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2.
Dis Markers ; 2019: 2364943, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31360262

RESUMO

Rheumatoid arthritis (RA) is a systematic autoimmune disease, predominantly causing chronic polyarticular inflammation and joint injury of patients. For the treatment of RA, biologic disease-modifying antirheumatic drugs (bDMARDs) have been used to reduce inflammation and to interfere with disease progression through targeting and mediating the immune system. Although the therapeutic effects of bDMARDs in RA patients have been widely reported, whether these drugs also play important roles in T-cell repertoire status is still unclear. We therefore designed the study to identify the role of T-cell repertoire profiles in RA patients with different types of bDMARD treatments. A high-throughput sequencing approach was applied to profile the T-cell receptor beta chain (TCRB) repertoire of circulating T lymphocytes in eight patients given adalimumab (anti-TNF-α) with/without the following use of either rituximab (anti-CD20) or tocilizumab (anti-IL6R). We subsequently analyzed discrepancies in the clonal diversity and CDR3 length distribution as well as usages of the V and J genes of TCRB repertoire and interrogated the association between repertoire diversity and disease activities followed by the treatment of bDMARDs in these RA patients. All groups of patients showed well-controlled DAS28 scores (<2.6) after different treatment regimens of drugs and displayed no significant statistical differences in repertoire diversity, distribution of CDR3 lengths, and usage of V and J genes of TCRB. Nonetheless, a trend between overall TCRB repertoire diversity and disease activity scores in all bDMARD-treated RA patients was observed. Additionally, age was found to be associated with repertoire diversity in RA patients treated with bDMARDs. Through the profiling of the TCR repertoire in RA patients receiving different biologic medications, our study indicated an inverse tendency between TCR repertoire diversity and disease activity after biologic treatment in RA patients.

3.
Eur J Haematol ; 103(3): 178-189, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31177553

RESUMO

OBJECTIVES: The diagnosis of hematologic malignancies integrates multiple diagnostic and clinical disciplines. Historically, targeted (single-analyte) genetic testing has been used as reflex to initial prescreening by other diagnostic modalities including flow cytometry, anatomic pathology, and clinical cytogenetics. Given the wide range of mutations associated with hematologic malignancies a DNA/RNA-based NGS panel can provide a more effective and economical approach to comprehensive testing of patients as an initial, tier-1 screen. METHODS: Using a cohort of 380 patients, we performed clinical validation of a gene panel designed to assess 40 genes (DNA), and 29 fusion driver genes with over 600 gene fusion partners (RNA), including sample exchange data across three clinical laboratories, and correlation with cytogenetic testing results. RESULTS: The clinical validation of this technology demonstrated that its accuracy, sensitivity, and specificity are comparable to the majority of targeted single-gene approaches, while assessment of the initial patient cohort data demonstrated a high diagnostic yield of 50.5%. CONCLUSIONS: Implementation of a tier-1 NGS-based protocol for gene panel screening provides a comprehensive alternative to targeted molecular testing in patients with suspected hematologic malignancies, with increased diagnostic yield, scalability, reproducibility, and cost effectiveness, making it ideally suited for implementation in clinical laboratories.

4.
Org Lett ; 21(13): 5040-5045, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31247785

RESUMO

( S)-2,15-Br2-DHTP-catalyzed asymmetric conjugate addition of boronic acids to ß-trifluoromethyl α,ß-unsaturated ketones and enones was studied. The reaction afforded the corresponding Michael addition products in moderate to high yields with excellent enantioselectivities (up to 99:1 er). This catalytic system features mild reaction conditions, high efficiency, and tolerance to heteroarylboronic acids.

5.
Chem Commun (Camb) ; 55(52): 7446-7449, 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31165809

RESUMO

A facile and practical approach for the difluoromethylation of aliphatic alcohols with an S-(difluoromethyl)sulfonium salt was developed. A wide variety of alcohols with broad functional groups are compatible to furnish the corresponding alkyl difluoromethyl ethers in good to excellent yields under mild reaction conditions. Control experiments and DFT computational studies suggest that the difluoromethylation of alcohols mainly proceeds via a difluorocarbene pathway involving a five-membered transition state with the participation of water, whose crucial role in this reaction was also elucidated by control experiments.

6.
Org Lett ; 21(10): 3795-3798, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31042044

RESUMO

The cycloisomerization of 1,8-enynes in the presence of platinum(II) chloride was developed to generate bicyclic nitrogen-containing heterocycle species via 6- endo-dig cyclization and [3,3]-sigmatropic rearrangement in acceptable to good yields. The related control experiments and preliminary mechanistic studies indicate a plausible mechanism involving 1,6- endo-dig aminoplatination of the alkyne and allylic [3,3]-sigmatropic rearrangement with total inversion of the allylic moiety.

7.
Nutr Cancer ; 71(6): 954-970, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31058551

RESUMO

Background: Weight loss is frequently observed in pancreatic cancer patients. We aimed to study the prognostic impacts of weight loss early during chemotherapy. Methods: A total of 72 patients of Chinese ethnicity with unresectable pancreatic cancer who underwent chemotherapy were reviewed. Critical weight loss (CWL) was defined as weight loss ≥ 5% within one month after treatment. The prognostic impact of weight loss and CWL were analyzed. Results: 47 patients (65.3%) had weight loss after one month of treatment, with 14 (19.4%) suffering from CWL. Baseline characteristics were similar between patients with and without CWL. The median OS and Time-to-treatment-failure (TTF) of patients with CWL were shorter than those without CWL (OS: 4.8 months [CWL] versus [vs.] OS 7.1 months [No CWL]; TTF 1.6 months [CWL] vs. 3.2 months [No CWL]; both P < 0.01). CWL was an independent adverse prognosticator for OS (Hazard Ratio [HR] = 2.50; P = 0.01) and TTF (HR = 2.71; P < 0.01). Other independent prognosticators for OS were serum albumin <35 mg/dl and CA19-9 ≥ 1000 IU/ml, while CWL was the only independent prognosticator for TTF (HR 2.71 [95% CI 1.33-5.52]; P < 0.01). Conclusions: Development of CWL in early course of chemotherapy was associated with worse prognosis in Chinese patients with unresectable pancreatic cancers.

8.
Org Lett ; 21(8): 2546-2549, 2019 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-30860388

RESUMO

An efficient synthetic protocol involving iron-catalyzed cross-coupling reactions between organolithium compounds and alkenyl iodides as key coupling partners was achieved. More than 30 examples were obtained with moderate to good yields and high stereospecificity. Gram-scale and synthetic applications of this procedure are recorded herein to demonstrate its feasibility and potential utilization.

9.
BMC Bioinformatics ; 20(Suppl 2): 91, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30871471

RESUMO

BACKGROUND: Dermoscopy is one of the common and effective imaging techniques in diagnosis of skin cancer, especially for pigmented lesions. Accurate skin lesion border detection is the key to extract important dermoscopic features of the skin lesion. In current clinical settings, border delineation is performed manually by dermatologists. Operator based assessments lead to intra- and inter-observer variations due to its subjective nature. Moreover it is a tedious process. Because of aforementioned hurdles, the automation of lesion boundary detection in dermoscopic images is necessary. In this study, we address this problem by developing a novel skin lesion border detection method with a robust edge indicator function, which is based on a meshless method. RESULT: Our results are compared with the other image segmentation methods. Our skin lesion border detection algorithm outperforms other state-of-the-art methods. Based on dermatologist drawn ground truth skin lesion borders, the results indicate that our method generates reasonable boundaries than other prominent methods having Dice score of 0.886 ±0.094 and Jaccard score of 0.807 ±0.133. CONCLUSION: We prove that smoothed particle hydrodynamic (SPH) kernels can be used as edge features in active contours segmentation and probability map can be employed to avoid the evolving contour from leaking into the object of interest.


Assuntos
Dermoscopia/métodos , Interpretação de Imagem Assistida por Computador/métodos , Neoplasias Cutâneas/diagnóstico , Humanos , Neoplasias Cutâneas/patologia
10.
Clin Endocrinol (Oxf) ; 91(1): 3-9, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30903626

RESUMO

CONTEXT: Calorie restriction and overtraining are increasingly seen in young men who suffer from increasing societal pressure to attain a perceived ideal male body image. The resulting energy deficit can lead to multiple endocrine consequences, including suppression of the male gonadal axis. DESIGN: We reviewed the literature, including two unpublished cases. RESULTS: We identified 23 cases, aged median (range) 20 years (16-33), with a body mass index of 15.9 kg/m2 (12.5-20.5). Total testosterone was 3.0 nmol/L (0.6-21.3), and luteinizing hormone (LH) 1.2 mIU/L (<0.2-7.5), with 91% of cases demonstrating hypogonadotropic hypogonadism. Associated findings included evidence of growth hormone resistance (increased growth hormone in 57% and low insulin-like growth factor-1 in 71%), hypercortisolaemia (50%) and a nonthyroidal illness picture (67%). In cases with longitudinal measurements following weight regain, serum testosterone (n = 14) increased from median [interquartile range] 3.2 nmol/L [1.9-5.1] to 14.3 nmol/L [9.3-21.2] (P < 0.001), and LH (n = 8) from 1.2 IU/L [0.8-1.8] to 3.5 IU/L [3.3-4.3] (P = 0.008). CONCLUSIONS: Hypogonadotropic hypogonadism can occur in the context of energy deprivation in young otherwise healthy men and may be underrecognized. The evidence suggests that gonadal axis suppression and associated hormonal abnormalities represent an adaptive response to increased physiological stress and total body energy deficit. The pathophysiology likely involves hypothalamic suppression due to dysregulation of leptin, ghrelin and pro-inflammatory cytokines. The gonadal axis suppression is functional, because it can be reversible with weight gain. Treatment should focus on reversing the existing energy deficit to achieve a healthy body weight, including psychiatric input where required.

11.
J Bone Miner Res ; 34(7): 1275-1283, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30779856

RESUMO

The stiffness index (SI) from quantitative ultrasound measurements is a good indicator of BMD and may be used to predict the risk of osteoporotic fracture. We conducted a genomewide association study (GWAS) for SI using 7742 individuals from the Taiwan Biobank, followed by a replication study in a Korean population (n = 2955). Approximately 6.1 million SNPs were subjected to association analysis, and SI-associated variants were identified. We further conducted a meta-analysis of Taiwan Biobank significant SNPs with a Korean population-based cohort. Candidate genes were prioritized according to epigenetic annotations, gene ontology, protein-protein interaction, GWAS catalog, and expression quantitative trait loci analyses. Our results revealed seven significant single-nucleotide polymorphisms (SNPs) within three loci: 7q31.31, 17p13.3, and 11q14.2. Conditional analysis showed that three SNPs, rs2536195 (CPED1/WNT16), rs1231207 (SMG6), and rs4944661 (LOC10050636/TMEM135), were the most important signals within these regions. The associations for the three SNPs were confirmed in a UK Biobank estimated BMD GWAS; these three cytobands were replicated successfully after a meta-analysis with a Korean population cohort as well. However, two SNPs were not replicated. After prioritization, we identified two novel genes, RAB15 and FNTB, as strong candidates for association with SI. Our study identified three SI-associated SNPs and two novel SI-related genes. Overall, these results provide further insight into the genetic architecture of osteoporosis. Further studies in larger East Asian populations are needed. © 2019 American Society for Bone and Mineral Research.

12.
Org Lett ; 21(3): 700-704, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30675791

RESUMO

A new strategy was developed for the efficient synthesis of di-, tetra-, and hexa-substituted 1,3-butadienes. This one-pot procedure involves lithium-iodine exchange to generate the corresponding vinyllithium intermediates. A subsequent iron-catalyzed ligand-free oxidative homo-coupling eventually led to the formation of 1,3-butadienes in acceptable to excellent isolated yields.

13.
Eur J Cardiothorac Surg ; 56(3): 612-614, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30689801

RESUMO

The Thoraflex™ device is a composite 4-branched graft with a distal endovascular stent that allows either a one-stage treatment or an endovascular second-stage treatment of multisegment aortic pathologies. Reports on open second-stage treatment after the Thoraflex™ device implantation are sparse especially regarding the technical aspects. We described our surgical procedure of open second-stage descending thoracic aortic replacement after Thoraflex™ implantation with a special focus on the anastomosis technique to a stent graft. We found excellent haemostasis and a good postoperative outcome using our approach of the stent graft to graft anastomosis.

14.
J Med Chem ; 62(3): 1684-1689, 2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30693770

RESUMO

Pironetin, the only crystallographically confirmed natural product to target α-tubulin, displays potent cytotoxic activity against sensitive and resistant A2780 ovarian cancer cell lines but is only marginally active in vivo. We now report that pironetin has a short half-life (<7 min) in human liver microsomes, suggesting that its limited in vivo efficacy is due to rapid metabolism. Further, we describe the discovery of epoxypironetin as pironetin's major metabolite in human liver microsomes.

15.
Chem Commun (Camb) ; 55(3): 397-400, 2019 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-30540301

RESUMO

An excellent level of enantioselectivity in asymmetric sulfenylation of 4-substituted pyrazolones was achieved with chiral iminophosphorane as the organocatalyst under continuum solvation conditions (up to 99% ee). Importantly, this catalytic process features high efficiency with excellent enantioselectivities, easy separation of products, low catalytic loadings and scale-up to grams without loss of enantioselectivity.

16.
Org Lett ; 20(21): 6925-6929, 2018 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-30350647

RESUMO

Air- and light-stable electrophilic difluoromethylating reagents, S-(difluoromethyl)- S-phenyl- S-(2,4,6-trialkoxyphenyl) sulfonium salts were successfully developed, and the introduction of intramolecular hydrogen bonds plays a crucial role for the stabilities and reactivities of these reagents. C-selective difluoromethylation of a broad range of ß-ketoesters and malonates proceeded smoothly under mild reaction conditions to give good to excellent yields with excellent C/O regioselectivities.

17.
Biosci Rep ; 38(6)2018 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-30355649

RESUMO

Osteoporosis is defined by low bone mineral density (BMD), which is mainly due to the imbalances in osteoclast and osteoblast activity. Previous studies indicated that early activation of osteoclasts relies on calcium entry through store-operated calcium (SOC) entry, and several genes, including STIM1, ORAI1, and ITPKC, are known as key regulators of SOC entry. However, the relationships between STIM1, ORAI1, ITPKC, and human BMD are still unclear. In order to investigate the plausible associations between these genes and BMD, we conducted a meta-analysis of genes expression and BMD using the publicly available GEO database. We further recruited 1044 subjects and tested associations between polymorphisms in these genes and BMD. Clinical information (including age, sex, and BMI) was collected and used for the analysis. Our results indicated that ITPKC gene expression was significantly associated with BMD. Furthermore, we found that one ITPKC SNP (rs2607420) was significantly associated with lumbar spine BMD. Through bioinformatics analysis, rs2607420 was found to be very likely to participate in the regulation of ITPKC expression. Our findings suggest that ITPKC is a susceptibility gene for BMD, and rs2607420 may play an important role in the regulation of this gene.

18.
Oncoimmunology ; 7(9): e1468951, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30228934

RESUMO

Intricate relationships among cytokines (including chemokines) shape the tumor microenvironment (TME) and reflect cell-cell interactions between malignant cells and other cells from the TME. Although our previous study indicated the transcriptional landscape of cytokines in 19 cancer types, the global pattern somatic copy number (SCN) alterations and the clinical relevance of cytokines have not been systematically investigated. Here, we reported a significant negative selection on cytokine genes. We also linked the SCN losses of cytokine genes to the abundance of immune infiltrates which affects cancer progression and patient prognoses. We also demonstrated and validated the correlations between SCN alterations of cytokine-containing loci and drug sensitivity. The results indicated the genomic loss of cytokines in malignant cells as a crucial theme for interrogating cancer progression, malignant cell-TME interactions, and therapeutics.

19.
Angew Chem Int Ed Engl ; 57(35): 11365-11368, 2018 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-29989283

RESUMO

A novel gold-catalyzed tandem protocol, initiated by hydride transfer in the presence of catalytic (C6 F5 )3 PAuCl/AgSbF6 , for the formation of fused polycyclic ring systems has been achieved. This tandem reaction provides rapid access to various fused polycyclic species in a single chemical operation, leading to stereospecific formation of two carbon-carbon bonds and three rings.

20.
J Org Chem ; 83(12): 6325-6333, 2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29790346

RESUMO

An efficient ligand-free iron-catalyzed cross-coupling reaction involving alkenyllithium and vinyl iodides was developed to form diene species in moderate to good yields. This new iron-catalyzed cross-coupling reaction provides a mild, inexpensive, and environmentally friendly avenue toward synthesis of diversified diene derivatives.

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