Biomarkers

摘要： Temporal lobe epilepsy is the most common form of focal epilepsy in adults,accounting for one third of all diagnosed epileptic patients,with seizures originating from or involving mesial temporal structures such as the hippocampus,and many of these patients being refractory to treatment with anti-epileptic drugs.Temporal lobe epilepsy is the most common childhood neurological disorder and,compared with adults,the symptoms are greatly affected by age and brain development.Diagnosis of temporal lobe epilepsy relies on clinical examination,patient history,electroencephalographic recordings,and brain imaging.Misdiagnosis or delay in diagnosis is common.A molecular biomarker that could distinguish epilepsy from healthy subjects and other neurological conditions would allow for an earlier and more accurate diagnosis and appropriate treatment to be initiated.Among possible biomarkers of pathological changes as well as potential therapeutic targets in the epileptic brain are micro RNAs.Most of the recent studies had performed micro RNA profiling in body fluids such as blood plasma and blood serum and brain tissues such as temporal cortex tissue and hippocampal tissue.A large number of micro RNAs were dysregulated when compared to healthy controls and with some overlap between individual studies that could serve as potential biomarkers.For example,in adults with temporal lobe epilepsy,possible biomarkers are miR-199a-3p in blood plasma and miR-142-5p in blood plasma and blood serum.In adults with mesial temporal lobe epilepsy,possible biomarkers are miR-153 in blood plasma and miR-145-3p in blood serum.However,in many of the studies involving patients who receive one or several anti-epileptic drugs,the influence of these on micro RNA expression in body fluids and brain tissues is largely unknown.Further studies are warranted with children with temporal lobe epilepsy and consideration should be given to utilizing mouse or rat and non-human primate models of temporal lobe epilepsy.The animal models could be used to confirm micro RNA findings in human patients and to test the effects of targeting specific micro RNAs on disease progression and behavior.

摘要： Charcot-Marie-Tooth neuropathies(CMT)constitute a group of common but highly heterogeneous,non-syndromic genetic disorders affecting predominantly the peripheral nervous system.CMT type 1A(CMT1A)is the most frequent type and accounts for almost~50%of all diagnosed CMT cases.CMT1A results from the duplication of the peripheral myelin protein 22(PMP22)gene.Overexpression of PMP22 protein overloads the protein folding apparatus in Schwann cells and activates the unfolded protein response.This leads to Schwann cell apoptosis,dys-and de-myelination and secondary axonal degeneration,ultimately causing neurological disabilities.During the last decades,several different gene therapies have been developed to treat CMT1A.Almost all of them remain at the pre-clinical stage using CMT1A animal models overexpressing PMP22.The therapeutic goal is to achieve gene silencing,directly or indirectly,thereby reversing the CMT1A genetic mechanism allowing the recovery of myelination and prevention of axonal loss.As promising treatments are rapidly emerging,treatment-responsive and clinically relevant biomarkers are becoming necessary.These biomarkers and sensitive clinical evaluation tools will facilitate the design and successful completion of future clinical trials for CMT1A.

摘要： Triple-negative breast cancer(TNBC)is a highly complex,heterogeneous disease and historically has limited treatment options.It has a high probability of disease recurrence and rapid disease progression despite adequate systemic treatment.Immunotherapy has emerged as an important alternative in the management of this malignancy,showing an impact on progression-free survival and overall survival in selected populations.In this review we focused on immunotherapy and its current relevance in the management of TNBC,including various scenarios(metastatic and early-neoadjuvant,adjuvant-),new advances in this subtype and the research of potential predictive biomarkers of response to treatment.

摘要： Hepatocellular carcinoma(HCC)is the second cause of cancer-related mortality.The diagnosis of HCC depends mainly on-fetoprotein,which is limited in its diagnostic and screening capabilities.There is an urgent need for a biomarker that detects early HCC to give the patients a chance for curative treatment.New targets of therapy could enhance survival and create future alternative curative methods.In silico analysis provides both;discovery of biomarkers,and understanding of the molecular pathways,to pave the way for treatment development.This review discusses the role of in silico analysis in the discovery of biomarkers,molecular pathways,and the role the author has contributed to this area of research.It also discusses future aspirations and current limitations.A literature review was conducted on the topic using various databases(PubMed,Science Direct,and Wiley Online Library),searching in various reviews,and editorials on the topic,with overviewing the author’s own published and unpublished work.This review discussed the steps of the validation process from in silico analysis to in vivo validation,to incorporation into clinical practice guidelines.In addition,reviewing the recent lines of research of bioinformatic studies related to HCC.In conclusion,the genetic,molecular and epigenetic markers discoveries are hot areas for HCC research.Bioinformatics will enhance our ability to accomplish this understanding in the near future.We face certain limitations that we need to overcome.

摘要： The management of patients with liver metastases from colorectal cancer is still debated.Several therapeutic options and treatment strategies are available for an extremely heterogeneous clinical scenario.Adequate prediction of patients’outcomes and of the effectiveness of chemotherapy and loco-regional treatments are crucial to reach a precision medicine approach.This has been an unmet need for a long time,but recent studies have opened new perspectives.New morphological biomarkers have been identified.The dynamic evaluation of the metastases across a time interval,with or without chemotherapy,provided a reliable assessment of the tumor biology.Genetics have been explored and,thanks to their strong association with prognosis,have the potential to drive treatment planning.The liver-tumor interface has been identified as one of the main determinants of tumor progression,and its components,in particular the immune infiltrate,are the focus of major research.Image mining and analyses provided new insights on tumor biology and are expected to have a relevant impact on clinical practice.Artificial intelligence is a further step forward.The present paper depicts the evolution of clinical decision-making for patients affected by colorectal liver metastases,facing modern biomarkers and innovative opportunities that will characterize the evolution of clinical research and practice in the next few years.

摘要： BACKGROUND Gastric cancer(GC)is one of the most frequently diagnosed tumor globally.In most cases,GC develops in a stepwise manner from chronic gastritis or atrophic gastritis(AG)to cancer.One of the major issues in clinical settings of GC is diagnosis at advanced disease stages resulting in poor prognosis.Micro RNAs(mi RNAs)are small noncoding molecules that play an essential role in a variety of fundamental biological processes.However,clinical potential of mi RNA profiling in the gastric cancerogenesis,especially in premalignant GC cases,remains unclear.AIM To evaluate the AG and GC tissue mi RNomes and identify specific mi RNAs’potential for clinical applications(e.g.,non-invasive diagnostics).METHODS Study included a total of 125 subjects:Controls(CON),AG,and GC patients.All study subjects were recruited at the Departments of Surgery or Gastroenterology,Hospital of Lithuanian University of Health Sciences and divided into the profiling(n=60)and validation(n=65)cohorts.Total RNA isolated from tissue samples was used for preparation of small RNA sequencing libraries and profiled using next-generation sequencing(NGS).Based on NGS data,deregulated mi RNAs hsa-mi R-129-1-3 p and hsa-mi R-196 a-5 p were analyzed in plasma samples of independent cohort consisting of CON,AG,and GC patients.Expression level of hsa-mi R-129-1-3 p and hsa-mi R-196 a-5 p was determined using the quantitative real-time polymerase chain reaction and 2-ΔΔCt method.RESULTS Results of tissue analysis revealed 20 differentially expressed mi RNAs in AG group compared to CON group,129 deregulated mi RNAs in GC compared to CON,and 99 altered mi RNAs comparing GC and AG groups.Only 2 mi RNAs(hsa-mi R-129-1-3 p and hsa-mi R-196 a-5 p)were identified to be step-wise deregulated in healthy-premalignant-malignant sequence.Area under the curve(AUC)-receiver operating characteristic analysis revealed that expression level of hsa-mi R-196 a-5 p is significant for discrimination of CON vs AG,CON vs GC and AG vs GC and resulted in AUCs:88.0%,93.1%and 66.3%,respectively.Comparing results in tissue and plasma samples,hsa-mi R-129-1-3 p was significantly down-regulated in GC compared to AG(P=0.0021 and P=0.024,tissue and plasma,respectively).Moreover,analysis revealed that hsa-mi R-215-3 p/5 p and hsa-mi R-934 were significantly deregulated in GC based on Helicobacter pylori(H.pylori)infection status[log2 fold change(FC)=-4.52,P-adjusted=0.02;log2 FC=-4.00,P-adjusted=0.02;log2 FC=6.09,P-adjusted=0.02,respectively].CONCLUSION Comprehensive mi RNome study provides evidence for gradual deregulation of hsa-mi R-196 a-5 p and hsa-mi R-129-1-3 p in gastric carcinogenesis and found hsami R-215-3 p/5 p and hsa-mi R-934 to be significantly deregulated in H.pylori carrying GC patients.

摘要： Blood exosomes,which are extracellular vesicles secreted by living cells into the circulating blood,are regarded as a relatively noninvasive novel tool for monitoring brain physiology and disease states.An increasing number of blood cargo-loaded exosomes are emerging as potential biomarkers for preclinical and clinical Alzheimer's disease.Therefo re,we conducted a meta-analysis and systematic review of molecular biomarkers derived from blood exosomes to comprehensively analyze their diagnostic performance in preclinical Alzheimer's disease,mild cognitive impairment,and Alzheimer's disease.We performed a literature search in PubMed,Web of Science,Embase,and Cochrane Library from their inception to August 15,2020.The research subjects mainly included Alzheimer's disease,mild cognitive impairment,and preclinical Alzheimer's disease.We identified 34 observational studies,of which 15 were included in the quantitative analysis(Newcastle-Ottawa Scale score 5.87 points)and 19 were used in the qualitative analysis.The meta-analysis results showed that core biomarkers including Aβ_(1-42),P-T181-tau,P-S396-tau,and T-tau were increased in blood neuro nderived exosomes of preclinical Alzheimer's disease,mild cognitive impairment,and Alzheimer's disease patients.M olecules related to additional risk facto rs that are involved in neuroinflammation(C1q),metabolism disorder(P-S312-IRS-1),neurotrophic deficiency(HGF),vascular injury(VEGF-D),and autophagy-lysosomal system dysfunction(cathepsin D)were also increased.At the gene level,the differential expression of transc ription-related factors(REST)and microRNAs(miR-132)also affects RNA splicing,transport,and translation.These pathological changes contribute to neural loss and synaptic dysfunction.The data confirm that the above-mentioned core molecules and additional ris k-related factors in blood exosomes can serve as candidate biomarkers for preclinical and clinical Alzheimer's disease.These findings support further development of exosome biomarkers for a clinical blood test for Alzheimer's disease.This meta-analysis was registered at the International Prospective Register of Systematic Reviews(Registration No.CRD4200173498,28/04/2020).

摘要： Glaucoma is a neurodegenerative disease in which optic nerve damage and visual field defects occur.It is a leading cause of irreversible blindness.Its pathogenesis is largely unknown although several risk factors have been identified,with an increase in intraocular pressure being the main one.Lowering of intraocular pressure is the only treatment available.Open-angle glaucoma is the most common form of the condition,accounting for~90%of all cases of glaucoma,with primary open-angle glaucoma and exfoliation glaucoma being the most frequent types.There are strong indications that microRNAs play important roles in the pathogenesis of primary open-angle glaucoma.Most of the recent studies reviewed had performed microRNA profiling in aqueous humor from glaucoma patients compared to controls who were chiefly cataract patients.A very large number of microRNAs were dysregulated but with limited overlap between individual studies.MiRNAs in aqueous humor that could be possible targets for therapeutic intervention are miR-143-3p,miR-125b-5p,and miR-1260b.No ove rlap of findings occurred within the dysregulated miRNAs for blood plasma,blood serum,peripheral blood mononuclear cells,and tears of primary open-angle glaucoma patients.Seve ral impo rtant limitations were identified in these studies.Further studies are warranted of mic roRNA expression in aqueous humor and blood samples of primary open-angle glaucoma patients in the early stages of the disease so that validated biomarkers can be identified and treatment initiated.In addition,whether modifying the levels of specific microRNAs in aqueous humor or tears has a beneficial effect on intraocular pressure and ophthalmic examination of the eyes should be investigated using suitable animal models of glaucoma.

摘要： Schistosomiasis mansoni is a neglected disease and key public health problem,mainly due to its high prevalence,the scarcity of public policies,and the severity of some clinical forms.Periportal fibrosis(PPF)is the commonest complication of chronic schistosomiasis mansoni and its diagnosis requires different techniques.Even though wedge biopsy of the liver is considered the gold standard,it is not justified in non-surgical patients,and percutaneous liver biopsy may be informative but does not have sufficient sensitivity.Noninvasive PPF tests mostly include biological(serum biomarkers or combined scores)or physical assessments(imaging assessment of fibrosis pattern or tissue stiffness).Moreover,imaging techniques,such as ultrasound,computed tomography,magnetic resonance imaging,and elastography are applied not only to support the diagnosis of schistosomiasis,but also to assess and detect signs of portal hypertension and organ damage due to chronic schistosomiasis.A combination between a comprehensive history and physical examination with biomarkers for liver fibrosis and imaging methods seems to offer the best approach for evaluating these patients.In addition,understanding their strengths and limitations will allow a more accurate interpretation in the clinical context and can lead to greater accuracy in estimating the degree of fibrosis in patients with Schistosomiasis mansoni(S.mansoni)infection.This review will discuss the different noninvasive methods that are currently available for the evaluation of PPF in S.mansoni infection,and their application,advantages,and limitations in clinical practice.

摘要： Non-alcoholic fatty liver disease(NAFLD)prevalence has increased drastically in recent decades,affecting up to 25%of the world’s population.NAFLD is a spectrum of different diseases that starts with asymptomatic steatosis and continues with development of an inflammatory response called steatohepatitis,which can progress to fibrosis.Several molecular and metabolic changes are required for the hepatocyte to finally vary its function;hence a“multiple hit”hypothesis seems a more accurate proposal.Previous studies and current knowledge suggest that in most cases,NAFLD initiates and progresses through most of nine hallmarks of the disease,although the triggers and mechanisms for these can vary widely.The use of animal models remains crucial for understanding the disease and for developing tools based on biological knowledge.Among certain requirements to be met,a good model must imitate certain aspects of the human NAFLD disorder,be reliable and reproducible,have low mortality,and be compatible with a simple and feasible method.Metabolism studies in these models provides a direct reflection of the workings of the cell and may be a useful approach to better understand the initiation and progression of the disease.Metabolomics seems a valid tool for studying metabolic pathways and crosstalk between organs affected in animal models of NAFLD and for the discovery and validation of relevant biomarkers with biological understanding.In this review,we provide a brief introduction to NAFLD hallmarks,the five groups of animal models available for studying NAFLD and the potential role of metabolomics in the study of experimental NAFLD.

摘要： 本发明提供一种肾癌血液生物标志物的检测方法及试剂盒。具体地说，本发明涉及一种对肾癌血液生物标志物NNMT、LCP1及NM23A全部进行检测的方法及试剂盒，这些检测结果能由医师之类的医疗专家有效地用来判断肾癌罹患与否、肾癌发展程度、肾癌治疗经过，尤其是能够有效地适用于肾癌的早期诊断、肾细胞癌类型中占大多数的透明细胞型肾细胞癌的诊断。

摘要： 本发明涉及造血干细胞移植技术领域，且公开了一种基于aGVHD biomarker的非复发死亡风险监测模型，所述通过动态监测病人群体(199例，一年内的非复发死亡约占12％)不同时间点的aGVHD biomarker指标(sST2，REG3α)。计算病人移植后100天内每个检测时间点sST2和REG3α之间的距离值(value)，选取检测时间点中sST2和REG3α距离值达到最大时的aGVHD biomarker作为病人最坏情况的指标，建立模型数据集。该基于aGVHD biomarker的非复发死亡风险监测模型，通过建立分层标准，对病人进行风险分组，其180天非复发死亡的累积发生率为：低风险(2.38％)vs中风险(16.67％)vs高风险(52.0％)，分层结果优于已有研究[5](初始治疗时aGVHD biomarker分组：低风险(6％)vs中风险(20％)vs高风险(49％))。

摘要： 本发明涉及结合症状及biomarker信息的用于aGVHD病人精准风险分层的方法，包括以下步骤：选取多中心200例出现aGVHD症状的患者，其中非复发死亡约占15％,作为观测样本；通过Luminex平台检测步骤1)病人群体出现aGVHD症状时的biomarker(sST2，REG3α)指标。该结合症状及biomarker信息的用于aGVHD病人精准风险分层的方法，将病人出现aGVHD症状时(onset)的biomarker信息与基于症状轻重度的临床分级信息(I‑IV)相结合，对aGVHD病人进行非复发死亡风险精细划分，划分结果显示，临床症状表现为轻度(I‑II)的aGVHD病人中有21％(33/159)为非复发死亡高风险，临床症状表现为重度(III‑IV)的aGVHD病人中有24％为非复发死亡低风险，本发明在现有aGVHD治疗标准的基础上，充分发挥了biomarker信息对非复发死亡的分层价值，更具临床应用和指导意义。

摘要： 本发明涉及造血干细胞移植技术领域，且公开了一种基于aGVHDbiomarker的一线糖皮质激素治疗反应预测模型，其特征在于，包括以下步骤：通过Luminex平台监测aGVHD病人一线糖皮质激素治疗一周后的aGVHDbiomarker指标(sST2，REG3α)，作为基本数据条；将上述病人的基本数据条以及aGVHD发生时是否为重度与临床aGVHD一线糖皮质激素治疗反应进行关联，并采用逻辑回归技术，建立aGVHD一线糖皮质激素耐药/依赖预测模型。该基于aGVHDbiomarker的一线糖皮质激素治疗反应预测模型，通过建立机器学习模型，对发生aGVHD病人一线糖皮质激素治疗后是否发生激素抵抗/依赖进行预测及分层，为临床决策提供参考。

摘要： 本发明公开了一种基于aGVHD biomarker的重度肠道aGVHD模型的方法，属于造血干细胞移植技术领域，包括aGVHD biomarker指标监测及数据筛选与分组、单个重度肠道aGVHD模型训练、多模型融合、重度肠道aGVHD模型性能前瞻性验证的四个步骤。该基于aGVHD biomarker的重度肠道aGVHD模型的方法，通过建立机器学习模型，采用多模型融合技术对病人发生重度肠道aGVHD的严重程度进行评估，效果优于单个肠道aGVHD模型，对病人发生肠道aGVHD严重程度进行精准划分，为临床决策提供指导；同时仅需检测血清中aGVHD biomarker指标，避免了例如内窥镜检查和肠粘膜活检等的肠道aGVHD常规诊断方法给病人带来的强烈不适感，更适应于中国病人群体。

摘要： 本发明公开了一种用于真实世界数据的biomarker预测性研究方法，涉及造血干细胞移植技术领域。S1、biomarker指标监测及数据筛选与分组，动态监测真实世界病人群体重要时间点的biomarker指标；S2、基于sST2或REG3α峰值浓度进行风险分层，选取病人移植后100天内sST2、REG3α峰值浓度作为病人最坏情况的指标，并与病人的长期预后(生存、非复发死亡)进行统计关联；S3、动态监测病人风险分层变化及趋势。该用于真实世界数据的biomarker预测性研究方法，本发明更适应于真实世界数据，本发明摆脱了研究结论对具体检测时间点的依赖，更具临床参考性，本发明可动态监测病人所处的风险状态和趋势，便于医生随时关注和及时跟进病人的风险变化。

摘要： 本发明属于造血干细胞移植领域；本发明公开了一种基于aGVHD biomarker的风险分层及监测方法，包括以下步骤，S1：aGVHD biomarker指标监测及病人群体分组；S2：模型训练；S3：重度综合、肠道aGVHD风险分层；S4：动态监测病人风险分层变化及趋势；本发明采用模型融合技术，对病人进行重度综合、肠道aGVHD的低、中、高风险分层；可动态监测不同时间点病人的aGVHD biomarker指标、风险分层状态及变化趋势，为临床决策提供参考；相对应现有的技术本发明更适应于中国病人群体。

摘要： 本发明提供一种肾癌血液生物标志物的检测方法及试剂盒。具体地说，本发明涉及一种对肾癌血液生物标志物NNMT、LCP1及NM23A全部进行检测的方法及试剂盒，这些检测结果能由医师之类的医疗专家有效地用来判断肾癌罹患与否、肾癌发展程度、肾癌治疗经过，尤其是能够有效地适用于肾癌的早期诊断、肾细胞癌类型中占大多数的透明细胞型肾细胞癌的诊断。