated FGF23 compared with normal individuals. Among 102 patients, 44 distinct PHEX mutations were identified. Several mutations recurred in multiple unrelated Taiwanese families. We discovered a high frequency of novel PHEX mutations and identified variants associated with extreme FGF23 elevation and tumorigenesis. CONCLUSION: Our findings revealed the PHEX genotypic variants and FGF23 levels in Taiwanese patients with XLH. These results are crucial given the recent approval of burosumab, a monoclonal FGF23 antibody, for XLH therapy. This study provides key insights into the clinical management of XLH in Taiwan.
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Raquitismo Hipofosfatémico Familiar , Humanos , Anticuerpos Monoclonales , Raquitismo Hipofosfatémico Familiar/genética , Raquitismo Hipofosfatémico Familiar/metabolismo , Factores de Crecimiento de Fibroblastos/genética , Factores de Crecimiento de Fibroblastos/metabolismo , Mutación , Recurrencia Local de Neoplasia , Endopeptidasa Neutra Reguladora de Fosfato PHEX/genética , Estudios RetrospectivosRESUMEN
The U.S. Food and Drug Administration has approved a total of 37 new drugs in 2022, which are composed of 20 chemical entities and 17 biologics. In particular, 20 chemical entities, including 17 small molecule drugs, 1 radiotherapy, and 2 diagnostic agents, provide privileged scaffolds, breakthrough clinical benefits, and a new mechanism of action for the discovery of more potent clinical candidates. The structure-based drug development with clear targets and fragment-based drug development with privileged scaffolds have always been the important modules in the field of drug discovery, which could easily bypass the patent protection and bring about improved biological activity. Therefore, we summarized the relevant valuable information about clinical application, mechanism of action, and chemical synthesis of 17 newly approved small molecule drugs in 2022. We hope this timely and comprehensive review could bring about creative and elegant inspiration on the synthetic methodologies and mechanism of action for the discovery of new drugs with novel chemical scaffolds and extended clinical indications.
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ETHNOPHARMACOLOGICAL RELEVANCE: The incidence of premature ovarian insufficiency (POI) is gradually increasing, the proportion is rising especially in female infertility patients. The risk of death of POI patients with cardiovascular disease also increases significantly. The cause of POI is complex and unclear, and clinical treatment is still in the exploratory stage, are two major constraints of treating POI. Traditional Chinese medicine (TCM) is widely used in the treatment of POI, and it is a good way to combine the development of modern new drugs with the help of TCM to predict the therapeutic targets. AIM OF THE STUDY: In this study, four herbs commonly used in clinical treatment of POI, namely Radix Paeoniae, Polygonatum sibiricum, Rehmannia glutinosa and Eucommia ulmoides were selected to predict their mechanism in the treatment of POI, using network pharmacology methods. Then verify the predicted targets by animal test. Aim to find more effective POI potential core treatment targets and main pathways. MATERIALS AND METHODS: We screened the active ingredients of drugs from the TCM System Pharmacology Analysis Platform (TCMSP), Performed target prediction of active ingredients from databases such as SwissTargetPrediction and compare and analyze the POI-related targets retrieved from them to obtain potential targets for drug treatment of POI. Used STRING database to construct a protein interaction network, Cytoscape 3.7.2 software to construct an active ingredient-target-pathway network, and DAVID database to conduct the Kyoto Encyclopedia of Genes and Genomes (KEGG) on the intersection targets and gene ontology (GO) enrichment analysis. RESULTS: The result is: there were 25 key targets for the treatment of POI with Radix Paeoniae Alba, 31 for the treatment of POI by Eucommia ulmoides, 28 for the treatment of POI by Polygonatum sibiricum, and 8 key targets for the treatment of Rehmannia glutinosa. The intersection targets of four herbs were defined as the core targets, which are CYP19A1, EGF, ESR1, ESR2, MDM2, AR, PCYP17A1, PPARG. Four Chinese herbs treat POI mainly through HIF-1 signaling pathway, PI3K-Akt signaling pathway, FoxO signaling pathway, Estrogen signaling pathway etc. A mouse model of POI was constructed based on the results of network pharmacology to verify the predicted targets. The results showed that the protein expression of the core target changed, and the estrogen level was increased by reducing the expression of peroxisome proliferator-activated receptor gamma (PPARG). CONCLUSIONS: This study predicts the mechanism of multiple herbs in the treatment of POI, screens out more potential therapeutic drug targets and main pathways of POI treatment and provides new ideas for the subsequent development of POI therapeutic drugs.
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Medicamentos Herbarios Chinos , Menopausia Prematura , Insuficiencia Ovárica Primaria , Femenino , Animales , Ratones , Humanos , Farmacología en Red , PPAR gamma , Fosfatidilinositol 3-Quinasas , Insuficiencia Ovárica Primaria/tratamiento farmacológico , Estrógenos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Simulación del Acoplamiento Molecular , Medicina Tradicional ChinaRESUMEN
In this study, CiteSpace was used to conduct bibliometric statistics and visualization of the research papers on the exosomes in traditional Chinese medicine(TCM) and application status in CNKI, Wanfang, VIP, and Web of Science. The authors, research institutions, and keywords of the relevant papers were analyzed to summarize the research status, hotspots, and development trends of TCM application of exosomes, thereby providing references for future research. A total of 340 Chinese papers and 9 English papers were included. In Chinese papers, GUO Hai-dong is the author with the largest amount of research papers, and his research interest is the mechanism of electroacupuncture in promoting functional recovery after sciatic nerve injury by regulating the release of exosomes. Shanghai University of Traditional Chinese Medicine is the research institution with the largest amount of papers, followed by Nanjing University of Chinese Medicine and Hunan University of Chinese Medicine. There was less cooperation among these research institutions, and cooperation between teams and agencies should be strengthened. The overall volume of publications in English was comparatively small, and the connections between the authors were weak. The publishing organizations were mostly distributed in medical schools, hospitals, comprehensive universities, and the cooperation between institutions was scattered. The main keywords in Chinese papers include microRNA, mesenchymal stem cells, bone marrow mesenchymal stem cells, mechanism of action, and extracellular vesicles. The research of exosomes in TCM is increasing in recent years. The research hotspot is that exosomes can both serve as biomarkers for the diagnosis and prognosis of certain diseases in TCM and drug carriers of Chinese medicine for targeted treatment of diseases. Keyword prominence suggested that exosomes derived from osteoblasts and macrophages in the treatment of diseases might still be a future research trend.
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Exosomas , Medicina Tradicional China , Bibliometría , China , PublicacionesRESUMEN
BACKGROUND: Prenatal anxiety is a common concern which may have adverse effects on maternal and infant health outcomes. Studies addressing needs-based education interventions for prenatal anxiety are limited. AIM: To explore the effects of needs-based education on alleviating prenatal anxiety among advanced multiparas when compared with routine prenatal health education. METHODS: A total of 86 advanced multiparas were randomized into the intervention group (n = 43) or the control group (n = 43) in this study. The control group received routine prenatal care. The intervention group received five needs-based education programs presented by trained researchers. The Pregnancy-related Anxiety Questionnaire was used to evaluate changes in anxiety level of participants. Concurrent physiological parameters, including blood pressure, heart rate and non-stress test were also measured. RESULTS: Scores on the Pregnancy-related Anxiety Questionnaire of the intervention group were significantly lower than those of the control group (t = 4.21, P < 0.05). Systolic blood pressure (t = 3.64, P < 0.05) and heart rate (t = 2.39, P < 0.05) of the intervention group were also significantly lower than the control group whereas no differences were noted in diastolic blood pressure and non-stress test. CONCLUSION: A needs-based education program is an effective intervention strategy to allay prenatal anxiety in advanced multiparas. TRIAL REGISTRATION: The trial was retrospectively registered in the Chinese Clinical Trial Registry as number ChiCTR2100047552 .
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Ansiedad , Atención Prenatal , Ansiedad/terapia , Trastornos de Ansiedad , Femenino , Educación en Salud , Frecuencia Cardíaca/fisiología , Humanos , EmbarazoRESUMEN
As a class of novel biomaterials manufactured by synthetic biology technologies, recombinant collagens are candidates for a variety of medical applications. In this article, a regulatory scientific perspective on recombinant collagens and their medical devices is presented with a focus on the definition, translation, classification and technical review. Recombinant collagens are categorized as recombinant human collagen, recombinant humanized collagen and recombinant collagen-like protein, as differentiated by specific compositions and structures. Based on their intended uses and associated risks, recombinant collagen-based medical devices are generally classified as Class â ¡ or â ¢ in China. The regulatory review of recombinant collagen-based medical devices aims to assess their safety and efficacy demonstrated by scientific evidences generated from preclinical and clinical evaluations. Taken together, opportunities as well as challenges for their future clinical translation of recombinant collagen-based medical devices abound, which highlights the essential role of regulatory science to provide new tools, standards, guidelines and methods to evaluate the safety and efficacy of medical products.
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As one of the most challenging inflammatory diseases, the incidence of ulcerative colitis (UC) is increasing year by year, but the existing therapeutic drugs are not effective and lack of targeting. Nanomaterials are expected to become promising delivery system due to their good targeting effects. Here, we designed a nanomaterial sensitive to reactive oxygen species, which can be used to treat IBD, especially UC. It is a self-assembled polyether micelle that can be oxidized at the inflammation site where the concentration of reactive oxygen increases, and effectively release the encapsulated budesonide (Bud). Experiments have proved that for DSS-induced colitis, the synthetic drug-loaded nanoparticles have excellent therapeutic effects, can effectively repair intestinal barrier, and significantly improve the damaged colon tissue. At the same time, it has a beneficial regulatory effect on inflammatory factors. Molecular mechanism studies have shown that it achieves its therapeutic effects by activating the peroxisome proliferators-activated receptors-γ (PPAR-γ) pathway and inhibiting the nuclear factor (NF)-κB pathway. This study proves that oral nano-micelles have an important impact on improving the efficacy of UC treatment drugs and have far-reaching significance for the targeted treatment of gastrointestinal diseases.
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Colitis Ulcerosa , Nanoestructuras , Animales , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/metabolismo , Colon/metabolismo , Sulfato de Dextran/efectos adversos , Modelos Animales de Enfermedad , Micelas , FN-kappa B/metabolismo , Especies Reactivas de OxígenoRESUMEN
BACKGROUND: As an early complication after liver transplantation, early allograft dysfunction (EAD) indicates a poor prognosis. This study analyzes the risk factors related to early allograft dysfunction (EAD) after liver transplantation using grafts from donation after citizen death (DCD) to provide a reference for the prevention of EAD after DCD liver transplantation. METHODS: A total of 32 patients who underwent DCD liver transplantation in the organ transplantation center of our hospital from September 2013 to January 2021 were enrolled in this study. The patients were divided into the EAD group and non-EAD group according to whether they developed EAD after transplantation. The general data of the donors and recipients before transplantation, intraoperative conditions, and clinical data within one week after transplantation were compared between the two groups, and related complications were statistically analyzed. The follow-up time was one week postoperatively or, if they died within the first week postoperatively, until the patient died. RESULTS: The subjects included 10 females and 22 males, and the incidence of postoperative EAD was 25% (8/32). Four patients (12%) had primary malignant tumors (primary liver cancer and cholangiocarcinoma), and five donors (15%) had fatty liver. The univariate analysis revealed that the donor BMI (P = 0.005), degree of fatty liver (P = 0.025), aspartate aminotransferase (P = 0.001), alanine aminotransferase (P < 0.001), and total bilirubin (P = 0.009) were related to the occurrence of EAD after DCD liver transplantation. By analyzing the correlation between the incidence EAD and postoperative complications after liver transplantation using grafts from DCD donors, it was shown that the incidence of primary nonfunction (PNF) is related to EAD (P = 0.024). CONCLUSION: Donor BMI, the degree of fatty liver, and preoperative liver function are risk factors for EAD after DCD liver transplantation, and the occurrence of EAD after DCD liver transplantation significantly increases the probability of PNF.
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Hígado Graso , Hepatopatías , Trasplante de Hígado , Hígado Graso/etiología , Femenino , Supervivencia de Injerto , Humanos , Trasplante de Hígado/efectos adversos , Masculino , Estudios Retrospectivos , Factores de Riesgo , Donantes de Tejidos , Resultado del TratamientoRESUMEN
OBJECTIVE: This study aims to summarize a clinical experience on the diagnosis and treatment of acute graft-versus-host disease (aGVHD) after liver transplantation. METHODS: Between April 2005 and August 2016, 11 recipients who underwent OLT developed aGVHD with clinical symptoms of fever, rash, diarrhea and pancytopenia. T lymphocyte chimerism was detected though STR-PCR. These patients were treated with immunosuppressant adjustment, methylprednisolone, basiliximab, etc. All the results were recorded and summarized. RESULTS: We demonstrated the diagnostic criteria of aGVHD based on our experiences: 1 aGVHD occurred from two weeks to two months after the liver transplantation. Fever, rash, digestive tract symptoms and bone marrow suppression were the four symptoms that appeared in any orde, All the percentages of donor T lymphocytes of aGVHD patients were more than 10%. All 11 recipients underwent treatments including immunosuppressant adjustment, glucocorticoids, IVIG and organ function support. Among these recipients, two survived due to successful treatment, while nine recipients died due to infection and cerebral and digestive tract hemorrhage. It is noteworthy that the occurrence of aGVHD was related to the dose of immunosuppressive agents, and we suggest the concept of "aGVHD induced by immunosuppression". CONCLUSIONS: The diagnostic criteria of aGVHD is mainly based on time, clinical symptoms, T-lymphocyte chimerism and histopathology. The concept of "aGVHD induced by immunosuppression" provides important guidance in immunosuppressant management, control, and prevention of infection. Support treatment is very important in the treatment of aGVHD.
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Basiliximab/uso terapéutico , Enfermedad Injerto contra Huésped/diagnóstico , Inmunosupresores/uso terapéutico , Trasplante de Hígado , Metilprednisolona/uso terapéutico , Complicaciones Posoperatorias/diagnóstico , Linfocitos T/inmunología , Enfermedad Aguda , Adulto , Anciano , Quimerismo , Femenino , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/tratamiento farmacológico , Complicaciones Posoperatorias/mortalidad , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Direct relationships between biological molecules connected in a gene co-expression network tend to reflect real biological activities such as gene regulation, protein-protein interactions (PPIs), and metabolisation. As correlation-based networks contain numerous indirect connections, those direct relationships are always 'hidden' in them. Compared with the global network, network communities imply more biological significance on predicting protein function, detecting protein complexes and studying network evolution. Therefore, identifying direct relationships in communities is a pervasive and important topic in the biological sciences. Unfortunately, this field has not been well studied. A major thrust of this study is to apply a deconvolution algorithm on communities stemming from different gene co-expression networks, which are constructed by fixing different thresholds for robustness analysis. Using the fifth Dialogue on Reverse Engineering Assessment and Methods challenge (DREAM5) framework, the authors demonstrate that nearly all new communities extracted from a 'deconvolution filter' contain more genuine PPIs than before deconvolution.
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Biología Computacional/métodos , Redes Reguladoras de Genes , Mapeo de Interacción de Proteínas/métodos , AlgoritmosRESUMEN
BACKGROUND: The long-term administration of nucleotide analogues (NAs) and hepatitis B immune globulin (HBIG) comprises standard prophylaxis for patients with hepatitis B virus (HBV)-related liver diseases to prevent HBV reinfection after liver transplantation (LT). However, prolonging the prophylaxis strategy involves safety issues, such as the development of escape mutations and/or emerging resistant strains, and is also associated with high costs; further, it remains unclear how long prophylactic treatment should be continued. METHOD: Liver transplantation recipients responding to hepatitis B vaccination due to HBV-related liver diseases were retrospectively analysed after stopping HBIG and/or NAs, administered to prevent HBV reinfection, after long-term follow-up. The safety and effectiveness of the strategy were then evaluated for these responders. RESULT: Seventy-eight responders were enrolled. All responders discontinued HBIG, among which 36 stopped both HBIG and NAs. During follow-up, four recipients experienced HBV reinfection, which was associated with HBV escape mutations, after the withdrawal of both HBIG and NAs. No death or graft loss occurred in recipients during the follow-up period. CONCLUSION: A careful withdrawal of HBIG and/or NAs is feasible and safe for responders to hepatitis B vaccination receiving transplants for HBV-related liver diseases.
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Vacunas contra Hepatitis B/administración & dosificación , Hepatitis B/prevención & control , Trasplante de Hígado , Privación de Tratamiento , Adulto , Anciano , Antivirales/administración & dosificación , Femenino , Estudios de Seguimiento , Hepatitis B/etiología , Vacunas contra Hepatitis B/inmunología , Humanos , Inmunoglobulinas/administración & dosificación , Trasplante de Hígado/efectos adversos , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Factores de TiempoRESUMEN
BACKGROUND: Pathological manifestations of hepatic tumours are often associated with prognosis. Although surgical specimens (SS) can provide more information, currently, pre-treatment needle core biopsy (NCB) is increasingly showing important value in understanding the nature of liver tumors and even in diagnosis and treatment decisions. However, the concordance of the clinicopathological characteristics and immunohistochemical (IHC) staining between NCB and SS from patients with hepatic tumours were less concerned. AIM: To introduce a more accurate method for interpreting the IHC staining results in order to improve the diagnostic value of hepatic malignancy in NCB samples. METHOD: A total of 208 patients who underwent both preoperative NCB and surgical resection for hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC) between 2008 and 2015 were enrolled in this study. The expression of CK19, GPC3, and HepPar1 were detected by IHC staining. Clinicopathological, NCB, and surgical data were collected and analysed using χ 2 and kappa statistics. RESULTS: Morphologically, the presence of compact tumour nests or a cord-like structure in NCB was considered the primary cause of misdiagnosis of HCC from ICC. The kappa statistic showed a moderate agreement in histomorphology (k = 0.504) and histological grade (k = 0.488) between NCB and SS of the tumours. A 4-tier (+++, ++, +, and -) scoring scheme that emphasized the focal neoplastic cell immunoreactivity of tumour cells revealed perfect concordance of CK19, GPC3 and HepPar1 between NCB and SS (k = 0.717; k = 0.768; k = 0.633). Furthermore, with the aid of a binary classification derived from the 4-tier score, a high concordance was achieved in interpreting the IHC staining of the three markers between NCB and final SS (k = 0.931; k = 0.907; k = 0.803), increasing the accuracy of NCB diagnosis C (k = 0.987; area under the curve = 0.997, 95%CI: 0.990-1.000; P < 0.001). CONCLUSION: These findings imply that reasonable interpretation of IHC results in NCB is vital for improving the accuracy of tumour diagnosis. The simplified binary classification provides an easy and applicable approach.
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BACKGROUND: Glutaric aciduria type 1 (GA-1) is an organic acidemia with potentially severe neurological sequelae. In Taiwan, newborn screening (NBS) for GA-1 began in 2001, but large-scale reporting is lacking. This study describes Taiwan's largest newborn screening population to date. METHODS: Between 2001 and 2015, 1,490,636 newborns were screened for GA-1. Confirmatory examinations included the carnitine loading test. Confirmed patients were treated with a low lysine diet, carnitine, and high-energy intake during illness. Clinical, laboratory, and neuroimaging data were analyzed. RESULTS: Fourteen newborns were diagnosed with GA-1 (incidence: 1/106,474). C5DC concentration was clearly increased after carnitine loading in the affected newborns, but not in false-positive newborns (p = 0.004), indicating that this test is useful as an adjuvant diagnostic method. Eleven patients followed in our hospital were enrolled, namely nine NBS patients and two patients diagnosed clinically. IVS10-2A>C was the most common mutation. Two novel mutations (T36fs and N291K) were identified. Pendular nystagmus was found in two pediatric GA-1 patients. The corresponding pathology was optic atrophy in one patient, but remained undetermined in the other patient. The frequency of encephalopathic crisis decreased substantially following NBS. Among patients diagnosed by NBS, cognitive functioning was better among patients with good compliance than patients with poor compliance (p = 0.03). Abnormalities were detected by brain MRI including diffusion-weighted imaging and apparent diffusion coefficient maps; these affected various brain regions at different stages of the disease. Basal ganglion injuries occurred after an encephalopathic crisis. White matter disease was prevalent among older patients, either with or without an encephalopathic crisis. CONCLUSION: Early diagnosis by newborn screening followed by full compliance with treatment guidelines is important to a good outcome.
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Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Encefalopatías Metabólicas/diagnóstico , Glutaril-CoA Deshidrogenasa/deficiencia , Tamizaje Neonatal , Errores Innatos del Metabolismo de los Aminoácidos/complicaciones , Errores Innatos del Metabolismo de los Aminoácidos/terapia , Encefalopatías Metabólicas/complicaciones , Encefalopatías Metabólicas/terapia , Femenino , Genotipo , Humanos , Recién Nacido , Imagen por Resonancia Magnética , Masculino , FenotipoRESUMEN
Prompt and accurate prediction of the outcome is the key to make correct medical decision and to reduce the mortality in patients with HBV-related acute-on-chronic liver failure (ACLF). Increasing evidence have certified that small, noncoding microRNAs (miRNAs) play critically regulatory roles in the pathogenesis of liver diseases. However, it remains unclear whether and how miRNAs involve in the prognosis of ACLF.Microarray analysis was performed to characterize the miRNA expression profiles in liver tissues from 1 HBV-related ACLF patient and 1 matched healthy control. Nine miRNAs with at least 5 folds difference between these 2 persons were picked out. The present prospective study involving 39 HBV-related ACLF patients including 20 recovered and 19 nonrecovered patients, which include death (nâ=â9) and liver transplantation (nâ=â10). The serum expression of these miRNAs detected by quantitative real-time Polymerase Chain Reaction (qRT-RCR) was then compared between the 2 groups. Moreover, the correlation between the serum miRNAs and the prognostic indexes for ACLF was analyzed.The result of microarray analysis showed 9 miRNAs had different expression in liver tissues of ACLF patient compared with healthy control (upregulated: miRNA-130a, -21, -143, and -200a; downregulated: miRNA-486-5p, -192, -148a, -122, and -194). Unlike the expression profiles in liver tissue, 8 serum miRNAs except miRNA-194 were markedly upregulated in ACLF patients (Pâ<â0.05). Remarkably, the serum expression of miRNA-130a and miRNA-486-5p was higher in recovered than nonrecovered ACLF patients (Pâ<â0.05). Especially, the serum miRNA-130a was negatively correlated with international normalized ratio, prothrombin time, Model for End-Stage Liver Disease score, and positively correlated with prothrombin time activity. The AUC for recovered versus nonrecovered patients of miRNA-130a was 0.741 (Pâ=â0.02).miRNA-130a might be a useful prognosis biomarker in patients with HBV-related ACLF.
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Insuficiencia Hepática Crónica Agudizada/genética , Insuficiencia Hepática Crónica Agudizada/virología , Hepatitis B Crónica/complicaciones , MicroARNs/genética , Insuficiencia Hepática Crónica Agudizada/sangre , Insuficiencia Hepática Crónica Agudizada/mortalidad , Adulto , Femenino , Regulación de la Expresión Génica , Humanos , Masculino , MicroARNs/sangre , Pronóstico , Estudios Prospectivos , Tasa de Supervivencia , Regulación hacia ArribaRESUMEN
Our knowledge about pathophysiology of intracerebral hemorrhage (ICH) mainly originates from preclinical models of ICH. In this study, cerebral ultrastructure surrounding hematoma and its correlation with clinical severity were investigated in ICH patients. Thirty patients with basal ganglia hemorrhage and 6 control subjects were enrolled. Surgical evacuation was performed for patients with a blood loss >30 ml. Stroke severity was assessed using the Glasgow Coma Scale (GCS) and the National Institute of Health Stroke Scale (NIHSS). Transmission electron microscopy (TEM) was used to evaluate the ultrastructural characteristics of tissue specimens. Neural cells surrounding the hematomas showed evidence of cell swelling and necrosis. Decreased numbers of organelles and mitochondrial cristae were accompanied by cytoplasmic vacuolization, nuclear membrane invagination and breakdown, and intranuclear chromatic agglutination. These changes resulted in disintegration together with malacia, disappearance of the nucleus and nucleolus, and karyopyknosis. More serious ultrastructural damage was seen in patients with greater NIHSS scores, lower GCS scores, and greater bleeding volumes (p < 0.001). These findings suggest that neural cells undergo unfavorable ultrastructural changes that are responsible for dysfunction after ICH.
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Hemorragia de los Ganglios Basales/patología , Encéfalo/ultraestructura , Adulto , Anciano , Femenino , Escala de Coma de Glasgow , Hematoma/patología , Humanos , Masculino , Microscopía Electrónica de Transmisión , Persona de Mediana Edad , Accidente Cerebrovascular/patologíaRESUMEN
OBJECTIVE: To investigate the pathogenesis of ischemic-type biliary lesions (ITBLs) in post-liver transplant patients and the possible therapeutic mechanisms of sirolimus. METHODS: The clinic data of 32 post-liver transplant patients with ITBLs from May 2004 to December 2010 was analyzed. There were including 25 male and 7 female patients with a median age of 46 years (ranging from 19 to 61 years). Patients were divided into those who received sirolimus (sirolimus group) and those who did not (control group). The expression of IL-2, FoxP3, and IL-10 in the portal area, liver function indexes, and bile duct injury score were assessed pre-ITBL, when ITBLs were identified, and after 6 months of sirolimus treatment. RESULTS: Compared with pre-ITBL optical density (OD) values, there was a significantly increase in IL-2 OD(0.138 ± 0.050 in control group and 0.141 ± 0.052 in sirolimus group), but not FoxP3 and IL-10 OD in both groups at the time ITBLs were diagnosed. After 6 months of treatment, the IL-2, FoxP3, and IL-10 OD values in the control group were not different from those when ITBLs were diagnosed. There was a significant reduction in post-therapy IL-2 OD(0.107 ± 0.043, t = 2.087, P = 0.044), and a significant elevation in FoxP3(0.213 ± 0.039) and IL-10 OD(0.187 ± 0.048) in sirolimus group as compared with those when ITBLs were diagnosed(t = -3.822 and -4.350, both P < 0.01). There was a significant increase in serum levels of ALT, AST, total bilirubin, γ-glutamyl transpeptidase and ALP at the time ITBLs were diagnosed compared with pre-ITBL levels in both groups. After 6 months of treatment, the above indexes had not changed in the control group, but significantly improved in the sirolimus group, and the bile duct injury score in the sirolimus group had significantly decreased(4.4 ± 2.4, Z = -2.568, P = 0.010). The 1-year and 3-year graft survival rates in the control group were 6/13 and 5/13, respectively, and 17/19 and 13/19, respectively, in the sirolimus group (χ(2) = 7.166, P = 0.007; χ(2) = 5.398, P = 0.020, respectively). CONCLUSIONS: Sirolimus can downregulate IL-2 expression and upregulate FoxP3 and IL-10 expression, thereby stimulating FoxP3+ Treg cells, suppressing immunopathological damage, and promoting epithelial repair in bile ducts.
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Enfermedades de los Conductos Biliares/tratamiento farmacológico , Isquemia/dietoterapia , Complicaciones Posoperatorias/tratamiento farmacológico , Sirolimus/uso terapéutico , Adulto , Femenino , Factores de Transcripción Forkhead/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Interleucina-10/metabolismo , Interleucina-2/metabolismo , Trasplante de Hígado , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Acute-on-chronic liver failure (ACLF) is a severe clinical condition for which liver transplantation (LT) is the only curative option. However, there are little published data on risk factors and outcomes of LT for ACLF. METHODS: The objective of this study was to analyze preoperative, intraoperative, postoperative, and overall survival data on 100 consecutive cases with ACLF in order to try to determine for which patients LT are futile. RESULTS: One hundred consecutive patients with pathology-confirmed ACLF who underwent LT from June 2004 to September 2012 were enrolled. The preoperative data showed that all patients were in a serious condition with a median high model for end-stage liver disease (MELD) score of 32, total bilirubin of 440.20 umol/L, international normalized ratio (INR) of 3.012, and at least one organ dysfunction as assessed by a Sequential Organ Failure Assessment (SOFA) score of ≥9. The patients had either deceased or a living donor LT with an overall mortality of 20%. The 1-, 3-, and 5-year cumulative survival rates were 76.8%, 75.6%, and 74.1%, respectively, and graft 1-, 3-, and 5-y accumulative survival rates were 73.3%, 72.1%, and 70.6%, respectively. However, the area under receiver operating characteristic of SOFA score, MELD score, as well as Child-Pugh score were 0.552, 0.547, and 0.547, respectively. CONCLUSIONS: Both deceased and living donor LT are effective therapeutic options for patients with ACLF and the short- and long-term survival rates are encouraging. It is important to conduct more prospective and multi-center studies to define preoperatively which patients would benefit from LT.
Asunto(s)
Enfermedad Hepática en Estado Terminal/cirugía , Fallo Hepático Agudo/cirugía , Trasplante de Hígado , Adulto , Enfermedad Hepática en Estado Terminal/mortalidad , Femenino , Humanos , Fallo Hepático Agudo/mortalidad , Donadores Vivos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia , Donantes de Tejidos , Resultado del TratamientoRESUMEN
We hypothesized that responses to growth hormone (GH) therapy by idiopathic short stature (ISS) and growth hormone deficiency (GHD) patients were associated with single nucleotide polymorphisms (SNPs) in the leptin (LEP) and leptin receptor (LEPR) genes. We retrospectively enrolled ISS (n = 32) and GHD (n = 38) patients and forty healthy age-and gender-matched children. They were genotyped for the LEP promoter at nt.-2548, and LEPR K109R and LEPR Q223R polymorphisms. Clinical and laboratory variables were determined before and after 2 years of GH treatment. ISS patients with G/A or A/A genotypes of the LEPR Q223R SNP had a significantly higher height velocity (cm/y) than ISS patients with the G/G genotype at 2 years after GH treatment. For GHD patients, G/A or A/A genotype of the LEPR K109R SNP was associated with higher body weight, higher BMI, and higher weight velocity than patients with the G/G genotype before GH treatment, but not after GH treatment. G/A or A/A genotype of the LEPR Q223R SNP was associated with a significantly higher body weight, higher height velocity before treatment, but not after GH treatment. G/A or A/A genotype of the LEPR Q223R SNP was associated with a significantly higher weight velocity before treatment, but a significantly lower weight velocity was found at 2 years after GH treatment. These results suggest LEPR Q223R SNP (rs1137101) is associated with outcomes of GH replacement therapy in ISS and GHD patients.