Use of residue pairs in protein sequence-sequence and sequence-structure alignments

Two new sets of scoring matrices are introduced: H2 for the protein sequence comparison and T2 for the protein sequence-structure correlation. Each element of H2 or T2 measures the frequency with which a pair of amino acid types in one protein, k-residues apart in the sequence, is aligned with another pair of residues, of given amino acid types (for H2) or in given structural states (for T2), in other structurally homologous proteins. There are four types, corresponding to the k-values of 1 to 4, for both H2 and T2. These matrices were set up using a large number of structurally homologous protein pairs, with little sequence homology between the pair, that were recently generated using the structure comparison program SHEBA. The two scoring matrices were incorporated into the main body of the sequence alignment program SSEARCH in the FASTA package and tested in a fold recognition setting in which a set of 107 test sequences were aligned to each of a panel of 3,539 domains that represent all known protein structures. Six procedures were tested; the straight Smith-Waterman (SW) and FASTA procedures, which used the Blosum62 single residue type substitution matrix; BLAST and PSI-BLAST procedures, which also used the Blosum62 matrix; PASH, which used Blosum62 and H2 matrices; and PASSC, which used Blosum62, H2, and T2 matrices. All procedures gave similar results when the probe and target sequences had greater than 30% sequence identity. However, when the sequence identity was below 30%, a similar structure could be found for more sequences using PASSC than using any other procedure. PASH and PSI-BLAST gave the next best results.     

HEART与GRACE危险评分对急性冠脉综合征患者危险分层的对比研究

目的:探讨HEART与GRACE危险评分对急性冠脉综合症(ACS)患者主要心血管不良事件(MACE)发生的预测应用价值。方法:回顾性分析自2015年6月至2018年6月就诊于我院急诊入院的ACS患者591例,分别使用HEART与GRACE危险评分对研究对象进行危险分层(低危组,中危组,高危组),随访患者发病后90天MACE发生情况,分析不同危险分层ACS患者发病后90天MACE发生情况与评分之间的关系,并比较两种评分对ACS患者90天发生MACE事件的预测能力。结果:本研究纳入371例患者,其中男性324例(87.3%),女性47例(12.7%),年龄(58±11.70)岁;167患者(45.1%)在3个月内发生MACE。随着HEART和GRACE危险评分越高,发病90天发生MACE事件的发生率显著增加(P<0.05),HEART评分中高危组预测MACE准确性较GRACE评分高,GRACE评分低危险组预测MACE准确性较HEART评分高。HEART和GRACE评分对ACS患者预测MACE敏感性分别为76.51%,64.73%,特异性分别为96.71%,96.25%。HEART评分具有良好的预测价值,其ROC曲线下面积为0.908(95%CI 0.846~0.974),与GRACE评分ROC曲线下面积的0.801相比,差异有统计学意义(P<0.05)。结论:HEART和GRACE评分都可以应用于ACS患者的危险分层,预后评估和预测MACE发生,但HEART危险评分更可靠。     

Nilotinib based pharmacophore models for BCRABL

Tyrosine kinase inhibitors have revolutionized the treatment of several malignancies, converting lethal diseases in a manageable aspect. Imitanib, a small molecule ABL kinase inhibitor is a highly effective therapy for early phase chronic myeloid leukemia (CML), which has constitutively active ABL kinase activity owing to the over expression of the BCR-ABL fusion protein. But some patients develop imatinib resistance, particularly in the advanced phases of CML.The discovery of resistance mechanisms of imitanib; urge forward the development of second generation drugs. Nilotinib, a second generation drug is more potent inhibitor of BCR-ABL than imatinib. But nilotinib also develops dermatologic events and headache in patients. Large information about BCR-ABL structure and its inhibitors are now available. Based on the pharmacophore modeling approaches, it is possible to decipher the molecular determinants to inhibit BCR-ABL. We conducted a structure based and ligand based study to identify potent natural compounds as BCR-ABL inhibitor. First kinase inhibitors were docked with the receptor (BCR-ABL) and nilotinib was selected as a pharmacophore due its high binding efficiency. Eleven compounds were selected out of 1457 substances which have mutual pharmacopohre features with nilotinib. These eleven compounds were validated and used for docking study to find the drug like molecules. The best molecules from the final set of screening candidates can be evaluated in cell lines and may represent a novel class of BCR-ABL inhibitors.

Abbreviations

CML - Chronic myeloid leukemia, PDGFR - Platelet derived growth factor receptor, TKI - Tyrosine kinase inhibitors.     

Fast and accurate Bayesian polygenic risk modeling with variational inference

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NLR、IL-6及鼻窦CT评分对慢性鼻窦炎伴鼻息肉的诊断价值分析

摘要 目的：探讨外周血中性粒细胞/淋巴细胞比值（NLR）、血清白细胞介素-6（IL-6）及鼻窦CT评分诊断慢性鼻窦炎伴鼻息肉（CRSwNP）的价值。方法：选择2019年2月至2021年12月济宁医学院附属医院收治的91例CRSwNP患者纳入观察组，87例鼻中隔偏曲患者纳入对照组，根据《中国慢性鼻窦炎诊断与治疗指南（2018）》将CRSwNP患者分为轻度组（29例）、中度组（40例）和重度组（22例）。所有受试者均检测外周血中性粒细胞、淋巴细胞计数以及血清IL-6水平，计算外周血NLR，行鼻窦CT检查，根据CT检测结果，采用Lund-Mackay CT评分标准对受试者进行鼻窦CT评分。对比各组外周血NLR、血清IL-6水平及鼻窦CT评分差异，分析CRSwNP 患者外周血NLR、血清IL-6与鼻窦CT评分的相关性以及外周血NLR、血清IL-6、鼻窦CT评分诊断CRSwNP的价值。结果：观察组外周血NLR、血清IL-6水平及鼻窦CT评分均高于对照组（P＜0.05）。重度组外周血NLR、血清IL-6水平及鼻窦CT评分均高于中度组和轻度组（P＜0.05），且中度组高于轻度组（P＜0.05）。CRSwNP患者外周血NLR、血清IL-6水平与鼻窦CT评分均呈正相关（r=0.502、0.539，P＜0.05）。外周血NLR、血清IL-6及鼻窦CT评分诊断CRSwNP的曲线下面积（AUC）分别为0.683、0.659、0.697，联合三项指标诊断CRSwNP的AUC为0.882，高于各指标单独诊断。结论：外周血NLR、血清IL-6水平及鼻窦CT评分上升可反映CRSwNP患者病情加重，外周血NLR、血清IL-6水平与鼻窦CT评分呈正相关，外周血NLR、血清IL-6及鼻窦CT评分联合诊断CRSwNP具有一定的临床价值。     

Life Expectancy and Treatment Patterns in Elderly Patients With Low-Risk Papillary Thyroid Cancer: A Population-Based Analysis

ObjectiveGuidelines endorse active surveillance for low-risk papillary thyroid carcinoma (PTC), but this is not commonly utilized. Those with limited life expectancy due to age and comorbidity may be best suited for active surveillance given their higher likelihood of other-cause mortality compared to disease-specific mortality.MethodsSurveillance, epidemiology, and end results-Medicare was queried for patients >65 years with T1, N0, M0 PTC who received surgery. We evaluated the overall survival, disease-specific survival (DSS), and survival based on tumor size and extent of surgery (hemi- vs total thyroidectomy). We created a competing risk model to identify the cumulative incidence of other-cause mortality to define patient groups with life expectancies of less than 10 and 15 years.ResultsA total of 3280 patients were included. The 20-year overall survival and DSS were 38.2% and 98.5%, respectively. DSS was comparable between patients based on tumor size and surgery. The cancer cohort had better survival compared to matched controls (P < .001). Life expectancy was less than 15 years for any patient aged >80 years regardless of Charlson comorbidity score (CCS ≥ 0) and any patient aged >70 years with CCS ≥ 1. Life expectancy was less than 10 years for any patient a >80 years with CCS ≥ 1 and aged >70 years with CCS ≥ 3.ConclusionOlder patients with comorbidities have limited life expectancies but excellent DSS from low-risk PTC. Incorporating life expectancy into management decisions and guidelines would likely promote selection of less aggressive management for populations that are most suited for this approach.     

Bone Quality as Measured by Trabecular Bone Score in Normocalcemic Primary Hyperparathyroidism

ObjectiveThe impact of normocalcemic hyperparathyroidism (NHPT) on bone quality remains largely unexplored. We aimed to investigate the usefulness of trabecular bone score (TBS) assessment in NHPT and the accuracy of TBS in predicting vertebral fractures (VFs) in NHPT.MethodsIn this multicentric cross-sectional study, we assessed the TBS in 47 subjects with NHPT, 41 with primary hyperparathyroidism (PHPT), and 39 age- and sex-matched control subjects.ResultsTBS values did not differ among the 3 groups. The prevalence of low TBS (TBS < 1.2) was 23.4% in NHPT, 26.8% in PHPT, and 15.4% in controls, without statistically significant differences between groups. However, we found a lower lumbar spine Z-score adjusted for TBS (LS Z-score1TBS) in PHPT participants when compared with controls (-0.48 ± 1.06 vs 0.07 ± 0.93, P = .017). In NHPT group, LS Z-score1TBS did not detect patients with overall VFs (threshold, -0.15; area under the curve, 0.45; 95% CI, 0.253-0.648; accuracy, 55.3%). Instead, it was useful for moderate-severe VFs (threshold, 0.55; area under the curve, 0.81; 95% CI, 0.62-0.996; accuracy, 83%). In PHPT subjects also, TBS did not predict VFs.ConclusionIn NHPT, TBS is not reduced. When adjusted for TBS, the LS Z-score might predict moderate-to-severe VFs.     

Application of Magnetic Resonance Imaging in the Evaluation of Disease Activity in Graves’ Ophthalmopathy

ObjectiveTo evaluate magnetic resonance imaging parameters, T2 signal intensity ratios (SIRs), and normalized apparent diffusion coefficients (n-ADC) of the extraocular muscles (EOMs) in the identification of different stages of Graves’ ophthalmopathy (GO) and to find out the correlation of T2-SIRs and n-ADC values with disease changes after anti-inflammatory treatment.MethodsAltogether, 43 patients (86 orbits) were enrolled and classified into “active” or “inactive” stages by clinical activity score (CAS). Twenty-three (53.5%) patients received anti-inflammatory treatment and underwent a follow-up evaluation. Fifteen age- and gender-matched control participants (30 orbits) were included. T2-SIRs and n-ADC values of EOMs were calculated among GO and healthy controls and were correlated with CAS. Changes in these parameters were also evaluated before and after anti-inflammatory treatment.ResultsMean T2-SIRs and n-ADC values were both significantly higher in GO patients than in controls and higher in active GO than in inactive GO. In the inactive stage, n-ADC values of inferior rectus muscles were still higher than those in healthy controls. Both T2-SIRs and n-ADC values decreased after intravenous steroid pulse therapy. The cutoff value of pretreatment n-ADC was 1.780 to detect stages with specificity of 93.7% and sensitivity of 48.3% (P = .035).ConclusionT2-SIRs and n-ADC values are valuable magnetic resonance imaging indicators of the inflammatory activity in GO by detecting involvement of EOMs. They are also ideal tools to monitor the efficacy of anti-inflammatory treatment in patients with active stage GO. n-ADC values, when combined with CAS, can be promising predictive factors in the detection of stages of diseases.     

Automated and rapid identification of multidrug resistant Escherichia coli against the lead drugs of acylureidopenicillins,cephalosporins, and fluoroquinolones using specific Raman marker bands

A Raman‐based, strain‐independent, semi‐automated method is presented that allows the rapid (<3 hours) determination of antibiotic susceptibility of bacterial pathogens isolated from clinical samples. Applying a priori knowledge about the mode of action of the respective antibiotic, we identified characteristic Raman marker bands in the spectrum and calculated batch‐wise weighted sum scores from standardized Raman intensity differences between spectra of antibiotic exposed and nonexposed samples of the same strains. The lead substances for three relevant antibiotic classes (fluoroquinolone ciprofloxacin, third‐generation cephalosporin cefotaxime, ureidopenicillin piperacillin) against multidrug‐resistant Gram‐negative bacteria (MRGN) revealed a high sensitivity and specificity for the susceptibility testing of two Escherichia coli laboratory strains and 12 clinical isolates. The method benefits from the parallel incubation of control and treated samples, which reduces the variance due to alterations in cultivation conditions and the standardization of differences between batches leading to long‐term comparability of Raman measurements.