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1.
J Formos Med Assoc ; 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33012636

RESUMO

In Taiwan, the incidence and prevalence of psoriatic arthritis (PsA) have risen significantly in recent years. Moreover, data from the Taiwan National Health Insurance Research Database (NHIRD) show that more than 85% of PsA patients are treated with just non-steroidal anti-inflammatory drugs (NSAIDs) and/or conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). Taiwanese clinicians have also expressed concerns regarding uncertainties in the diagnosis of PsA and the delayed, interrupted, and/or tapered use of biologics, as well as differences in therapeutic preferences between and within dermatologists and rheumatologists. To address these issues, the Taiwan Rheumatology Association and the Taiwanese Association for Psoriasis and Skin Immunology jointly convened a committee of 28 clinicians from the fields of rheumatology, dermatology, orthopedics, and rehabilitation, to develop evidence-based consensus recommendations for the practical management of PsA in Taiwan. A total of six overarching principles and 13 recommendations were developed and approved, as well as a treatment algorithm with four separate tracks for axial PsA, peripheral PsA, enthesitis, and dactylitis. Psoriasis (PsO) management was not discussed here, as the Taiwanese Dermatological Association has recently published a comprehensive consensus statement on the management of PsO. Together, these recommendations provide an up-to-date, evidence-based framework for PsA care in Taiwan.

2.
Nat Commun ; 11(1): 4947, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33009392

RESUMO

Pseudomonas syringae is a Gram-negative and model pathogenic bacterium that causes plant diseases worldwide. Here, we set out to identify binding motifs for all 301 annotated transcription factors (TFs) of P. syringae using HT-SELEX. We successfully identify binding motifs for 100 TFs. We map functional interactions between the TFs and their targets in virulence-associated pathways, and validate many of these interactions and functions using additional methods such as ChIP-seq, electrophoretic mobility shift assay (EMSA), RT-qPCR, and reporter assays. Our work identifies 25 virulence-associated master regulators, 14 of which had not been characterized as TFs before.


Assuntos
Proteínas de Bactérias/metabolismo , DNA Bacteriano/metabolismo , Pseudomonas syringae/metabolismo , Fatores de Transcrição/metabolismo , Sistemas de Secreção Bacterianos , Sítios de Ligação , Matrizes de Pontuação de Posição Específica , Ligação Proteica , Multimerização Proteica , Pseudomonas syringae/patogenicidade , Reprodutibilidade dos Testes , Técnica de Seleção de Aptâmeros , Virulência
3.
Cell Biol Int ; 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33049093

RESUMO

Non-small-cell lung cancer (NSCLC) is one of the most common malignancies, and the occurrence of drug-resistance severely limits the efficacy of anticancer drugs in the treatment of NSCLC. Identification of new agents to reverse drug-resistance in NSCLC treatment is of great importance and urgency both clinically and scientifically. In the present study, we found that A549/Taxol cells displayed a high level of resistance to paclitaxel with the resistance index up to 231. Importantly, esomeprazole could potentiate the antiproliferative effect of paclitaxel in A549/Taxol cells, but not in A549 cells. Further exploration on the underlying mechanisms revealed that esomeprazole decreased the intracellular pH via inhibiting V-ATPase expression in A549/Taxol cells. Meanwhile, esomeprazole pretreatment significantly promoted paclitaxel-induced polymerization of tubulin and enhanced the proportion of G2/M-arrested cells in A549/Taxol cells. Unfortunately, esomeprazole could only result in a slight decrease in the expression of P-gp in A549/Taxol cells. Interestingly, esomeprazole significantly increased paclitaxel-induced apoptosis, which was impeded by the autophagy inhibitor 3-MA in A549/Taxol cells. Taken together, our data suggest that esomeprazole is a promising chemosensitizer against paclitaxel-resistant NSCLC by inducing autophagy. Our study also offers a new strategy to solve the paclitaxel-resistance problem during NSCLC treatment.

4.
Orphanet J Rare Dis ; 15(1): 288, 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33054853

RESUMO

BACKGROUND: Isolated macrodactyly is a severe congenital hand anomaly with functional and physiological impact. Known causative genes include PIK3CA, AKT1 and PTEN. The aim of this study is to gain insights into the genetics basis of isolated macrodactyly. RESULTS: We enrolled 24 patients with isolated macrodactyly. Four of them were diagnosed with Proteus syndrome based on skin presentations characteristic to this disease. Targeted next-generation sequencing was performed using patients' blood and affected tissues. Overall, 20 patients carry mosaic PIK3CA pathogenic variants, i.e. p.His1047Arg (N = 7), p.Glu542Lys (N = 6), p.Glu545Lys (N = 2), p.His1047Leu (N = 2), p.Glu453Lys (N = 1), p.Gln546Lys (N = 1) and p.His1047Tyr (N = 1). Four patients who met the diagnostic criteria of Proteus syndrome carry mosaic AKT1 p.Glu17Lys variant. Variant allele frequencies of these mosaic variants obtained through next-generation sequencing range from 10 to 33%. In genotype-phenotype correlation analysis of patients with PIK3CA variant, we found that patients with the macrodactyly of the lower limbs tend to carry PIK3CA variants located in the helical domain (P = 0.005). CONCLUSIONS: Mosaic PIK3CA and AKT1 variants can be found in all of our samples with isolated macrodactyly. Insights into phenotypic and genetic spectrum of isolated macrodactyly may be helpful in perusing a more precise and effective management of isolated macrodactyly.

5.
Medicine (Baltimore) ; 99(42): e22599, 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33080693

RESUMO

INTRODUCTION: Whether there is the long-term effect of acupuncture on patients with knee osteoarthritis (KOA) or not is controversial. According to the basic theory of traditional acupuncture, deqi is the key to the efficacy of acupuncture. This randomized controlled trial aims to evaluate the existence of long-term effects caused by deqi in patients with KOA. METHODS AND ANALYSIS: A three-armed, parallel-design, randomized controlled trial is underway in China.108 KOA patients recruited by the rehabilitation center of the First Affiliated Hospital of Henan University of Traditional Chinese Medicine will be randomly assigned to the acupuncture with deqi group (A group), the acupuncture without deqi group (B group) and the waiting-list group (C group). Each patient will receive 5 30-minute sessions per week for 4 consecutive weeks and rest for 2 days between treatments, and undergo a 20-week follow-up. The primary outcome is the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC score). The secondary outcomes include Western Ontario and McMaster Universities Osteoarthritis index (WOMAC score), Knee Injury and Osteoarthritis Outcome Score (KOOS), arthritis quality of life measurement scale simplified scale (AIMS2-SF), emotional monitoring and expectation scale. The pain visual analogue scale (VAS) and the Chinese version of modified Massachusetts General Hospital Acupuncture Sensation Scale (C-MMASS) will be used to evaluate the deqi sensation after each acupuncture treatment. At the same time, adverse events (AEs) occurred in the whole process will be recorded and analyzed. We will perform an intention-to-treat analysis and protocol (PP) analysis to statistically analyze the results of the trial. DISCUSSION: This trial will be useful to study the long-term effect of acupuncture and the influence of the deqi sensation on the long-term in the treatment of KOA, and to provide a clinical basis for treatment of patients with mild to moderate knee osteoarthritis in clinic. TRIAL REGISTRATION: Chinese Clinical Trial Registry, IDF: ChiCTR2000029291. Registered on January 21, 2020.

6.
Artigo em Inglês | MEDLINE | ID: mdl-33020921

RESUMO

OBJECTIVE: To investigate the relationship between single/multiple HPV infections and cervical lesions, and the correlation between viral load and the degree of cervical lesions. METHODS: A total of 27 284 patients who underwent testing for HPV were retrospectively screened and 3728 women were enrolled who tested positive for HPV when examined by liquid-based ThinPrep cervical smear cytology test and diagnosed by histopathology at the Shanxi Provincial People's Hospital between May 2017 and March 2019. The genotype and viral load of HPV were determined by fluorescence quantitative polymerase chain reaction. Based on the pathological grade, the cervical lesions were stratified into three groups: chronic cervicitis/cervical intraepithelial neoplasia (CIN) I; CIN II/CIN III; and cervical cancer. RESULTS: There were significant intergroup differences in the distribution of single and multiple HPV infections. There was a positive correlation between the viral load and cervical pathological grade when the infections were caused by HPV 16, 18, 31, 33, 51, 52, 53, and 58. CONCLUSION: Multi-type HPV infections are more likely to aggravate the degree of cervical lesions than single-type infections. The HPV type-dependent viral load is associated with the cervical pathological grade.

7.
Transl Oncol ; 14(1): 100888, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33096337

RESUMO

BACKGROUND: Extensive evidence showed that gastric cancer (GC) is heterogeneous, and many studies have been focused on identifying GC subtypes based on genomic profiles. However, few studies have specifically explored the GC classification and predicted the classification accuracy that may help facilitate the optimal stratification of GC patients responsive to immunotherapy. METHODS: Using two publicly available GC genomics datasets, we classified GC on the basis of 797 immune related genes. Unsupervised and supervised machine learning methods were used to predict the classification. RESULTS: We identified two GC subtypes that we named as Immunity-High (IM-H) and Immunity- Low (IM-L), and demonstrated that this classification was duplicable and predictable by analyzing other datasets. IM-H subtype was characterized by greater immune cell infiltration, stronger immune activities, lower tumor purity, as well as worse survival prognosis compared to IM-L subtype. Besides the immune signatures, some cancer-associated pathways were hyperactivated in IM-H, including TGF-beta signaling pathway, Focal adhesion, Cell adhesion molecules (CAMs), Calcium signaling pathway, mTOR signaling pathway, MAPK signaling pathway and Wnt signaling pathway. In contrast, IM-L presented depressed immune signatures and increased activation of base excision repair, DNA replication, homologous recombination, non-homologous end-joining and nucleotide excision repair pathways. Furthermore, we identified subtype-specific genomic or clinical features, and subtype-specific gene ontology and networks in IM-H and IM-L subtype. CONCLUSIONS: We proposed and validated two reproducible immune molecular subtypes of GC, which has potential clinical implications for GC patient selection of immunotherapy.

8.
Environ Res ; 192: 110300, 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33038368

RESUMO

Airborne particulate matter (PM) is a complex mixture containing various kinds of harmful components. Exposure to air PM is associated with childhood respiratory disease, but epidemiological data are limited concerning the circulating respiratory injury protein on the etiology of childhood respiratory disease. Specifically, the role of PM toxic components or its biological effective dose (adduct) in respiratory injury remains unclear. To demonstrate the dose-response relationship and the main mechanism on circulating club cell secretory protein (CC16) from PM compositions among children, we enrolled 273 boarding schoolchildren in China, including 110 and 163 children of whom were in the low- and high-PM exposed areas, respectively. In this study, we measured the internal exposure levels, including serum polycyclic aromatic hydrocarbons (PAH) adduct, urinary metals, and AhR expression, and detected the serum CC16 level as a lung injury marker. Environmental tobacco exposure in children was assessed by urinary cotinine. We found that significantly higher levels of serum CC16, benzo[a]pyridin-7,8-dihydroglycol-9,10-epoxide (BPDE)-albumin adduct, urinary molybdenum, selenium, arsenic, cadmium and barium, and lower level of AhR expression in high-PM exposed group. There was a good association between serum BPDE-albumin adduct and CC16 (ß = 0.222, P = 0.006). There was no association on urinary metals and serum CC16. BPDE-albumin adduct was directly associated with serum CC16 alternation [direct effect = 0.2044, 95% confidence interval (CI) = (0.0426, 0.36)]. PM could cause serum CC16 increased in children. PAH and its adduct might play a key role in lung injury during PM exposure.

9.
J Environ Radioact ; 222: 106355, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32892907

RESUMO

The gamma dose rate caused by airborne radionuclides is a major concern in the mitigation of nuclear accidents. Unfortunately, there is no fast method for calculating the three-dimensional (3D) gamma dose rate field near the source, because the corresponding airborne radionuclide distribution is usually calculated on non-equispaced grids and existing fast methods are only suitable for equispaced grids. This paper presents a method that accurately calculates the 3D dose rate field on non-equispaced grids, accelerating the computation by around two orders of magnitude. This method splits the time-consuming 3D integral in the dose rate model into a large convolution with a regularized smooth function and a small correction term. A nonuniform fast Fourier transform (NFFT) is used to rapidly calculate the convolution, which significantly enhances the computational speed. Our approach is applied to different grids and is compared with the FFT-based convolution method in two complex air dispersion simulations and a field experiment. The results show that the proposed method is in good agreement with the original 3D integral method and avoids grid-dependent interpolation errors in the FFT-based convolution method. This method enables a coupled analysis of wind, radioactivity, and dose rate on arbitrary grids, which is important for simplifying the emergency response in the case of small modular reactors.


Assuntos
Raios gama , Monitoramento de Radiação , Radioisótopos , Algoritmos , Análise de Fourier , Radioisótopos/análise
10.
Theranostics ; 10(21): 9830-9842, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32863962

RESUMO

It is universally accepted that aberrant metabolism facilitates tumor growth. However, how cancer cells coordinate glucose metabolism and tumor proliferation is largely unknown. Sine oculis homeobox homolog 1 (SIX1) is a transcription factor that belongs to the SIX family and is believed to play an important role in the regulation of the Warburg effect in tumors. However, whether the role of SIX1 and the molecular mechanisms that regulate its activity are similar in hepatocellular carcinoma (HCC) still needs further investigation. Methods: Western blotting was performed to determine the levels of SIX1 and O-linked ß-N-acetylglucosaminylation (O-GlcNAcylation) in HCC tissues. Cell Counting Kit 8 (CCK8), colony formation and mouse tumor model assays were used to establish the role of SIX1 and O-GlcNAcylation in HCC processes. Mass spectrometry, immunoprecipitation and site-directed mutagenesis were performed to confirm the O-GlcNAcylation of SIX1. Results: Here, we demonstrated that SIX1, the key transcription factor regulating the Warburg effect in cancer, promotes HCC growth in vitro and in vivo. Furthermore, we revealed that SIX1 could also enhance the levels of a posttranslational modification called O-GlcNAcylation. Importantly, we found that SIX1 was also highly modified by O-GlcNAcylation and that O-GlcNAcylation inhibited the ubiquitination degradation of SIX1. In addition, site-directed mutagenesis at position 276 (T276A) decreased the O-GlcNAcylation level and reversed the protumor effect of SIX1. Conclusions: We conclude that O-GlcNAcylation of SIX1 enhances its stability and promotes HCC proliferation. Our findings illustrate a novel feedback loop of SIX1 and O-GlcNAcylation and show that O-GlcNAcylation of SIX1 is an important way to coordinate glucose metabolism and tumor progression.

11.
Mol Genet Genomic Med ; : e1485, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32870608

RESUMO

BACKGROUND: Neurodevelopmental disorders (NDDs) are a group of disorders with high genetic and phenotypic heterogeneities. The 16p11.2 microdeletion has been implicated as an important genetic risk factor for NDDs. METHODS: Multiple genetic tests were used to detect the 16p11.2 microdeletion from 918 Chinese children with NDDs. Targeted sequencing of genes in the 16p11.2 interval was performed in all carriers of the 16p11.2 microdeletion, and whole-genome expression profiling analysis was performed for the patient carriers and normal carriers in their intra-family. RESULTS: Three patients carrying the 16p11.2 microdeletion were screened out, indicating a frequency of 0.33% for the 16p11.2 microdeletion in this cohort. We reviewed the neurodevelopmental trajectories of the 16p11.2 microdeletion carriers from childhood to puberty and confirmed that this microdeletion was associated with abnormal neurodevelopment, with varied neurodevelopmental phenotypes. A differential PRRT2 genotype (rs10204, T>C) was identified between patients and normal carriers of the 16p11.2 microdeletion. Moreover, the determination of differential whole-genome expression profiling demonstrated the destruction of the top-ranked network in neurogenesis and accounted for observation of abnormal neurodevelopmental phenotypes in the 16p11.2 microdeletion carriers. CONCLUSIONS: We have provided the frequency of the 16p11.2 microdeletion in a Chinese pediatric NDD cohort with a variable NDD phenotype from childhood to puberty, which is useful for Chinese geneticists/pediatricians to conduct the 16p11.2 microdeletion testing in children with NDDs.

12.
Org Lett ; 22(18): 7118-7122, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32877199

RESUMO

N-Alkenoxypyridinium salts were found to be highly active electrophilic reagents that could be used to activate the C-N bond of amides. Both aromatic amides and aliphatic amides could be transformed into the corresponding ß-oxo esters with good yields via the combined use of N-alkenoxypyridinium salts and water. The methodology proceeds under mild reaction conditions and is tolerant of various functional groups in both reaction partners.

13.
Am J Pathol ; 190(11): 2185-2193, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32919978

RESUMO

Chronic alcohol consumption is linked to the development of alcohol-associated liver disease (ALD). This disease is characterized by a clinical spectrum ranging from steatosis to hepatocellular carcinoma. Several cell types are involved in ALD progression, including hepatic macrophages. Kupffer cells (KCs) are the resident macrophages of the liver involved in the progression of ALD by activating pathways that lead to the production of cytokines and chemokines. In addition, KCs are involved in the production of reactive oxygen species. Reactive oxygen species are linked to the induction of oxidative stress and inflammation in the liver. These events are activated by the bacterial endotoxin, lipopolysaccharide, that is released from the gastrointestinal tract through the portal vein to the liver. Lipopolysaccharide is recognized by receptors on KCs that are responsible for triggering several pathways that activate proinflammatory cytokines involved in alcohol-induced liver injury. In addition, KCs activate hepatic stellate cells that are involved in liver fibrosis. Novel strategies to treat ALD aim at targeting Kupffer cells. These interventions modulate Kupffer cell activation or macrophage polarization. Evidence from mouse models and early clinical studies in patients with ALD injury supports the notion that pathogenic macrophage subsets can be successfully translated into novel treatment options for patients with this disease.

14.
Chemosphere ; 258: 127385, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32947675

RESUMO

2,2,4,4-tetrabromodiphenyl ether (BDE-47) has received considerable attention because of its high detection level in biological samples and potential developmental toxicity. Here, using zebrafish (Danio rerio) as the experimental animal, we investigated developmental effects of BDE-47 and explored the potential mechanism. Zebrafish embryos at 4 h post-fertilization (hpf) were exposed to 0.312, 0.625 and 1.25 mg/L BDE-47 to 74-120 hpf. We found that BDE-47 instigated a dose-related developmental toxicity, evidenced by reduced embryonic survival and hatching rate, shortened body length and increased aberration rate. Meanwhile, higher doses of BDE-47 reduced mitochondrial membrane potential and ATP production but increased apoptosis in zebrafish embryos. Expression of genes involved in mitochondrial oxidative phosphorylation (OXPHOS) (ndufb8, sdha, uqcrc1, cox5ab and atp5fal) were negatively related to BDE-47 doses in zebrafish embryos. Moreover, exposure to BDE-47 at 0.625 or 1.25 mg/L impaired mitochondrial biogenesis and mitochondrial dynamics. Our data further showed that BDE- 47 exposure induced excessive reactive oxygen species (ROS) and oxidative stress, which was accompanied by the activation of c-Jun N-terminal Kinase (JNK). Antioxidant NAC and JNK inhibition could mitigate apoptosis in embryos and improve embryonic development in BDE-47-treated zebrafish, suggesting the involvement of ROS/JNK pathway in embryonic developmental changes induced by BDE-47. Altogether, our data suggest here that developmental toxicity of BDE-47 may be associated with mitochondrial ROS-mediated JNK signaling in zebrafish embryo.


Assuntos
Éteres Difenil Halogenados/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Peixe-Zebra/metabolismo
15.
AAPS J ; 22(6): 125, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32996028

RESUMO

Linagliptin demonstrates substantial nonlinear pharmacokinetics due to its saturable binding to its pharmacological target dipeptidyl peptide 4 (DPP-4), a phenomenon known as target-mediated drug disposition (TMDD). In the current study, we established a novel whole-body physiologically-based pharmacokinetic (PBPK)-TMDD model for linagliptin. This comprehensive model contains plasma and 14 tissue compartments, among which TMDD binding process was incorporated in 9 of them, namely the plasma, kidney, liver, spleen, lung, skin, salivary gland, thymus, and reproductive organs. Our final model adequately captured the concentration-time profiles of linagliptin in both plasma and various tissues in both wildtype rats and DPP4-deficient rats following different doses. The association rate constant (kon) in plasma and tissues were estimated to be 0.943 and 0.00680 nM-1 h-1, respectively, and dissociation rate constant (koff), in plasma and tissues were estimated to be 0.0698 and 0.00880 h-1, respectively. The binding affinity of linagliptin to DPP-4 (Kd) was predicted to be higher in plasma (0.0740 nM) than that in tissue (1.29 nM). When scaled up to a human, this model captured the substantial and complex nonlinear pharmacokinetic behavior of linagliptin in human adults that is characterized by less-than dose-proportional increase in plasma exposure, dose-dependent clearance and volume of distribution, as well as long terminal half-life with minimal accumulation after repeated doses. Our modeling work is not only novel but also of high significance as the whole-body PBPK-TMDD model platform developed using linagliptin as the model compound could be applied to other small-molecule compounds exhibiting TMDD to facilitate their optimal dose selection. Graphical abstract.

16.
Clin Rheumatol ; 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32929648

RESUMO

INTRODUCTION: Pediatric SAPHO syndrome is regarded as the equivalent of chronic recurrent multifocal osteomyelitis or chronic non-bacterial osteomyelitis. This study aimed to evaluate the clinical features and treatment options for Chinese pediatric patients with SAPHO syndrome. METHOD: We conducted a single-center, retrospective study on a sample of 24 pediatric patients with SAPHO syndrome who were diagnosed at Peking Union Medical College Hospital from April 2014 to August 2018. The demographic, clinical, laboratory, imaging, histological, and therapeutic data were collected and analyzed. RESULTS: A total of 15 boys and 9 girls were included. The mean age of onset of bone and skin symptoms was 11.7 ± 3.8 and 14.4 ± 2.7 years, respectively. The mean follow-up period was 39.2 months. Seventeen patients had skin manifestations (46% had severe acne, 100% were boys; 21% had palmoplantar pustulosis, 100% were girls). Bone lesions were localized in four of the following major regions: anterior chest wall (42%), mandible (29%), peripheral bones (50%), and spine and sacroiliac joints (21%). Six patients had been treated with non-steroidal anti-inflammatory drugs, 10 with bisphosphonate, 10 with a tumor necrosis factor-α antagonist, and 1 with glucocorticoids, with variable responses. A total of 70% of the patients had complete remission after bisphosphonate or TNF-α antagonist therapy. CONCLUSION: Pediatric patients with SAPHO syndrome have different characteristics from other cohorts in the sex ratio, frequency of mandibular involvement, and sex distribution of skin lesions. Bisphosphonate and TNF-α antagonists show a favorable response in pediatric SAPHO syndrome treatment. Key points •Being the first study that describes an Asian pediatric SAPHO case series. •Chinese pediatric patients with SAPHO syndrome have different characteristics from Chinese adult patients and Caucasian pediatric patients.

17.
Orphanet J Rare Dis ; 15(1): 250, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32933559

RESUMO

BACKGROUND: We previously reported a novel clinically distinguishable subtype of congenital scoliosis (CS), namely, TBX6-associated congenital scoliosis (TACS). We further developed the TBX6-associated CS risk score (TACScore), a multivariate phenotype-based model to predict TACS according to the patient's clinical manifestations. In this study, we aimed to evaluate whether using the TACScore as a screening method prior to performing whole-exome sequencing (WES) is more cost-effective than using WES as the first-line genetic test for CS. METHODS: We retrospectively collected the molecular data of 416 CS patients in the Deciphering disorders Involving Scoliosis and COmorbidities (DISCO) study. A decision tree was constructed to estimate the cost and the diagnostic time required for the two alternative strategies (TACScore versus WES). Bootstrapping simulations and sensitivity analyses were performed to examine the distributions and robustness of the estimates. The economic evaluation considered both the health care payer and the personal budget perspectives. RESULTS: From the health care payer perspective, the strategy of using the TACScore as the primary screening method resulted in an average cost of $1074.2 (95%CI: $1044.8 to $1103.5) and an average diagnostic duration of 38.7d (95%CI: 37.8d to 39.6d) to obtain a molecular diagnosis for each patient. In contrast, the corresponding values were $1169.6 (95%CI: $1166.9 to $1172.2) and 41.4d (95%CI: 41.1d to 41.7d) taking WES as the first-line test (P < 0.001). From the personal budget perspective, patients who were predicted to be positive by the TACScore received a result with an average cost of $715.1 (95%CI: $594.5 to $835.7) and an average diagnostic duration of 30.4d (95%CI: 26.3d to 34.6d). Comparatively, the strategy of WES as the first-line test was estimated to have significantly longer diagnostic time with an average of 44.0d (95%CI: 43.2d to 44.9d), and more expensive with an average of $1193.4 (95%CI: $1185.5 to $1201.3) (P < 0.001). In 100% of the bootstrapping simulations, the TACScore strategy was significantly less costly and more time-saving than WES. The sensitivity analyses revealed that the TACScore strategy remained cost-effective even when the cost per WES decreased to $8.8. CONCLUSIONS: This retrospective study provides clinicians with economic evidence to integrate the TACScore into clinical practice. The TACScore can be considered a cost-effective tool when it serves as a screening test prior to performing WES.

18.
BMC Biotechnol ; 20(1): 42, 2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32819342

RESUMO

An amendment to this paper has been published and can be accessed via the original article.

19.
Artif Intell Med ; 107: 101921, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32828458

RESUMO

OBJECTIVES: Lung cancer is the leading cause of cancer death worldwide. Prognosis of lung cancer plays a crucial role in the clinical decision-making process to optimize the treatment for patients. Most of the existing data-driven prognostic prediction models explore the relations between patient's characteristics and outcomes at a specific time interval. Although valuable, they neglect the relations between long-term and short-term prognoses and thus may limit the prediction performance. METHODS: In this study, we present a novel prognostic prediction approach for postoperative NSCLC patients. Specifically, we formulate the learning objective function by exploiting the relations between long-term and short-term prognoses via a long short-term relational regularization. The regularization term is composed of two parts, i.e., the similarities between prognoses measured by patients' outcomes and the L2 -norms between the corresponding prognoses' weight vectors. Based on this regularization, the proposed method can extract critical risk factors that comprehensively consider the long-term and short-term prognoses to facilitate the estimation of clinical risks. RESULTS: We evaluate the proposed model on a clinical dataset containing 693 consecutive postoperative NSCLC patients with more than 5-year follow-up from 2006 to 2015. Our best models achieve 0.743, 0.709, and 0.746 AUCs for 1-year, 3-year, and 5-year survival prediction, 0.696, 0.724, and 0.736 AUCs for 1-year, 3-year, and 5-year recurrence prediction, respectively. The experimental results show the efficiency of our proposed model in improving the performances on 1-year prognostic prediction in comparison with benchmark models. By comparing with the model without the long short-term relational regularization, the proposed model extracts more consistent critical risk factors for both long-term and short-term prognoses and contains fewer unreasonable risk factors under the clinician's review. CONCLUSIONS: We conclude that the proposed model can effectively exploit the relations between long-term and short-term prognoses. And the risk factors recognized by the proposed model have the potentials for further prognostic prediction of postoperative non-small cell lung cancer patients.

20.
Mol Genet Genomic Med ; : e1453, 2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32815649

RESUMO

BACKGROUND: Congenital scoliosis (CS) is a spinal deformity due to vertebral malformations. Although insufficiency of TBX6 dosage contributes to a substantial proportion of CS, the molecular etiology for the majority of CS remains largely unknown. TBX6-mediated genes involved in the process of somitogenesis represent promising candidates. METHODS: Individuals affected with CS and without a positive genetic finding were referred to this study. Proband-only exome sequencing (ES) were performed on the recruited individuals, followed by analysis of TBX6-mediated candidate genes, namely MEOX1, MEOX2, MESP2, MYOD1, MYF5, RIPPLY1, and RIPPLY2. RESULTS: A total of 584 patients with CS of unknown molecular etiology were recruited. After ES analysis, protein-truncating variants in RIPPLY1 and MYF5 were identified from two individuals, respectively. In addition, we identified five deleterious missense variants (MYOD1, n = 4; RIPPLY2, n = 1) in TBX6-mediated genes. We observed a significant mutational burden of MYOD1 in CS (p = 0.032) compared with the in-house controls (n = 1854). Moreover, a potential oligogenic disease-causing mode was proposed based on the observed mutational co-existence of MYOD1/MEOX1 and MYOD1/RIPPLY1. CONCLUSION: Our study characterized the mutational spectrum of TBX6-mediated genes, prioritized core candidate genes/variants, and provided insight into a potential oligogenic disease-causing mode in CS.

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