Potential Biomarkers In Patients Research Articles

32P Prosaposin A as a potential biomarker in patients of squamous cell carcinoma of head and neck

Head and neck squamous cell carcinoma (HNSCC) is one of the leading causes of cancer as well as cancer related deaths. Most patients present in a locally advanced state which lead to significant morbidity and mortality. A biomarker for HNSCC has potential for earlier detection and better treatment of cases but it’s search has been elusive so far. In a previous analysis by investigators as well as at our centre, the levels of Prosaposin A (PSAP) were found to be differentially expressed in the serum of HNSCC patients when compared to age and sex matched healthy controls.

The role of hypoxia-related genes in TACE-refractory hepatocellular carcinoma: Exploration of prognosis, immunological characteristics and drug resistance based on onco-multi-OMICS approach.

Transcatheter arterial chemoembolization (TACE) is an effective treatment for hepatocellular carcinoma (HCC). During TACE, chemotherapeutic agents are locally infused into the tumor and simultaneously cause hypoxia in tumor cells. Importantly, the poor effect of TACE in some HCC patients has been shown to be related to dysregulated expression of hypoxia-related genes (HRGs). Therefore, we identified 33 HRGs associated with TACE (HRGTs) by differential analysis and characterized the mutational landscape of HRGTs. Among 586 HCC patients, two molecular subtypes reflecting survival status were identified by consistent clustering analysis based on 24 prognosis-associated HRGs. Comparing the transcriptomic difference of the above molecular subtypes, three molecular subtypes that could reflect changes in the immune microenvironment were then identified. Ultimately, four HRGTs (CTSO, MMP1, SPP1, TPX2) were identified based on machine learning approachs. Importantly, risk assessment can be performed for each patient by these genes. Based on the parameters of the risk model, we determined that high-risk patients have a more active immune microenvironment, indicating “hot tumor” status. And the Tumor Immune Dysfunction and Exclusion (TIDE), the Cancer Immunome Atlas (TCIA), and Genome of Drug Sensitivity in Cancer (GDSC) databases further demonstrated that high-risk patients have a positive response to immunotherapy and have lower IC50 values for drugs targeting cell cycle, PI3K/mTOR, WNT, and RTK related signaling pathways. Finally, single-cell level analysis revealed significant overexpression of CTSO, MMP1, SPP1, and TPX2 in malignant cell after PD-L1/CTLA-4 treatment. In conclusion, Onco-Multi-OMICS analysis showed that HRGs are potential biomarkers for patients with refractory TACE, and it provides a novel immunological perspective for developing personalized therapies.

Laminin-5, Fibronectin, and Type IV Collagen as Potential Biomarkers of Brain Glioma Malignancy.

The presented work is based on the quantification of LN-5, FN, and COL IV in blood plasma as potential biomarkers in patients diagnosed with glioma in grades G1 to G4. The obtained concentration results were compared with the protein content in the control group, which consisted of smokers of different ages. The obtained results were statistically analysed and interpreted based on the available clinical description. Quantitative determinations of LN-5, FN, and COL IV were performed with the use of SPRi biosensors specific to the tested proteins. Comparing groups K and G4, as well as G2 and G4, statistically significant relationships between changes in the concentration of individual proteins, were observed. The analysis showed significant correlations between FN and LN-5, between FN and COL IV, and between LN-5 and COL IV. There was a moderate positive correlation between individual proteins and the age of the patient. The ROC analysis distinguished patients with advanced disease from the control group. The results of the research show that LN-5, FN, and COL IV are effective biomarkers of brain glioma that may be helpful in non-invasive diagnosis and determining the grade of the disease.

Polymorphisms in the Genes Coding for TLRs, NLRs and RLRs Are Associated with Clinical Parameters of Patients with Acute Myeloid Leukemia.

Toll-like receptors (TLRs), NOD-like receptors (NLRs), and RIG-I-like receptors (RLRs) are major elements of the innate immune system that recognize pathogen-associated molecular patterns. Single-nucleotide polymorphisms (SNPs) in the TLR, NLR, and RLR genes may lead to an imbalance in the production of pro- and anti-inflammatory cytokines, changes in susceptibility to infections, the development of diseases, and carcinogenesis. Acute myeloid leukemia (AML) is a bone marrow malignancy characterized by uncontrolled proliferation of transformed myeloid precursors. We retrospectively analyzed 90 AML patients. We investigated the effect of fifteen SNPs located in the genes coding for RLR1 (rs9695310, rs10738889, rs10813831), NOD1 (rs2075820, rs6958571), NOD2 (rs2066845, rs2066847, rs2066844), TLR3 (rs5743305, rs3775296, 3775291), TLR4 (rs4986791, rs4986790), and TLR9 (rs187084, rs5743836). We observed that TLR4 rs4986791, TLR9 rs5743836, and NOD2 rs2066847 were associated with CRP levels, while RLR-1 rs10738889 was associated with LDH level. Furthermore, we found TLR3 rs5743305 AA to be more common in patients with infections. We also found TLR9 rs187084 C to be associated with more favorable risk, and RLR-1 rs9695310 GG with higher age at diagnosis. In conclusion, the current study showed that SNPs in the genes encoding TLRs, NLRs, and RLRs may be potential biomarkers in patients with AML.

Association between circulating oxidized OxLDL/LDL-C ratio and the severity of coronary atherosclerosis, along with other emerging biomarkers of cardiovascular disease in patients with type 2 diabetes

AimsThe aim of this study was to evaluate the association between circulating oxLDL/LDL-C ratio and the severity of coronary atherosclerosis, along with other emerging biomarkers of cardiovascular disease (CVD) in patients with type 2 diabetes. MethodsWe recruited 152 patients with type 2 diabetes for our study. ELISA measured the plasma levels of oxLDL and other biomarkers. The severity of coronary lesions was evaluated using Gensini scores, which were calculated based on results of coronary computed tomographic angiography (CCTA). All patients were allocated into four groups according to CCTA findings and Gensini score: normal group (score = 0), mild coronary atherosclerosis group (0 < scores ≤ 3), moderate coronary atherosclerosis group (3.01 ≤ scores ≤ 32.67) and severe coronary atherosclerosis group (32.68 ≤ scores ≤ 180). Association between the oxLDL/LDL-C ratio and the severity of coronary atherosclerosis were evaluated using logistic regression models. ResultsMultivariate logistic regression analysis showed that the oxLDL/LDL-C ratio was positively associated with severity of coronary atherosclerosis (OR 2.03, 95% CI 1.31–3.14, p < 0.01). Interleukin 33 (IL33) correlated positively with oxLDL/LDL-C ratio (r = 0.274, p < 0.01). However, vascular cell adhesion molecular-1 (VCAM-1) had similar trends with oxLDL/LDL-C ratio in these 4 groups. ConclusionsOxLDL/LDL-C ratio is considered as a potential biomarker in patients with diabetes for early recognition and intervention of severe coronary atherosclerosis, and will be more effective if tested IL33 and VCAM-1 at the same time.

Leukocyte Telomere Length Variability as a Potential Biomarker in Patients with PolyQ Diseases.

SCA1, SCA2, and SCA3 are the most common forms of SCAs among the polyglutamine disorders, which include Huntington’s Disease (HD). We investigated the relationship between leukocyte telomere length (LTL) and the phenotype of SCA1, SCA2, and SCA3, comparing them with HD. The results showed that LTL was significantly reduced in SCA1 and SCA3 patients, while LTL was significantly longer in SCA2 patients. A significant negative relationship between LTL and age was observed in SCA1 but not in SCA2 subjects. LTL of SCA3 patients depend on both patient’s age and disease duration. The number of CAG repeats did not affect LTL in the three SCAs. Since LTL is considered an indirect marker of an inflammatory response and oxidative damage, our data suggest that in SCA1 inflammation is present already at an early stage of disease similar to in HD, while in SCA3 inflammation and impaired antioxidative processes are associated with disease progression. Interestingly, in SCA2, contrary to SCA1 and SCA3, the length of leukocyte telomeres does not reduce with age. We have observed that SCAs and HD show a differing behavior in LTL for each subtype, which could constitute relevant biomarkers if confirmed in larger cohorts and longitudinal studies.

Type IV Collagen in Human Colorectal Liver Metastases-Cellular Origin and a Circulating Biomarker.

Simple SummaryPatients with colorectal liver metastases (CLM) can be cured through surgery if metastases are detected early in disease progression. Today, CLM diagnosis relies heavily on diagnostic imaging, and cheap, non-invasive, and efficiently measurable biomarkers are needed. Circulating type IV collagen (COL IV) is a potential biomarker for detecting CLM. Patients with CLM show elevated circulating levels of COL IV and increased tissue expression of COL IV in CLM tissue, which could result from enhanced production and degradation of COL IV. This study aimed to establish the cellular source behind enhanced COL IV levels, which is helpful in the evaluation of the biomarker potential of COL IV. We show that fibroblasts express COL IV both in vitro and in the stromal tissue of CLM. We also found that CLM tissue expresses COL IV-degrading proteases. Lastly, CLM patients have higher circulating COL IV levels than healthy controls.Circulating type IV collagen (cCOL IV) is a potential biomarker for patients with colorectal liver metastases (CLM) who present with elevated levels of COL IV in both CLM tissue and circulation. This study aimed to establish the cellular origin of elevated levels of COL IV and analyze circulating COL IV in CLM patients. The cellular source was established through in situ hybridization, immunohistochemical staining, and morphological evaluation. Cellular expression in vitro was assessed by immunofluorescence. Tissue expression of COL IV-degrading matrix metalloproteinases (MMPs)-2, -7, -9, and -13 was studied with immunohistochemical staining. Plasma levels of COL IV in CLM patients and healthy controls were analyzed with ELISA. This study shows that cancer-associated fibroblasts (CAFs) express COL IV in the stroma of CLM and that COL IV is expressed in vitro by fibroblasts but not by tumor cells. MMP-2, -7, -9, and -13 are expressed in CLM tissue, mainly by hepatocytes and immune cells, and circulating COL IV is significantly elevated in CLM patients compared with healthy controls. Our study shows that stromal cells, not tumor cells, produce COL IV in CLM, and that circulating COL IV is elevated in patients with CLM.

Correlation of Ionized Magnesium with the Parameters of Oxidative Stress as Potential Biomarkers in Patients with Anxiety and Depression: A Pilot Study.

BackgroundMagnesium (Mg) is the second most abundant intracellular cation. Ionized Mg is the only active form of Mg. The concentration of ionized Mg could be a potentially novel biomarker for anxiety and depression.AimThe aim of this study was to assess the serum concentration of ionized Mg and its correlation with biomarkers of oxidative stress and inflammation in patients with anxiety and depression.MethodsIn this study included 93 respondents were divided into 3 groups: C (control group—18 respondents); A (patients with anxiety disorder, dissociative/conversion disorders and somatoform disorders—36 patients); D (patients with depression—39 patients). Clinical diagnosis was based on ICD-10 criteria. Blood samples were used for standard laboratory analysis, ionized Mg analysis, oxidative stress, and inflammatory parameters.ResultsStatistical significance was recorded between healthy volunteers and patients (anxiety/depression) in ionized Mg values. In anxious patients, malondialdehyde (MDA) had a positive correlation between the parameters of oxidative stress with ionized Mg. In depressive patients, MDA had a positive correlation, and glutathione peroxidase 1 (GPX1) a negative correlation with the concentration of ionized Mg.ConclusionIonized Mg and its correlation with parameters of oxidative stress could be potential biomarkers in anxious and depressive patients.

Identification of Differentially Expressed Mirna by Next Generation Sequencing in Locally Advanced Breast Cancer Patients of South Indian Origin.

miRNAs are known to be aberrantly expressed in the serum, tissue, and Peripheral Blood Mononuclear Cells (PBMC) of cancer patients and could serve as potential noninvasive diagnostic markers for breast cancer. The aim of this study was to identify the differentially expressed miRNA using next-generation sequencing (NGS) from the paired PBMC samples from breast cancer patients and age-matched healthy individuals and explore their functional significance. In this study, PBMCs were employed for the detection of miRNAs by NGS in locally advanced breast cancer (LABC) women of South Indian origin who were divided into three age groups, (a) 40yrs-50yrs (b) 50yrs-60yrs and (c) 60yrs-70yrs, compared with age-matched control groups. Four miRNAs (hsa-miR-192-5p, hsa-miR-24-2-2p, hsa-miR-3609, and hsa-miR-664b-3p) were found to be differentially expressed among LABC patients compared with age matched healthy women of the South Indian population. While miR-24-2-5p, miR3609, and miR-664b-3p were down-regulated, miR-192-5p was up-regulated. Gene Ontology (GO) annotations implicated miRNA with signaling pathways in peripheral nerve synapses, glutamatergic synapse, and cell morphogenesis, all of which play a pivotal role in the manifestation of cancer. Four miRNAs- 3 (While miR-24-2-5p, miR3609, and miR-664b-3p) downregulated and one upregulated (miR-192-5p) were identified as potential biomarkers for patients with locally advanced breast cancer. These markers could be validated in studies with a larger sample size.

Serum Oxylipin Profiles Identify Potential Biomarkers in Patients with Acute Aortic Dissection.

Aortic dissection (AD) is a life-threatening cardiovascular disease with a dismal prognosis. Inflammation plays an important role in AD. Oxylipins are bioactive lipids involved in the modulation of inflammation and may be involved in the pathogenesis and progression of AD. This study aims to identify possible metabolites related to AD. A total of 10 type A Aortic dissection (TAAD) patients, 10 type B Aortic dissection (TBAD) patients and 10 healthy controls were included in this study. Over 100 oxylipin species were identified and quantified by liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis. Our investigation demonstrated substantial alterations in 91 oxylipins between AD and healthy individuals. Patients with TAAD had 89 entries accessible compared to healthy controls. According to orthogonal partial least squares discriminant analysis (OPLS-DA), fitness (R2X = 0.362 and R2Y = 0.807, p = 0.03) and predictability (Q2 = 0.517, p = 0.005) are the validation parameters between the two groups. Using multivariate logistic regression, 13-HOTrE and 16(17)-EpDPE were the risk factors in the aortic patients group compared to healthy people (OR = 2.467, 95%CI:1.256–7.245, p = 0.035; OR = 0.015, 95%CI:0.0002–0.3240, p = 0.016, respectively). In KEGG enrichment of differential metabolites, the arachidonic acid metabolism pathway has the most metabolites involved. We established a diagnostic model in distinguishing between AD and healthy people. The AUC was 0.905. Oxylipins were significantly altered in AD patients, suggesting oxylipin profile is expected to exploit a novel, non-invasive, objective diagnosis for AD.

FC032: Copeptin as a Potential Biomarker in Patients with Autosomal-Dominant Polycystic Kidney Disease (ADPKD)—Update from the AD(H)PKD Study

Abstract BACKGROUND Prediction of disease progression is one of the main challenges in the treatment of Autosomal-Dominant Polycystic Kidney Disease (ADPKD). In addition to already established biomarkers such as total kidney volume (TKV), further biomarkers that are feasible and easy to collect would be important to allow conclusions on prognosis as well as, in the best case, on long-term treatment response. Post-hoc analyses of the TEMPO 3:4 study showed that copeptin could serve as such a biomarker [1, 2]. In this study, we investigated copeptin over a multi-year course in participants of the AD(H)PKD study. METHOD Copeptin was measure from serum samples of 486 patients in the AD(H)PKD study at both initial and follow-up presentations. A total of 95 patients were on tolvaptan therapy at least at one of the measurement time points. We examined the measured values with respect to their distribution in different patient groups (e.g. age, Mayo class) and their changes on tolvaptan administration. Baseline eGFR values were developed using historic creatinine measurements up to 8000 days prior and 1500 days after copeptin measurements. For each patient with at least 5 creatinine measurements an eGFR slope was calculated. The models were developed using a robust linear modelling approach. Slopes were extracted to be the parameter associated to date and multiplied by 365 to retrieve an annual eGFR slope. eGFRs predicted for the specific dates at which copeptin has been measured were then calculated and used in subsequent modelling approaches. To develop a model predictive of eGFR, we used a stepwise regression approach, removing insignificant coefficients at each step. RESULTS As expected, copeptin was significantly lower in 391 tolvaptan naive patients than in 95 patients on therapy (9.95 pmol/L versus 19.78 pmol/L; P &amp;lt; 0.0001). More advanced CKD stages showed higher copeptin levels, both with and without tolvaptan, than at lower stages. Independent from kidney function, copeptin levels were consistently higher on tolvaptan than without therapy. Also, larger TKV showed higher copeptin levels in both groups. In 40 patients, copeptin measurements before the start of tolvaptan therapy and follow-up measurements under tolvaptan at the target dose (90/30 mg) were available, and a significant increase in copeptin levels on tolvaptan (copeptin before tolvaptan therapy: 9.798 pmol/L, copeptin on tolvaptan 23.83 pmol/L; P &amp;lt; 0.0001) could be traced during the course. Linear regression models showed that copeptin is an independent variable for the prediction of eGFR slope when added to age, height-adjusted total kidney volume (htTKV) and baseline eGFR. Besides, correlation of predicted future eGFR based on Mayo Classification is slightly but significantly improved by adding copeptin to the model (R2 Mayo 0.9244 and R2 Mayo + copeptin 0.9446). CONCLUSION Our data obtained from the real-life setting should again be reconciled with the results from the TEMPO 3:4 cohort. Our findings show that copeptin levels are both associated with kidney function and with future eGFR loss. Adding copeptin to the model of the Mayo Classification indeed improves the prediction of future eGFR. However, it is not clear yet whether this mild effect will have an impact in routine clinical care. Copeptin has the potential to facilitate prognostic assessment as a biomarker and thus could be helpful in deciding on therapy initiation and possibly more patient-specific dosing. Future analyses of outcome in relation to copeptin will provide further data and might enable implementation in clinical practice.

Association of galactose and insulin resistance in polycystic ovary syndrome: A case-control study

SummaryBackgroundPolycystic ovary syndrome (PCOS) is closely linked to metabolic disorders. Recent reports have identified galactose as having strong associations with metabolic disorders, however, the correlation between galactose and PCOS remains largely unknown.MethodsThe serum galactose levels of 104 patients with PCOS and 98 controls were measured, and their relationships with several metabolic parameters were analyzed. The study took place at the Center for Reproductive Medicine at Shengjing Hospital of China Medical University, Shenyang, China from July 13 to Oct 20, 2020. The relationships between serum galactose and PCOS as well as PCOS-related insulin resistance were investigated via logistic regression analyses, and the performance of serum galactose as a potential biomarker for PCOS was evaluated using receiver operating characteristic curve analysis.FindingsHigher serum galactose levels were observed in the patients with PCOS than in the controls (p = 0.001). There was still a correlation between circulating galactose levels and PCOS after adjusting for covariates (p = 0.002; odds ratio (OR), 1.133; 95% confidence interval (CI) 1.047–1.227). Serum galactose levels were shown to be most closely related to the fasting serum insulin level (r = 0.370, p = 0.001) and were higher in the insulin-resistant subgroup than in the non-insulin-resistant subgroup of patients with PCOS (p = 0.001). There was no difference in serum galactose levels between the insulin-resistant and non-insulin-resistant subgroups of women in the control group (p > 0.05). Furthermore, higher serum galactose levels were shown to be associated with insulin resistance in PCOS (p = 0.004; OR, 26.017; 95% CI, 2.907–232.810). The area under the curve for galactose-mediated prediction of PCOS was 80.0%, with a sensitivity of 71.0% and a specificity of 86.4%.InterpretationHigher circulating galactose levels correlate with PCOS and PCOS-related insulin resistance; therefore, it may serve as a potential biomarker for patients with PCOS. These findings require further validation in a study with a larger sample size.FundingNational Natural Science Foundation of China (No. 82,071,607 and 32,100,691); LiaoNing Revitalization Talents Program (No. XLYC1907071); Fok Ying Tung Education Foundation (No. 151,039); Key Research and Development Program of Liaoning Province (NO. 2,018,225,062); Outstanding Scientific Fund of Shengjing Hospital (No. 202,003).

The Pan-Cancer Landscape of Crosstalk Between TRP Family and Tumour Microenvironment Relevant to Prognosis and Immunotherapy Response.

BackgroundTransient Receptor Potential (TRP) channel is a kind of channel protein widely distributed in peripheral and central nervous system. They can be regulated by natural aromatic substances and serve as a therapeutic target for many diseases. However, the role and function of the TRP family genes in tumours remain unclear.MethodsGene alterations (mutation, copy number, methylation), expression, clinical features, and prognostic value of the TRP family genes were evaluated in pan-cancer using data from The Cancer Genome Atlas and Genotype-Tissue Expression databases. TRP score was calculated by the ssGSEA function of the R package “GSVA”. The association of TRP score and the tumour microenvironment (TME), especially the tumour immune microenvironment (TIME), along with immunotherapy response were explored in-depth.ResultsTRP family genes were involved in tumour progression and highly associated with poor prognosis in a variety of cancers. TRP score was positively associated with malignant pathways in pan-cancer, such as IL6–JAK–STAT3 signalling, interferon-gamma response, and inflammatory response. All pathways were closely associated with TIME. Elevated TRP score also correlated with multiple immune-related characteristics of the TIME in pan-cancer. Moreover, the TRP score was a predictive biomarker for immune checkpoint inhibitor (ICI) treatments in patients with tumours.ConclusionsTRP family genes play a key role in pan-cancer and are closely associated with TME. Patients with high TRP scores have excellent immune-activated TIME and immunotherapy sensitivity. Therefore, the TRP score could be a potential biomarker for patients with tumours treated with ICI.

Evaluation of the TCR Repertoire as a Predictive and Prognostic Biomarker in Cancer: Diversity or Clonality?

Simple SummaryThe TCR is the T cell antigen receptor, and it is responsible of the T cell activation, through the HLA-antigen complex recognition. Studying the TCR repertoire in patients with cancer can help to better understand the anti-tumoural responses and it has been suggested to have predictive and or/prognostic values, both for the disease and in response to treatments. The aim of this review is to summarize TCR repertoire studies performed in patients with cancer found in the literature, thoroughly analyse the different factors that can be involved in shaping the TCR repertoire, and draw the current conclusions in this field, especially focusing on whether the TCR diversity—or its opposite, the clonality—can be used as predictors or prognostic biomarkers of the disease.T cells play a vital role in the anti-tumoural response, and the presence of tumour-infiltrating lymphocytes has shown to be directly correlated with a good prognosis in several cancer types. Nevertheless, some patients presenting tumour-infiltrating lymphocytes do not have favourable outcomes. The TCR determines the specificities of T cells, so the analysis of the TCR repertoire has been recently considered to be a potential biomarker for patients’ progression and response to therapies with immune checkpoint inhibitors. The TCR repertoire is one of the multiple elements comprising the immune system and is conditioned by several factors, including tissue type, tumour mutational burden, and patients’ immunogenetics. Its study is crucial to understanding the anti-tumoural response, how to beneficially modulate the immune response with current or new treatments, and how to better predict the prognosis. Here, we present a critical review including essential studies on TCR repertoire conducted in patients with cancer with the aim to draw the current conclusions and try to elucidate whether it is better to encounter higher clonality with few TCRs at higher frequencies, or higher diversity with many different TCRs at lower frequencies.

Circulatory EVs as a predictor of chronic urticarial activity.

Background: Chronic urticaria (CU) is a common and complex disorder that occurs without any identifiable provoking factor. The mechanisms underlying CU pathogenesis are still not fully understood. The autoimmune theory of IgG autoantibodies to IgE/high-affinity receptor of IgE on mast cells and mast cell activation and autoallergy (IgE-mediated disease) might contribute to CU pathogenesis. Extracellular vesicles (EVs) are membranous vesicles released from apoptotic or activated cells of different types. In this study, we aimed to investigate circulating EVs as potential biomarkers in patients with CU compared with that in healthy controls. Methods: We studied 15 patients with CU and 16 healthy controls. Circulatory EVs (plasma) were characterized by the presence of externalized phosphatidylserine (annexin V staining). An unpaired t-test was used, and P < 0.05 was considered statistically significant. Results: We did not find significant differences in the total number of EVs in patients with CU. A significant decrease in the levels of T-cells (CD3) and endothelial cells (CD146) (P < 0.05) in these patients than in controls was found. No significant differences were observed between patients with CU and healthy controls in terms of platelets, macrophages, PECAM-1, B cells, and tissue factors. Conclusion: Endothelial cells have been shown to contribute to the pathogenesis of CU and are also targeted by mediators released by mast cells and other cellular infiltrates. We identified that circulatory endothelial and T-cell EVs might play an important role in CU pathogenesis. In addition, our study highlights the importance of EVs as future therapeutic targets to be investigated.

Long non-coding RNA screening and identification of potential biomarkers for type 2 diabetes.

BackgroundTo investigate new lncRNAs as molecular markers of T2D.MethodsWe used microarrays to identify differentially expressed lncRNAs and mRNAs from five patients with T2D and paired controls. Through bioinformatics analysis, qRT‐PCR validation, ELISA, and receiver operating characteristic (ROC) curve analysis of 100 patients with T2D and 100 controls to evaluate the correlation between lncRNAs and T2D, and whether lncRNAs could be used in the diagnosis of T2D patients.ResultsWe identified 68 and 74 differentially expressed lncRNAs and mRNAs, respectively. The top five upregulated lncRNAs are ENST00000381108.3, ENST00000515544.1, ENST00000539543.1, ENST00000508174.1, and ENST00000564527.1, and the top five downregulated lncRNAs are TCONS_00017539, ENST00000430816.1, ENST00000533203.1, ENST00000609522.1, and ENST00000417079.1. The top five upregulated mRNAs are Q59H50, CYP27A1, DNASE1L3, GRIP2, and lnc‐TMEM18‐12, and the top five downregulated mRNAs are GSTM4, PODN, GLYATL2, ZNF772, and CLTC. Examination of lncRNA‐mRNA interaction pairs indicated that the target gene of lncRNA XR_108954.2 is E2F2. Multiple linear regression analysis showed that XR_108954.2 (r = 0.387, p < 0.01) and E2F2 (r = 0.368, p < 0.01) expression levels were positively correlated with glucose metabolism indicators. Moreover, E2F2 was positively correlated with lipid metabolism indicators (r = 0.333, p < 0.05). The area under the ROC curve was 0.704 (95% CI: 0.578–0.830, p = 0.05) for lncRNA XR_108954.2 and 0.653 (95% CI: 0.516–0.790, p = 0.035) for E2F2.ConclusionsThis transcriptome analysis explored the aberrantly expressed lncRNAs and identified E2F2 and lncRNA XR_108954.2 as potential biomarkers for patients with T2D.

MicroRNAs as Potential Liquid Biopsy Biomarker for Patients with Castration-Resistant Prostate Cancer.

PurposeTo identify micro-RNAs (miRNAs) expression profiles in peripheral blood plasma that could play a role as potential biomarkers in patients who progressed to castration-resistant prostate cancer (CRPC). Liquid biopsy analysis of miRNAs is a fast-developing field with a considerable likelihood to predict tumor progression and metastasis by targeting genes involved in oncogenesis.Patients and MethodsDifferential expression analysis of miRNAs profile in CRPC patients was performed by creating small RNA libraries of circulating miRNAs using HiSeq2500 Illumina platform. A secondary analysis of aligned reads with miRNA identification and quantification was performed using miARmaSeq. Using the Bowtie algorithm, the selected variants were compared to reference nucleotide sequence GRCh38 and miRbase. Novel miRNA sequences were structurally analyzed using mirDeep2®.ResultsA total of 16 patients with CRPC were included for analysis. Identified circulating miRNAs were hsa-miR-885-3p, hsa-miR-4467, hsa-miR-4686, hsa-miR-146a-3p, hsa-miR-6514-5p. Genes identified as regulated by these miRNAs were GPR56, BDNF, CTNND1, C17orf62, and DTNA.ConclusionWe explored the miRNA expression profile in patients with CRPC, identifying five miRNAs implicated in the regulation of genes involved in prostate cancer (PCa) oncogenesis and progression. We also found miRNA 855–3p in peripheral blood for the first time, which has a critical role in tumor growth mechanisms and higher expression profile than in healthy individuals.

Selected Articles from This Issue

Approximately 20% of breast cancers harbor human epidermal growth factor receptor 2 (HER2/ERBB2) overexpression or amplification. KN026, a novel HER2 bispecific antibody, has been shown to overcome resistance to HER2 target therapies in preclinical models. Zhang and colleagues conducted a phase I trial of KN026 in patients with HER2-positive metastatic breast cancer who had progressed on prior anti-HER2 therapies. KN026 was well tolerated, and treatment led to an objective response rate of 28.1%. Furthermore, the authors associated CDK12 co-amplification with an improved response to KN026, supporting further assessment of this potential biomarker. Although these results are interesting, further clinical trials of this novel bispecific antibody are warranted.Metastasis is a common occurrence in patients with osteosarcoma. Although current therapeutics have shown limited ability to reduce metastasis, CCR2+ monocytes have emerged as an actionable target for the prevention of lung metastasis. Regan and colleagues conducted a clinical trial in pet dogs with spontaneous advanced metastatic osteosarcoma to assess high-dose losartan, an angiotensin receptor inhibitor, in this context. In combination with the kinase inhibitor toceranib, losartan inhibited the CCL2-CCR2 pathway, was well tolerated and led to a clinical benefit rate of 50%. These results support further clinical study of losartan, especially human clinical trials.Although immunotherapy has provided a benefit to many patients, predictive biomarkers are still needed to more effectively guide treatment in patients with advanced renal cell carcinoma (RCC). To identify potential biomarkers in patients with advanced RCC treated with avelumab plus axitinib or sunitinib, Bilen and colleagues conducted a post hoc analysis of data from the phase 3 JAVELIN Renal 101 trial. The authors found that a low neutrophil-to-lymphocyte ratio (NLR) was associated with longer progression-free survival, overall survival, and objective response rate. These results support the continued development of NLR as a predictive biomarker for immunotherapy in patients with advanced RCC.Prior studies have shown that cabozantinib, an inhibitor of VEGFRs and additional tyrosine kinases, is effective for the treatment of metastatic clear cell renal cell carcinoma (mccRCC). However, it is unclear whether the mechanism of this agent is via its targeting of VEGFR or another target. To address this question, Denize and colleagues assessed angiogenesis markers in patients treated with cabozantinib or everolimus as part of the METEOR trial. Microvascular density and mast cell density, both markers of angiogenesis, were both associated with longer progression-free survival. Furthermore, patients treated with cabozantinib had improved progression-free survival, overall survival, and objective response rate compared with those treated with everolimus; importantly, these results were not dependent on levels of microvascular density or mast cell density. These results support the activity of cabozantinib in patients with mccRCC and suggest that VEGFR-independent effects may be part of the mechanism of this agent.

Biomarkers for drug development in propionic and methylmalonic acidemias.

There is an unmet need for the development and validation of biomarkers and surrogate endpoints for clinical trials in propionic acidemia (PA) and methylmalonic acidemia (MMA). This review examines the pathophysiology and clinical consequences of PA and MMA that could form the basis for potential biomarkers and surrogate endpoints. Changes in primary metabolites such as methylcitric acid (MCA), MCA:citric acid ratio, oxidation of 13C‐propionate (exhaled 13CO2), and propionylcarnitine (C3) have demonstrated clinical relevance in patients with PA or MMA. Methylmalonic acid, another primary metabolite, is a potential biomarker, but only in patients with MMA. Other potential biomarkers in patients with either PA and MMA include secondary metabolites, such as ammonium, or the mitochondrial disease marker, fibroblast growth factor 21. Additional research is needed to validate these biomarkers as surrogate endpoints, and to determine whether other metabolites or markers of organ damage could also be useful biomarkers for clinical trials of investigational drug treatments in patients with PA or MMA. This review examines the evidence supporting a variety of possible biomarkers for drug development in propionic and methylmalonic acidemias.

The frequency and related factors of primary headaches in patients with Hashimoto thyroiditis.

The purpose of this study was to evaluate the incidence of primary headache and potential biomarkers in patients diagnosed with Hashimoto thyroiditis. Patients with Hashimoto thyroiditis referred to the outpatient endocrinology clinic were included in the study. The demographic data, thyroid function test results, and autoantibody titers were recorded. The headache's clinical characteristics were also determined. The same researcher used the visual analog scale for headache severity rating in all patients. 155 patients with Hashimoto thyroiditis were included the study. There were 95 (61.3%) cases diagnosed with headache consisting of 20 (21.1%) migraine cases, 17 (17.9%) tension type headaches (TTHs), and 20 (21.1%) new daily persistent headaches (NDPHs). 38 of 155 (24.5%) had hypothyroidism related headaches (HRHs). There was no statistically significant relationship between the headache type and a high blood antibody level anti thyroid peroxidase antibody (p=0.135), while a positive correlation was found with thyroid stimulating hormone (TSH) (p<0.001). Hashimoto patients with migraine (n=14, 70.0%) were found to have higher blood antibody levels, while these ratios were found as 86.8% (n=33) in HRH-patients, 76.5% (n=13) in TTH-patients, and 60.0% (n=12) in NDPH-patients. 86 of 155 (55.5%) patients reported new onset headaches after a Hashimoto's thyroiditis diagnosis, and the headaches persisted without hormone therapy in 48 (84.2%) of these patients. These patients diagnosed with primary headache and this was interpreted as demonstrating comorbidity between Hashimoto's disease and primary headaches. Detection of only the relationship between TSH level and headache suggested that different mechanisms play a role in the pathophysiology. In the diagnosis of primary headache, it is important to look into secondary reasons.