Can molecular biomarkers replace a clinical risk score for resectable colorectal liver metastasis?

In resectable colorectal liver metastasis(CRLM) the role and use of molecular biomarkers is still controversial. Several biomarkers have been linked to clinical outcomes in CRLM, but none have so far become routine for clinical decision making. For several reasons, the clinical risk score appears to no longer hold the same predictive value. Some of the reasons include the ever expanding indications for liver resection, which now increasingly tend to involve extrahepatic disease, such as lung metastases(both resectable and non-resectable) and the shift in indication from "what is taken out"(e.g., how much liver has to be resected) to "what is left behind"(that is, how much functional liver tissue the patient has after resection). The latter is amenable to modifications by using adjunct techniques of portal vein embolization and the associating liver partition and portal vein ligation for staged hepatectomy techniques to expand indications for liver resection. Added to this complexity is the increasing number of molecular markers, which appear to hold important prognostic and predictive information, for which some will be discussed here. Beyond characteristics of tissue-based genomic profiles will be liquid biopsies derived from circulating tumor cells and cell-free circulating tumor DNA in the blood. These markers are present in the peripheral circulation in the majority of patients with metastatic cancer disease. Circulating biomarkers may represent more readily available methods to monitor, characterize and predict cancer biology with future implications for cancer care.

Role of molecular biomarkers in glioma resection: a systematic review

New discoveries based on genetic and epigenetic evidence have significantly expanded the understanding of diffuse gliomas.Molecular biomarkers detected in diffuse gliomas are not only potential targets for radiotherapy,chemotherapy,and immunotherapy,but are also able to guide surgical treatment.Previous studies have suggested that the optimal extent of resection of diffuse gliomas varies according to the expression of specific molecular biomarkers.However,the specific guiding role of these biomarkers in the resection of diffuse gliomas has not been systemically analyzed.This review summarizes several critical molecular biomarkers of tumorigenesis and progression in diffuse gliomas and discusses different strategies of tumor resection in the context of varying genetic expression.With ongoing study and advances in technology,molecular biomarkers will play a more important role in glioma resection and maximize the survival benefit from surgery for diffuse gliomas.

Molecular biomarkers in current management of metastatic colorectal cancer

Over the past two decades,the treatment outcomes in metastatic colorectal cancer(mCRC)have been remarkably improved,largely from the evolution of systemic therapy.Also,the molecular biomarkers have played a major role in this improvement by their predictive value in current treatment paradigm in mCRC.Currently,extended RAS mutation analysis is required for consideration of anti-epidermal growth factor receptor therapy in patients with mCRC.Several uncommon gene alterations have emerged as the potential targets for their matched molecular targeted therapy.Although,most patients with mCRC do not derive benefit from immunotherapy.By using microsatellite instability or mismatch repair test,we are now able to identify a small subgroup of patients with mCRC who have a very good response to immune checkpoint inhibitors.With the increasing number of required biomarkers in mCRC management,multiplex gene panel testing is now replacing single gene testing strategy.In patients accessible to matched molecular targeted therapy,especially for clinical trials,the comprehensive genomic profiling might be the preferred testing method.Although,it is potentially benefit in mCRC treatment,the liquid biopsy is not yet clinically applicable.The optimal utilization of molecular biomarker testing is required for best treatment outcomes in individual patients.

Progress on molecular biomarkers and classification of malignant gliomas

Gliomas are the most common primary intracranial tumors in adults.Anaplastic gliomas(WHO gradeⅢ)and glioblastomas(WHO gradeⅣ)represent the major groups of malignant gliomas in the brain.Several diagnostic,predictive,and prognostic biomarkers for malignant gliomas have been reported over the last few decades,and these markers have made great contributions to the accuracy of diagnosis,therapeutic decision making,and prognosis of patients.However,heterogeneity in patient outcomes may still be observed,which highlights the insufficiency of a classification system based purely on histopathology.Great efforts have been made to incorporate new information about the molecular landscape of gliomas into novel classifications that may potentially guide treatment.In this review,we summarize three distinctive biomarkers,three most commonly altered pathways,and three classifications based on microarray data in malignant gliomas.

Molecular biomarkers,network biomarkers,and dynamic network biomarkers for diagnosis and prediction of rare diseases

The difficulty of converting scientific research findings into novel pharmacological treatments for rare and life-threatening diseases is enormous.Biomarkers related to multiple biological processes involved in cell growth,proliferation,and disease occurrence have been identified in recent years with the development of immunology,molecular biology,and genomics technologies.Biomarkers are capable of reflecting normal physiological processes,pathological processes,and the response to therapeutic intervention;as such,they play vital roles in disease diagnosis,prevention,drug response,and other aspects of biomedicine.The discovery of valuable biomarkers has become a focal point of current research.Numerous studies have identified molecular biomarkers based on the differential expression/concentration of molecules(e.g.,genes/proteins)for disease state diagnosis,characterization,and treatment.Although technological breakthroughs in molecular analysis platforms have enabled the identification of a large number of candidate biomarkers for rare diseases,only a small number of these candidates have been properly validated for use in patient treatment.The traditional molecular biomarkers may lose vital information by ignoring molecular associations/interactions,and thus the concept of network biomarkers based on differential associations/correlations of molecule pairs has been established.This approach promises to be more stable and reliable in diagnosing disease states.Furthermore,the newly-emerged dynamic network biomarkers(DNBs)based on differential fluctuations/correlations of molecular groups are able to recognize pre-disease states or critical states instead of disease states,thereby achieving rare disease prediction or predictive/preventative medicine and providing deep insight into the dynamic characteristics of disease initiation and progression.

Nomogram model including LATS2 expression was constructed to predict the prognosis of advanced gastric cancer after surgery

BACKGROUND Gastric cancer is a leading cause of cancer-related deaths worldwide.Prognostic assessments are typically based on the tumor-node-metastasis(TNM)staging system,which does not account for the molecular heterogeneity of this disease.LATS2,a tumor suppressor gene involved in the Hippo signaling pathway,has been identified as a potential prognostic biomarker in gastric cancer.AIM To construct and validate a nomogram model that includes LATS2 expression to predict the survival prognosis of advanced gastric cancer patients following ra-dical surgery,and compare its predictive performance with traditional TNM staging.METHODS A retrospective analysis of 245 advanced gastric cancer patients from the Fourth Hospital of Hebei Medical University was conducted.The patients were divided into a training group(171 patients)and a validation group(74 patients)to deve-lop and test our prognostic model.The performance of the model was determined using C-indices,receiver operating characteristic curves,calibration plots,and decision curves.RESULTS The model demonstrated a high predictive accuracy with C-indices of 0.829 in the training set and 0.862 in the validation set.Area under the curve values for three-year and five-year survival prediction were significantly robust,suggesting an excellent discrimination ability.Calibration plots confirmed the high concordance between the predictions and actual survival outcomes.CONCLUSION We developed a nomogram model incorporating LATS2 expression,which significantly outperformed conven-tional TNM staging in predicting the prognosis of advanced gastric cancer patients postsurgery.This model may serve as a valuable tool for individualized patient management,allowing for more accurate stratification and im-proved clinical outcomes.Further validation in larger patient cohorts will be necessary to establish its generaliza-bility and clinical utility.

Molecular Biomarker Characteristics of the Linxi Formation Source Rocks in the Middle-Western Region of Inner Mongolia:New evidence for late-stage tectonic evolution of the Paleo-Asian Ocean

Objective Two important geological issues have long been controversial in the Xing-Meng area of North China. The first concerns the final closure of Paleo-Asian Ocean in Xing-Meng area, and the other concerns the folding and lifting of the Xing-Meng Trough. The focus of thses issues is the Late Permian sedimentary environment, which is generally considered to be either an exclusively continental environment or from the closed inland sea environment in the Early to Middle stage to continental lacustrine environment in the late stage. In recent years, we have successively discovered abundant typical marine fossils （e.g., bryozoans and calcareous algae） in the Upper Permian thick limestone layer from Linxi County and Ar Horqin Banner in eastern region of Inner Mongolia and Jiutain County in Jilin Province. These significant findings have attracted the attention from fellow academics.

Molecular genetics of gastric adenocarcinoma in clinical practice

The molecular genetics of gastric carcinoma(GC) dictates their biology and clinical behavior. The two morphologically distinct types of gastric carcinoma by Lauren classification, i.e., intestinal and diffuse cell types, have a significant difference in clinical outcome. These two types of GC have different molecular pathogenetic pathways with unique genetic alterations. In addition to environmental and other etiologies, intestinal type GC is associated with Helicobacter pylori(H. pylori) infection and involves a multistep molecular pathway driving the normal epithelium to intestinal metaplasia, dysplasia, and malignant transformation by chromosomal and/or microsatellite instability(MSI), mutation of tumor suppressor genes, and loss of heterozygosity among others. Diffuse type shows no clear causal relationship with H. pylori infection, but is commonly associated with deficiency of cell-cell adhesion due to mutation of the E-cadherin gene(CDH1), and a manifestation of the hereditary gastric cancer syndrome. Thus, detection of CDH1 mutation or loss of expression of E-cadherin may aid in early diagnosis or screening of diffuse type GC. Detection of certain genetic markers, for example, MSI and matrix metalloproteinases, mayprovide prognostic information, particularly for intestinal type. The common genetic alterations may offer therapeutic targets for treatment of GC. Polymorphisms in Thymidylate synthase to metabolize 5-fluorouracil, glutathione S-transferase for degradation of Cisplatin, and amplification/overexpression of human epidermal growth factor receptor 2 targeted by monoclonal antibody Trastuzumab, are a few examples. P13K/Akt/mT OR pathway, c-Met pathways, epidermal growth factor receptor, insulin-like growth factor receptor, vascular endothelial growth factor receptor fibroblast growth factor receptor, and micro RNAs are several potential therapeutic biomarkers for GC under investigation.

Reclassification and distribution patterns of discovered oils in theDongying Depression, Bohai Bay Basin, China

The Dongying Depression is an important petrolifeous province,with diverse source rocks and complex petroleum distribution patterns.A total of 32 crude oils were analyzed by the gas chromatographyemass spectrometry and isotopic compositions to better understanding the petroleum systems in the study area.Three oil types were classified by hierarchical cluster analyses.Type I and II oils have closely correlation with the discovered source rocks,which have been confirmed to be mainly derived from the lower third and upper forth member of the Eocene Shahejie Formation source rocks(Es3^(L) and Es4^(U)),respectively.Obviously,type III oils contain abundant gammacerane,tricyclic terpanes and C_(29) steranes and have lower values of δ13C than type I and II oils,indicating a completely different source rock and biological origins.Until recently,type III oils fail to match any of the discovered source rock,which contains main contribution of aquatic organism or/and bacteria inputs.In addition,the spacial distribution of these three oil types were discussed.Type I oils mainly distributed in the Es3 and Es4 reservoirs that closed to the generative kitchens.Type II oils occurred in the Es4 reservoirs in the sourthern slope of the depression,which probably caused by lateral migration along the horizontal fractures and sandstone layers within the Es4 interval.Differently,type III oils in the sourthern slope of the depression were mainly discovered in the Eocene Kongdian or Ordocician reservoirs,which suggests great exploration potential of deep underlying strata.

The correlation and overlaps between PD-L1 expression and classical genomic aberrations in Chinese lung adenocarcinoma patients: a single center case series

Objective:To investigate the correlation and overlaps between PD-L1 expression and classical genomic aberrations in Chinese lung adenocarcinoma(LADC)patients.Methods:We reviewed 428 consecutive,surgically resected cases of LADC from October 2015 to December 2016 from our center.PD-L1 expression was evaluated based on tumor proportion score(TPS).Correlation and co-occurrence of PD-L1 expression level with those of classical driver genes,such as EGFR,ALK,ROS-1,and KRAS and with clinical variables and disease-free survival(DFS)were analyzed.Results:Seventy of the 428 cases(16.4%)showed TPS≥1%,and 21 cases(4.9%)showed TPS≥50%.PD-L1 positive expression was significantly associated with male gender,smoking,advanced TNM stage,and solid histologic subtype.Both TPS≥1% and ≥50%were correlated with the absence of an EGFR mutation(P<0.001)and the presence of ALK rearrangement(P=0.024).KRAS mutation was associated with TPS≥50%(P=0.035).PD-L1 positivity commonly overlapped with the alterations of classical driver oncogenes(58.5%with TPS≥1% and 42.9% with TPS≥50%).Approximately three-quarters of PD-L1 positive cases co-occurred with classical therapeutic-gene aberrations in cases with stage III/IV cancer or cancer progression.LADC could be divided into four subgroups based on the expression profile of current routine biomarkers for potential therapeutic strategies.Conclusions:PD-L1 expression is not only closely correlated with classic gene alterations but also commonly overlaps with the aberrations of classical driver oncogenes in Chinese LADC patients.These findings provide a useful overview of clinical strategies that rely on the profile of routinely used molecular biomarkers.

核形态学，核子学与前列腺癌的研究进展

Prostate cancer （PCa） results from a multistep process. This process includes initiation, which occurs through various aging events and multiple insults （such as chronic infection, inflammation and genetic instability through reactive oxygen species causing DNA double-strand breaks）, followed by a multistep process of progression. These steps include several genetic and epigenetic alterations, as well as alterations to the chromatin structure, which occur in response to the carcinogenic stress-related events that sustain proliferative signaling. Events such as evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis are readily observed. In addition, in conjunction with these critical drivers of carcinogenesis, other factors related to the etiopathogenesis of PCa, involving energy metabolism and evasion of the immune surveillance system, appear to be involved. In addition, when cancer spread and metastasis occur, the ＇tumor microenvironment＇ in the bone of PCa patients may provide a way to sustain dormancy or senescence and eventually establish a ＇seed and soil＇ site where PCa proliferation and growth may occur over time. When PCa is initiated and progression ensues, significant alterations in nuclear size, shape and heterochromatin （DNA transcription） organization are found, and key nuclear transcriptional and structural proteins, as well as multiple nuclear bodies can lead to precancerous and malignant changes. These series of cellular and tissue-related malignancy-associated events can be quantified to assess disease progression and management.

Stem cells for the treatment of musculoskeletal pain

Musculoskeletal-related pain is one of the most disabling health conditions affecting more than one third of the adult population worldwide. Pain from various mechanisms and origins is currently underdiagnosed and undertreated. The complexity of molecular mechanisms correlating pain and the progression of musculoskeletal diseases is not yet fully understood. Molecular biomarkers for objective evaluation and treatment follow-up are needed as a step towards targeted treatment of pain as a symptom or as a disease. Stem cell therapy is already under investigation for the treatment of different types of musculoskeletalrelated pain. Mesenchymal stem cell-based therapies are already being tested in various clinical trials that use musculoskeletal system-related pain as the primary or secondary endpoint. Genetically engineered stem cells, as well as induced pluripotent stem cells, offer promising novel perspectives for pain treatment. It is possible that a more focused approach and reassessment of therapeutic goals will contribute to the overall efficacy, as well as to the clinical acceptance of regenerative medicine therapies. This article briefly describes the principal types of musculoskeletal-related pain and reviews the stem cell-based therapies that have been specifically designed for its treatment.

Lung cancer screening, what has changed after the latest evidence?

Lung cancer(LC)is still one of the most frequent cancers with a high related mortality.Their prognosis is directly proportional to the stage at the time of diagnosis.Seventy percent are currently diagnosed in advanced or locally advanced stage(higher than stage III),making a cure unlikely for the majority of patients.Developments in LC treatment are significant however they do not seem to be enough to reverse the current situation,at least,in a short period of time.Despite recent advances in treatment,primary prevention and early diagnosis appear to be the key to reduce the incidence and mortality of this disease.Many countries have developed LC screening programs based on the results of clinical trials published in recent years.The aim of this paper is to review the latest results of the NEderlands Leuvens Longkanker Screenings Onderzoek and compare them with the findings of the National Lung Screening Trial.We address the question whether it is necessary to continue discussing the evidence regarding LC screening.In both trials,there is a clear impact on LC mortality but,with a modest reduction in over all mortality.Undoubtedly,the benefit of screening can be expected to grow as low-dose computed tomographys are performed over longer periods of time.

Revisiting chemoresistance in ovarian cancer:Mechanism,biomarkers,and precision medicine

Among the gynecological cancers,ovarian cancer is the most lethal.Its therapeutic options include a combination of chemotherapy with platinum-based compounds and cytoreductive surgery.Most ovarian cancer patients exhibit an initial response to platinum-based therapy,however,platinum resistance has led to up to 80%of this responsive cohort becoming refractory.Ovarian cancer recurrence and drug resistance to current chemotherapeutic options is a global challenge.Chemo-resistance is a complex phenomenon that involves multiple genes and signal transduction pathways.Therefore,it is important to elucidate on the underlying molecular mechanisms involved in chemo-resistance.This inform decisions regarding therapeutic management and help in the identification of novel and effective drug targets.Studies have documented the individual bidmarkers of platinum-resistance in ovarian cancer that are potential therapeutic targets.This review summarizes the molecular mechanisms of platinum resistance in ovarian cancer,novel drug targets,and clinical outcomes.

Biomarker for monitoring heavy metal pollution in aquatic environment:An overview toward molecular perspectives

Water pollution is a significant problem in almost all parts of the world.The complexity of anthropogenic activities along the watershed seems to lead the river to function as a giant disposal container.The river is under threat of degradation,mainly due to heavy metal pollution from anthropogenic actions.Heavy metals become harmful if they pollute waters since they are accumulative,toxic,and carcinogenic in water bodies and biota.Various biomarkers to evaluate heavy metal contamination in several aquatic organisms have been widely reported.The use of molecular biomarkers become more popular in the last years and still lead for future prospect.Proteomics and genomics with bioinformatics approaches have been expanded with technological methods through DNA and RNA sequencing and mass spectrometry based proteomics.Therefore,this article aims to review studies using biomarker approaches in many aquatic organisms.This review is expected to reference and encourage future biomarker research,especially for monitoring heavy metal pollution in rivers.

Developing DNA methylation-based diagnostic biomarkers

An emerging paradigm shift for disease diagnosis is to rely on molecular characterization beyond traditional clinical and symptom-based examinations. Although genetic alterations and transcription signature were first introduced as potential biomarkers, clinical implementations of these markers are limited due to low reproducibility and accuracy. Instead, epigenetic changes are considered as an alternative approach to disease diagnosis. Complex epigenetic regulation is required for normal biological functions and it has been shown that distinctive epigenetic disruptions could contribute to disease pathogenesis. Disease-specific epigenetic changes, especially DNA methylation, have been observed,suggesting its potential as disease biomarkers for diagnosis. In addition to specificity, the feasibility of detecting disease-associated methylation marks in the biological specimens collcted noninvasively,such as blood samples, has driven the clinical studies to validate disease-specific DNA methylation changes as a diagnostic biomarker. Here, we highlight the advantages of DNA methylation signature for diagnosis in different diseases and discuss the statistical and technical challenges to be overcome before clinical implementation.

胃癌及其淋巴结转移的诊断学分子标志物的鉴定

背景与目的:分子标志物是肿瘤快速诊断的重要工具。本研究旨在鉴定可用于临床诊断胃癌及其淋巴结转移的分子标记物。方法:前瞻性收集2014年12月1日至2015年12月31日期间的胃癌手术标本和相应的癌旁正常胃黏膜,以及胃周转移性和非转移性淋巴结标本,采用实时定量PCR方法对9个目标基因进行定量检测。采用相对表达量来计算目标基因的mRNA表达水平。采用单因素方差分析(ANOVA)和Tukey多重比较检验来进行统计学比较,采用GraphPad Prism软件绘制统计分析图。结果:在9个受检基因中,INHBA和SPP1在胃癌组织中稳定高表达,其mRNA表达水平分别是相应癌旁胃黏膜的15.4和15.6倍(P<0.001);前者诊断胃癌的敏感性和特异性分别为91.3%和95.7%(ROC曲线下面积0.974),后者的敏感性和特异性分别为82.6%和87.0%(ROC曲线下面积0.924)。进一步分析转移性与非转移性淋巴结组织中上述两个基因的表达差异,结果显示,SPP1 mRNA表达水平两者差异无统计学意义(P=0.470),而转移性淋巴结中INHBA mRNA表达水平上调了4.1倍(P<0.001),其诊断淋巴结转移的敏感性和特异性分别为80.0%和81.5%(ROC曲线下面积0.857),而且能有效区别更严重的肿瘤进展,如T3与T4(P=0.003)、M0与M1(P=0.043),以及不同的组织学类型,如肠型与弥漫型(P=0.019)。结论:INHBA是用于诊断胃癌及其淋巴结转移的一种理想的分子标志物。