Clinica Chimica Acta; International Journal Of Clinical Chemistry[JOURNAL]
Sun
200 papers
Circulating C1QC in cancer: analytical platforms, evidence gaps, and prospects for clinical chemistry translation.
Abu Zeid IM, Afzal M, Rafeeq M … +6 more , Zeyadi M, Chaieb K, Altayb HN, Alzarea SI, Nadeem MS, Kazmi I
Clin Chim Acta · 2026 Jun · PMID 42336257 · Publisher ↗
Traditional serum tumor markers, such as carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), cancer antigen 125 (CA 125), α-fetoprotein (AFP), and prostate-specific antigen (PSA), exhibit limited diagnos...
Traditional serum tumor markers, such as carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), cancer antigen 125 (CA 125), α-fetoprotein (AFP), and prostate-specific antigen (PSA), exhibit limited diagnostic sensitivity and specificity during the early stages of disease and in malignancies with overlapping clinical features. This limitation has led to the investigation of complement pathway proteins as potential clinical chemistry analytes. Measurements of circulating complement C1q C chain (C1QC) are frequently derived from total C1q or C1q-binding activity assays, rather than those specific to C1QC. These measurements are linked to the activation of the classical complement pathway, M2-like polarization of tumor-associated macrophages, and immunosuppressive metabolic reprogramming. However, many of the available data are based on transcriptomic analysis of tissues, single-cell analysis, bioinformatic datasets, or small retrospective cohorts without directly measuring the C1QC protein in the circulation. This narrative review critically evaluates C1QC within the clinical chemistry framework, covering its gene structure, proteoform heterogeneity, and post-translational modifications. This study also evaluated the analytical performance metrics of immunoassays, targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS), aptamer-based electrochemical biosensors, and surface plasmon resonance platforms. It critically appraises the reported diagnostic and prognostic associations, including the proposed incremental contributions of multimarker panels. Additionally, external quality assessment, prospective multicenter validation, assay harmonization, and consideration of interference from inflammatory, infectious, or immune-mediated conditions are required for this approach. Compliance with the In Vitro Diagnostic Medical Devices Regulation (IVDR) and United States Food and Drug Administration (FDA) regulatory pathways is also necessary.
Establishment and validation of intelligent review rules for blood cell analysis based on the gradient boosting decision tree algorithm.
Tang W, Chen S, Yu Z … +8 more , Gu X, Pan B, Wang B, Ding R, Zhang S, Wang C, Lin J, Guo W
Clin Chim Acta · 2026 Jun · PMID 42331130 · Publisher ↗
OBJECTIVE: To develop artificial intelligence (AI)-based intelligent review rules to accurately screen samples that require retests or blood smear microscopy examinations, thereby reducing the review rate, improving the...
OBJECTIVE: To develop artificial intelligence (AI)-based intelligent review rules to accurately screen samples that require retests or blood smear microscopy examinations, thereby reducing the review rate, improving the work efficiency of haematology laboratories, and ensuring the quality of whole blood analysis. METHODS: A total of 10,212 EDTA-K2 venous blood samples from the clinical laboratories of 4 hospitals from May 2022 to April 2025 were collected. Among them, 9000 samples from the First People's Hospital of Foshan, the Zhongda Hospital affiliated to Southeast University, and the First Affiliated Hospital of Sun Yat-sen University were used to establish the rules, and 1212 samples from the Zhongshan Hospital affiliated to Fudan University were used for rule validation. The obtained rules were compared with the 41 review rules set by the International Consensus Group for Haematology Review (ICGHR). All samples were tested using a haematology analyser under the customized dilution ratio (CDR) mode and smear microscopy, if the microscopic examination results trigger the 10 microscopic anomalous rules established by the ICGHR, then the sample is deemed to be an anomalous sample. Intelligent review rules were established using the gradient boosting decision tree (GBDT) algorithm. Moreover, the false negative rate, false positive rate, and review rate of the validation set were statistically analysed. RESULTS: (1) Among the 9000 samples in the establishment set, 4493 anomalous samples were identified by microscopic examination, and 26 intelligent review rules were established using the GBDT algorithm. (2) For the external validation set, 180 anomalous samples were identified by microscopic examination. Compared with those of the 41 international review rules, the false positive rate (14.60%) and review rate (27.55%) of the intelligent review rules were significantly lower (false positive rate: 30.19%, review rate: 44.14%). The false negative rate of the intelligent review rules (1.89%) was comparable to that of the 41 international review rules (0.90%) and met the ICGHR requirement of a false negative rate < 5%, with no critical hematologic cells missed. CONCLUSION: Intelligent review rules generated using AI techniques effectively reduce the false positive rate and review rate and prevent missed diagnoses of hematologic cells while ensuring test quality. The review rules generated by AI methods significantly increase laboratory efficiency and are especially suitable for medical institutions.
Elevated CD3 T-cell proportions and a dysregulated cytokine network characterize the Serofast state in treated syphilis: A cross-sectional study of 60 participants.
Qiang D, Peng M, Zhang W … +1 more , Tan M
Clin Chim Acta · 2026 Jun · PMID 42323072 · Publisher ↗
BACKGROUND: Syphilis serofast, characterized by persistent seropositivity despite adequate treatment and symptom resolution, poses significant clinical challenges. This study investigated the immunological basis of serof...
BACKGROUND: Syphilis serofast, characterized by persistent seropositivity despite adequate treatment and symptom resolution, poses significant clinical challenges. This study investigated the immunological basis of serofast status, focusing on CD3 T-cell populations and cytokine profiles. METHODS: This cross-sectional study included 20 healthy controls (HC), 20 serological cure patients (SC), and 20 serofast state patients (SS) with HIV-negative primary syphilis. Blood collection was uniformly performed at the 12-month post-treatment time point. Flow cytometry was used to analyze proportions of CD3 T-cells in peripheral blood mononuclear cells, and antibody array was utilized to determine cytokine levels. RESULTS: Serofast patients exhibited significantly elevated proportions of CD3 T-cells compared to both SC and HC groups (both p < 0.05). A distinct serum cytokine profile was revealed in serofast state group, including significant upregulation of Eotaxin (CCL11), IL-17 A, TGF-β1, ICAM-1, IL-7, IL-15, MIF, IL-10, and MCP-1 (CCL2), and downregulation of IL-2, G-CSF (CSF3), and IL-1Ra (all p < 0.05, SS vs. HC/SC). Bioinformatics identified these 12 dysregulated proteins as critically involved in lymphocyte (especially T-cell) activation, proliferation, and differentiation, linking them mechanistically to CD3 T-cell function. Linear regression demonstrated significant positive correlations between CD3 T-cell proportions and TGF-β1, Eotaxin, and IL-17 A levels (all p < 0.05). CONCLUSIONS: These findings suggest that dysregulated CD3 T-cell expansion and a specific cytokine imbalance may form a dysfunctional immune axis to promote chronic inflammation and sustain serological positivity, which offers potential targets for novel therapeutic strategies.
Circulating omentin-1 and HMGB1 levels in patients with Hashimoto thyroiditis.
Genc S, Mercantepe F, Aksu O … +3 more , Can U, Kizilarslanoglu MC, Klisic A
Clin Chim Acta · 2026 Jun · PMID 42323071 · Publisher ↗
BACKGROUND: Hashimoto thyroiditis (HT) is a chronic autoimmune disease that extends beyond abnormalities in thyroid hormone levels. The aim of this study was to evaluate circulating levels of omentin-1, an anti-inflammat...
BACKGROUND: Hashimoto thyroiditis (HT) is a chronic autoimmune disease that extends beyond abnormalities in thyroid hormone levels. The aim of this study was to evaluate circulating levels of omentin-1, an anti-inflammatory adipokine, and high-mobility group box 1 (HMGB1), an inflammatory alarmin, in patients with HT, and to examine their associations with clinical and biochemical parameters as well as their diagnostic performance. METHODS: This cross-sectional study included 45 patients with Hashimoto thyroiditis and 45 healthy controls. The diagnosis of HT was established based on positive thyroid autoantibodies and characteristic ultrasonographic findings. All patients with HT were clinically stable and receiving levothyroxine replacement therapy. Serum omentin-1 and HMGB1 concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Thyroid function tests and metabolic parameters were assessed using standard laboratory methods. Group comparisons and associations were analyzed using appropriate statistical methods. Diagnostic accuracy was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS: Circulating omentin-1 and HMGB1 levels were significantly lower in patients with Hashimoto thyroiditis compared with healthy controls (p < 0.001 for both). Free triiodothyronine (free T3) and free thyroxine (free T4) concentrations were similar between groups, whereas thyroid-stimulating hormone (TSH) levels and thyroid hormone ratios differed significantly. Omentin-1 and HMGB1 levels were positively correlated in both study groups. In additional analyses, the differences in biomarker levels between groups remained significant after adjustment for age, sex, and insulin levels. ROC curve analysis demonstrated good to excellent diagnostic accuracy for both biomarkers: HMGB1 achieved an AUC of 0.802 (sensitivity 75.6%, specificity 75.6%, cut-off 514 pg/mL) and omentin-1 an AUC of 0.724 (sensitivity 62.2%, specificity 84.4%, cut-off 172 pg/mL). CONCLUSION: Hashimoto thyroiditis is associated with reduced circulating levels of omentin-1 and HMGB1, even in patients who are biochemically euthyroid under levothyroxine therapy. These findings suggest that immune and metabolic regulation may be concomitantly affected in HT, and that hormonal normalization through levothyroxine replacement may not fully restore the immune-metabolic milieu associated with the disease. However, given the cross-sectional design, the results do not allow causal inference, and further studies are needed to clarify the clinical significance of these biomarkers.
Multi-omics profiling of oxeiptosis-associated biomarkers in cancer.
Khan A, Alruwaili MM, Alhuthali HM … +5 more , Alzahrani S, Alrehaili AA, Alshammari A, Siddique MI, Imran M
Clin Chim Acta · 2026 Jun · PMID 42323070 · Publisher ↗
Oxeiptosis is a form of regulated cell death that is independent of caspases and is generally considered to be non-inflammatory. This process is triggered by reactive oxygen species and involves the Kelch-like ECH-associ...
Oxeiptosis is a form of regulated cell death that is independent of caspases and is generally considered to be non-inflammatory. This process is triggered by reactive oxygen species and involves the Kelch-like ECH-associated protein 1 (KEAP1)-phosphoglycerate mutase family member 5 (PGAM5)-apoptosis-inducing factor mitochondria-associated 1 (AIFM1) signaling pathway. This review critically assesses the potential of oxeiptosis-related molecules and multi-omics signatures as biomarkers in human cancers, highlighting their analytical validity and future perspectives in the field of translational laboratory medicine. Other factors, such as KEAP1, PGAM5, and AIFM1, are not unique to oxeiptosis but are also involved in the regulation of other forms of cell death, including antioxidant signaling, mitophagy, and apoptosis. Concurrently, AIFM1 may need to be dephosphorylated at serine 116 (Ser116), PGAM5 must be activated, oxidative stress is required, and there must be no activation of caspases, although this pathway profile is not analytically validated. While many composite signatures exhibit hypothesis-generating potential for prognostic stratification, molecular subtyping, and prediction of therapeutic responsiveness, most have not yet been prospectively validated and are at risk of data set overlap, overfitting, algorithm instability, and poor inter-cohort transportability. Preanalytical variability, specimen stability, assay standardization, normalization, inter-platform concordance, and undefined clinical performance thresholds are other factors that limit translation. In summary, the current state of oxeiptosis-related biomarkers is not clinically validated and has a low level of translational readiness. To achieve future progress, standardized definitions of analytic measures, multicenter validation, and prospective clinical utility must be demonstrated.
BCL-2 in leukemia: Enhancing clinical utility.
Rehman ZU, Khan A, Imran M … +5 more , Singla N, Kamal MA, Khalid M, Ali MI, Bakht MA
Clin Chim Acta · 2026 Jun · PMID 42320667 · Publisher ↗
B-cell lymphoma 2 (BCL-2) is an important anti-apoptotic protein in the mitochondrial cell death pathway and is biologically significant for leukemic cell survival, apoptosis resistance, drug resistance, and disease pers...
B-cell lymphoma 2 (BCL-2) is an important anti-apoptotic protein in the mitochondrial cell death pathway and is biologically significant for leukemic cell survival, apoptosis resistance, drug resistance, and disease persistence. BCL-2 is clinically relevant in hematopathology and laboratory medicine, as it is a central regulator of apoptosis in several leukemia subtypes. This review evaluates BCL-2 primarily as a prognostic, treatment-stratifying, and venetoclax-related predictive biomarker in leukemia, while critically examining its more limited and context-dependent diagnostic contribution. We summarize existing data on the association of BCL-2 expression and functional dependency with leukemia biology, cytogenetic and molecular risk factors and survival. We also explore its use in distinguishing leukemic populations from non-malignant hematopoietic populations, primarily in conjunction with morphology, immunophenotyping, cytogenetics, molecular testing, and other markers of apoptosis. Laboratory considerations for clinical implementation are addressed, such as specimen selection, inter-platform variability, antibody and gating strategies, immunohistochemistry, flow cytometry, transcript-based assessment, functional apoptotic profiling, and preanalytical, analytical, and interpretative variability. We also discuss the clinical relevance of BCL-2 in venetoclax-based therapy, where dependence on BCL-2 may be more informative than expression. Overall, BCL-2 is better supported as prognostic and treatment-stratifying marker than a diagnostic marker in leukemia. To move BCL-2 assessment into routine laboratory practice, it will be necessary to establish harmonized thresholds for BCL-2 assays and to validate the analytical workflow and result in prospective studies. This review outlines the potential and current challenges of BCL-2 as an emerging biomarker in human leukemia within a laboratory medicine framework.
Evaluating circulating tumor DNA methylation patterns of a multi-gene panel for colorectal cancer diagnosis: A pilot study.
Usrof F, Abu Helal KM, Ashour MJ … +3 more , Abuwarda HN, Alzaharna MM, Sharif FA
Clin Chim Acta · 2026 Jun · PMID 42320666 · Publisher ↗
Colorectal cancer (CRC) is a leading cause of cancer-related mortality globally and a major public health burden in the Gaza Strip. As CRC is often asymptomatic in its early stages, early detection is critical. This stud...
Colorectal cancer (CRC) is a leading cause of cancer-related mortality globally and a major public health burden in the Gaza Strip. As CRC is often asymptomatic in its early stages, early detection is critical. This study evaluates the diagnostic performance of circulating tumor DNA (ctDNA) methylation biomarkers (SEPT9, SPG20, ALX4, MGMT, and RASSF1A) for non-invasive CRC detection. A pilot case-control study was conducted with 50 participants, comprising 25 confirmed CRC patients and 25 colonoscopy-verified CRC-free controls. Plasma cell-free DNA was extracted, bisulfite-converted, and analyzed via methylation-specific PCR. Diagnostic performance was assessed using receiver operating characteristic curve analysis, and multi-gene panels were evaluated using an OR-based logic model. Individual and combined methylation markers demonstrated robust diagnostic potential. The combination of SEPT9 and SPG20 achieved excellent discrimination between CRC patients and controls (AUC = 1.00). Other combinations, such as SPG20 + MGMT and SPG20 + ALX4, also exhibited high accuracy (AUC = 0.994 and 0.990, respectively). The inclusion of additional genes provided marginal diagnostic improvement, suggesting redundancy in larger panels. The two-gene panel of SEPT9 and SPG20 represents a highly sensitive and specific non-invasive biomarker combination for CRC detection. However, these preliminary findings should be interpreted with caution given the small sample size and require validation in larger, independent screening cohorts before clinical implementation.
M-protein detection using two immunofixation electrophoresis systems and impact of daratumumab interference on disease monitoring.
Kushima S, Nakamura T, Fukushima R … +4 more , Ishihara A, Kawano Y, Mori D, Tanaka Y
Clin Chim Acta · 2026 Jun · PMID 42320665 · Publisher ↗
M-protein identification by immunofixation electrophoresis (IFE) varies depending on equipment and reagents used. Daratumumab (DARA), an IgGκ monoclonal antibody for multiple myeloma treatment, frequently interferes with...
M-protein identification by immunofixation electrophoresis (IFE) varies depending on equipment and reagents used. Daratumumab (DARA), an IgGκ monoclonal antibody for multiple myeloma treatment, frequently interferes with IFE interpretation. This study compared the analytical performance of two IFE systems and evaluated the impact of DARA interference on IFE interpretation. We compared the current system, Epalyzer 2 Jr. (Helena), with the target system, HYDRASYS 2 (Sebia), using 104 clinical samples including suspicious positive cases, 20 AL amyloidosis patients, and 76 other clinical cases from our hospital. For 10 DARA-treated samples, changes were evaluated before and after DARA displacement using the HYDRASHIFT Daratumumab (Sebia) assay. The concordance rate between the two systems ranged from 60.0% to 88.5%. AL amyloidosis patient samples showed the lowest agreement rate. In 20 discordant cases, HYDRASYS detected additional bands, mainly light chains, that were missed by Epalyzer. Among DARA-treated samples, concordance was observed in only one case. In the remaining nine cases, IgGκ bands detected by the current method disappeared following DARA displacement, with three cases becoming entirely negative. HYDRASYS demonstrated superior sensitivity for detecting M-proteins and free light chains compared to Epalyzer. When DARA-derived bands interfere with IFE interpretation, DARA displacement is necessary for accurate assessment of hematologic response in patients with multiple myeloma.
Neutrophil activation parameter is a promising new biomarker of disease activity in ulcerative colitis.
Blavnsfeldt AG, Parkner T, Knudsen CS … +3 more , Fassov J, Dige A, Winther-Larsen A
Clin Chim Acta · 2026 Jun · PMID 42320664 · Publisher ↗
OBJECTIVES: Invasive endoscopy and fecal calprotectin remain the standard for monitoring of ulcerative colitis (UC) However, these procedures are resource- and time-consuming, and patients are reluctant to participate. A...
OBJECTIVES: Invasive endoscopy and fecal calprotectin remain the standard for monitoring of ulcerative colitis (UC) However, these procedures are resource- and time-consuming, and patients are reluctant to participate. As neutrophil granulocytes are mediators of inflammation in UC, we evaluated the biomarker capacity of two novel markers of neutrophil activation. We investigated the association between these markers and clinical disease scores and their ability to distinguish between patients with UC and healthy individuals. MATERIALS AND METHODS: In a prospective study setting, blood samples were collected from 68 consecutive patients with a suspected flare of UC and from 71 healthy controls. Neutrophil Reactivity Intensity (Neut-RI) and Neutrophil Granularity Intensity (Neut-GI) were analyzed using the automated hematology analyzer Sysmex XN-9000. ROC curve analysis assessed the ability to discriminate between controls and UC patients. In patients, the Mayo score, Simple Clinical Colitis Activity Index (SCCAI) score, fecal calprotectin and C-reactive protein (CRP) were recorded. Spearman's correlation coefficients between clinical data and the novel markers were calculated. RESULTS: Neut-RI and Neut-GI levels were significantly higher among patients than controls (p < 0.001). Neut-RI discriminated between patients and controls (AUC 0.756, 95% CI 0.676; 0.837) and correlated significantly with Mayo score and SCCAI (Spearman's Rho 0.40/0.27). No such correlations were found for fecal calprotectin or CRP. Furthermore, Neut-RI discriminated patients with proctitis from patients with more widespread disease (p < 0.05). CONCLUSIONS: Neut-RI significantly correlated with disease activity in UC patients and proved superiority to fecal calprotectin. Neut-RI could be a promising low-cost, non-invasive biomarker for disease activity in UC.
Analytical and clinical impact of bilirubin and glucose interference in Siemens Jaffé and enzymatic creatinine assays.
Calvera-Rayo A, Albéniz-Abaigar M, Llanos A … +4 more , Broseta JJ, Cuadrado E, Bedini JL, Rico N
Clin Chim Acta · 2026 Jun · PMID 42320663 · Publisher ↗
This study evaluated bilirubin and glucose interference in creatinine measurement using Jaffe (Crea_2) and enzymatic (ECre3) methods on Siemens' Atellica Solution system, to determine their clinical relevance and the pot...
This study evaluated bilirubin and glucose interference in creatinine measurement using Jaffe (Crea_2) and enzymatic (ECre3) methods on Siemens' Atellica Solution system, to determine their clinical relevance and the potential need to transition to the enzymatic method. In-vitro interference studies were performed by spiking serum pools at the clinical decision level (115.0 μmol/L creatinine) with bilirubin (8.55-1078 μmol/L) and glucose (3.0-128.5 mmol/L). Additionally, 125 patient serum samples with varying bilirubin levels and 72 peritoneal dialysis samples with elevated glucose were analysed in parallel by both methods. eGFR, CKD stages, and MELD-Na scores were calculated to evaluate clinical impact. Method comparison used Passing-Bablok regression, Cohen's kappa, and non-parametric tests. The Jaffe method showed minimal bilirubin interference until 676 μmol/L, with significant negative bias at 1078 μmol/L (-20.72%). The enzymatic method showed a gradual negative bias but remained within ±10%. For glucose, Jaffe exhibited significant positive interference above 26.1 mmol/L, reaching +56.86% at 128.5 mmol/L, while the enzymatic method remained stable. Patient serum comparisons revealed excellent correlation across the bilirubin range (median difference - 2.4 μmol/L; R = 0.998; κ = 0.873). CKD stage differed between methods in 11/125 patients, with Jaffe yielding a more advanced stage in 10, whereas MELD-Na category changed in 4/125 patients. In peritoneal dialysis fluids, Jaffe results increased significantly with glucose concentration, while the enzymatic method remained unaffected. Siemens' Jaffe method can be clinically interchangeable with the enzymatic method across routine ranges, but targeted reflex testing with the enzymatic method for high-glucose (>21.9 mmol/L) or extreme bilirubin (>891.6 μmol/L) samples is recommended.
Diagnostic biomarkers for heart failure-related pleural effusion.
Hao YL, Niu Y, Wen JX … +8 more , Wang QJ, Tian QF, Niu R, Yan L, Bao RT, Zheng WQ, Xu YN, Hu ZD
Clin Chim Acta · 2026 Jun · PMID 42314922 · Publisher ↗
Pleural effusion is common in clinical practice and has more than 60 causes, with heart failure (HF) being a common cause. The discrimination between HF and non-HF-related pleural effusions is challenging because most av...
Pleural effusion is common in clinical practice and has more than 60 causes, with heart failure (HF) being a common cause. The discrimination between HF and non-HF-related pleural effusions is challenging because most available diagnostic tools (e.g., imaging, echocardiography) are subjective. Some patients may even need to try diuretics to confirm the diagnosis. Serum and pleural fluid biomarkers, along with clinical scoring systems, which offer the advantages of objectivity, low cost, and minimal invasiveness, can aid in diagnosis. Many biomarkers have been identified previously, and their diagnostic value for HF-related pleural effusion has been evaluated. This review aimed to summarize research progress on biomarkers (e.g., natriuretic peptides, ischemia-modified albumin, CC class chemokine ligand 22, apolipoprotein E, soluble urokinase plasminogen activator receptor) and scoring systems in diagnosing HF-related pleural effusion. We found that serum and effusion natriuretic peptides (B-type natriuretic peptide, N-terminal pro-B-type natriuretic peptide, and midregional pro-Atrial natriuretic peptide) had high diagnostic accuracy for HF-related pleural effusion, and this accuracy has been validated by multiple studies. Ischemia-modified albumin, CC class chemokine ligand 22, apolipoprotein E, and soluble urokinase plasminogen activator receptor were emerging biomarkers, and their diagnostic accuracy needs to be validated by future studies. The Porcel's score and the BANCA score were the most promising diagnostic scores for HF-related pleural effusion. Taken together, natriuretic peptides, Porcel's score, and the BANCA score should be advocated for diagnosing HF-related pleural effusion.
Letter to the editor regarding: "Glycosylation-associated plasma SNORD99 as a novel diagnostic biomarker for early-stage lung adenocarcinoma". Clinica Chimica acta 580(2026) 120722.
Gao P, Liu F, Liu M … +1 more , Yu J
Clin Chim Acta · 2026 Jun · PMID 42309214 · Publisher ↗
Abstract loading — click title to view on PubMed.
Circulating NETosis biomarkers in oncology.
Imran M, Alzaharani AK, Alhuthali HM … +5 more , Alzahrani S, Alrehaili AA, Alshammari A, Rehman ZU, Khan A
Clin Chim Acta · 2026 Jun · PMID 42309213 · Publisher ↗
The use of minimally invasive circulating biomarkers is becoming increasingly important in cancer management, aiding in diagnosis, risk stratification, therapeutic monitoring, and evaluation of clinically relevant compli...
The use of minimally invasive circulating biomarkers is becoming increasingly important in cancer management, aiding in diagnosis, risk stratification, therapeutic monitoring, and evaluation of clinically relevant complications. Neutrophil activation and extracellular trap formation are increasingly recognized biological processes in cancer-related inflammation, thrombosis, and host-tumor interactions. Circulating biomarkers of these processes, such as myeloperoxidase, neutrophil elastase, citrullinated histone H3, myeloperoxidase-DNA complexes, cell-free DNA, and nucleosome-associated markers, can be detected in blood-based samples and potentially offer clinically relevant data in oncology. This review assesses the diagnostic, prognostic, and monitoring capabilities of circulating biomarkers of neutrophil activation and NETosis in cancer, focusing on their implications for clinical chemistry and diagnostic laboratory medicine. We synthesized existing evidence showing that these analytes are associated with adverse clinicopathological features, poor survival, systemic inflammation, and cancer-related thrombosis. We also discuss their possible applications in risk stratification, complication evaluation, longitudinal disease tracking, and complementary interpretation of established tumor markers. This review identifies laboratory parameters that influence clinical implementation, such as specimen matrix selection, preanalytical variability, assay heterogeneity, analytical validation, and reporting standardization. We also addressed interpretive issues due to limited disease specificity and confounding inflammatory, infectious, and thrombotic diseases. However, current predictive and longitudinal-monitoring evidence remains exploratory because most studies are small, assay-heterogeneous, and lack externally validated clinical decision thresholds. Overall, translating neutrophil activation- and NETosis-associated biomarkers into routine diagnostic laboratory practice will involve harmonized assays, standardized workflows, prospective clinical validation, and demonstrable incremental value for the management of patients. This review presents a laboratory medicine-centered perspective for understanding the opportunities and existing constraints of these emerging adjunctive biomarkers in cancer research.
TIM-3 as an immune and leukemia stem-cell biomarker in acute myeloid leukemia: diagnostic laboratory and translational perspectives.
Bhat AA, Fuloria S, Thapa R … +7 more , Narain K, Bhatia S, Ansari MT, Agnihotri S, Wu YS, Meenakshi DU, Fuloria NK
Clin Chim Acta · 2026 Jun · PMID 42309212 · Publisher ↗
Despite improvements in ELN-based risk stratification, acute myeloid leukemia (AML) still faces three significant challenges: relapse, resistance to therapy, and measurable residual disease (MRD). T-cell immunoglobulin a...
Despite improvements in ELN-based risk stratification, acute myeloid leukemia (AML) still faces three significant challenges: relapse, resistance to therapy, and measurable residual disease (MRD). T-cell immunoglobulin and mucin-domain-containing molecule 3 (TIM-3/HAVCR2) is a clinically relevant AML biomarker, as it is enriched in CD34CD38 AML leukemia stem cells, with limited expression in normal hematopoietic stem cells, and is involved in immune-checkpoint disruption in the leukemic microenvironment. This review focuses on the diagnostic, prognostic, and translational value of TIM-3 in AML, particularly in relation to clinical chemistry and laboratory medicine. We integrated existing knowledge from various cellular, molecular, and soluble analytical platforms, such as multiparameter flow cytometry, to identify leukemia stem cells based on TIM-3 expression, transcript and protein profiling analysis of HAVCR2, or soluble immunoassay of TIM-3/Galectin-9. The potential applications of TIM-3 in relapse-risk stratification, MRD refinement, immune profiling, and companion biomarker development are further explored. Several important laboratory parameters that influence clinical applicability are also discussed in this review, such as specimen-matrix selection, antibody clone variation, gating strategies and cut-off variability pre-analytical procedures, and cross-platform validation. More harmonized assay workflows, standardized reporting of results, prospectively validated thresholds, and demonstration of the clinical value of TIM-3 beyond known MRD and genetic risk models are needed to enable the translation of TIM-3 into routine AML laboratory practices. Therefore, TIM-3 should currently be regarded as a promising adjunctive AML biomarker; however, it is not recommended for standalone routine clinical decision-making outside clinical trials.
Irisin as a multi-target renoprotective mediator in chronic kidney disease: from molecular mechanisms to therapeutic perspectives.
Bandral SS, Ahuja S, Singh TG … +1 more , Kaur R
Clin Chim Acta · 2026 Jun · PMID 42303153 · Publisher ↗
BACKGROUND: Chronic kidney disease (CKD) is a progressive, multifactorial disorder affecting approximately 9-13% of the global population and is driven by interrelated mechanisms including inflammation, oxidative stress,...
BACKGROUND: Chronic kidney disease (CKD) is a progressive, multifactorial disorder affecting approximately 9-13% of the global population and is driven by interrelated mechanisms including inflammation, oxidative stress, endothelial dysfunction, and fibrosis. Despite advances in therapies such as SGLT2 inhibitors, significant residual risk persists, necessitating the identification of novel multi-target therapeutic strategies. OBJECTIVE: This review aims to provide an integrated view of the molecular pathways involved in CKD progression and to critically study the emerging evidence for irisin - a myokine derived from proteolytic cleavage of fibronectin type III domain-containing protein 5 (FNDC5) - as a potential multi-target renoprotective mediator. METHODS: A narrative literature review was conducted using PubMed, Scopus, and Google Scholar. The search strategy incorporated combinations of Medical Subject Headings (MeSH) terms and keywords such as "irisin," "FNDC5," "molecular signalling" "mechanistic pathways" "chronic kidney disease," "renal fibrosis," "inflammation," "oxidative stress," "Nrf2," "NF-κB," "NLRP3 inflammasome," and "gut-kidney axis." Boolean operators (AND, OR) were used to refine the search. Relevant literature was selected based on the relevance of CKD pathophysiology and irisin biology. RESULTS: Accumulating evidence demonstrates that irisin exerts pleiotropic protective effects in CKD by suppressing NF-κB and NLRP3 inflammasome activation, enhancing antioxidant defence via the Nrf2/HO-1 pathway, was associated with improvement in endothelial function in experimental models through AMPK/eNOS signalling, and attenuating TGF-β/Smad-mediated fibrosis. Additionally, irisin promotes autophagy and mitophagy, attenuates vascular smooth muscle cell pyroptosis, and modulates gut-kidney axis interactions by attenuating systemic inflammation and oxidative stress arising from elevated uremic toxins such as indoxyl sulfate and p-cresyl sulfate. Clinical observational studies suggest an inverse association between circulating irisin levels and CKD severity; however, these findings are confounded by various factors and do not establish causality. CONCLUSION: Preclinical findings and human observational studies suggest possible therapeutic relevance of irisin to act as a biomarker and a therapeutic candidate in CKD. However, the translational application of irisin in CKD remains speculative due to various confounders such as incomplete receptor characterisation, peptide instability, dosing uncertainty, assay heterogeneity, exercise status, variation in muscle mass, and dialysis status.
Multi-omics body-fluid biomarkers in immunoglobulin a nephropathy: Analytical Validation, standardization, and clinical chemistry translation of diagnostic and prognostic Analytes.
Rathore V, Asad M, Saxena S … +5 more , Agarwal C, Dhyani A, Negi R, Gupta G, Dolas A
Clin Chim Acta · 2026 Jun · PMID 42297320 · Publisher ↗
IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis worldwide. Although optimized supportive therapy is administered to these patients, a substantial proportion still progresses to end-stage kidney di...
IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis worldwide. Although optimized supportive therapy is administered to these patients, a substantial proportion still progresses to end-stage kidney disease. The advancement of these noninvasive laboratory tools will complement renal biopsies. This review focuses on evaluating the multi-omics serum and urinary biomarkers that reflect the multi-hit pathogenesis of IgAN, such as abnormal O-glycosylation of immunoglobulin A1 (IgA1), autoantibody production, deposition of immune complexes in the mesangium, complement system activation, podocyte dysfunction, and tubulointerstitial fibrosis. Galactose-deficient IgA1 can be measured using various methodologies, including lectin-based enzyme-linked immunosorbent assay (ELISA), KM55 monoclonal antibody assays, site-resolved mass spectrometric glycoprofiling, nuclear magnetic resonance (NMR), and liquid chromatography-mass spectrometry (LC-MS)-based metabolite and lipid fingerprinting techniques. Additionally, peptide classifiers are generated using sequential window acquisition of all theoretical spectra (SWATH), data-independent acquisition (DIA), and aptamer-based proteomics techniques. Machine learning classifiers, such as artificial neural networks, XGBoost, and random survival forests, enable the integration of these analytes, facilitating individualized diagnosis, prognosis, and therapy monitoring within the framework of guideline-directed therapy. However, the clinical evaluation of these biomarkers is constrained by several factors, including preanalytical variation, incomplete interlaboratory standardization, absence of reference materials, ambiguous biomarker thresholds, and inconsistent sensitivity and specificity. Additionally, further validation is required across different ethnic groups and in both pediatric and adult populations. Therefore, traditional markers of urinary involvement such as albuminuria, proteinuria, hematuria, and estimated glomerular filtration rate (eGFR) may need to be combined with multi-omics markers for better prognostic classification. These biomarkers can only meaningfully complement renal biopsy in routine laboratory use if standardized International Federation of Clinical Chemistry (IFCC)-traceable assays are used and serial testing algorithms are harmonized.
Detection of NADH/NAD dysregulation in MELAS via diazo-carboxyl click derivatization mass spectrometry.
Hu J, Liufu T, Li C … +6 more , Zhao Q, Yu M, Yuan Y, Quan L, Chen Z, Wang Z
Clin Chim Acta · 2026 Jun · PMID 42288275 · Publisher ↗
OBJECTIVES: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a mitochondrial disorder driven by mutations in mitochondrial or nuclear DNA, involving an altered NADH/NAD-associated red...
OBJECTIVES: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a mitochondrial disorder driven by mutations in mitochondrial or nuclear DNA, involving an altered NADH/NAD-associated redox metabolism as a key pathological mechanism. The traditional metabolomic analyses in MELAS face sensitivity and sample volume limitations, particularly for carboxylic acid metabolites. This study employed a recently established diazo-carboxyl/hydroxylamine-ketone double-click derivatization (DQmB-HA) mass spectrometry method to overcome these barriers, enabling highly sensitive quantification of NADH/NAD-related serum metabolites in minimal sample volumes. METHODS: Using DQmB-HA mass spectrometry, we analyzed lactate, pyruvate, β-hydroxybutyrate, acetoacetate, α-hydroxybutyrate, and malate in 5-μL serum samples from each of the MELAS patients (n = 70), healthy controls (n = 29), and CPEO patients (n = 17). Individual metabolite levels were quantified, and the lactate/pyruvate ratio and β-hydroxybutyrate/acetoacetate ratio were used as surrogate indicators of cytoplasmic and mitochondrial NADH/NAD+ redox states, respectively. Following this, analyses were performed to assess between-group differences in these indicators and to determine their correlations with disease duration. RESULTS: MELAS patients exhibited significantly elevated lactate, β-hydroxybutyrate, α-hydroxybutyrate, and malate levels, together with increased lactate/pyruvate and β-hydroxybutyrate/acetoacetate ratios compared with healthy controls. Among the evaluated biomarkers, the lactate/pyruvate ratio achieved the highest diagnostic performance (AUC = 0.993, 95% CI = 0.979-1.000), followed by lactate (AUC = 0.976) and β-hydroxybutyrate (AUC = 0.864). Although the β-hydroxybutyrate/acetoacetate ratio showed high sensitivity (95.7%), its overall diagnostic accuracy was limited by lower specificity. However, none of these serum markers show a significant correlation with the disease duration course in MELAS patients. Relative to MELAS, lower concentrations of α-hydroxybutyrate (p < 0.001) and malate (p = 0.026) and elevated lactate/pyruvate ratio (p < 0.001) were observed in CPEO. CONCLUSION: The DQmB-HA method enabled high-sensitivity metabolomic profiling in low-volume clinical samples and revealed broad alterations in metabolites and metabolite ratios associated with NADH/NAD + -related redox metabolism in MELAS, providing a useful framework for metabolomic screening in mitochondrial diseases.
A survey of external quality assessment schemes (EQAS) for faecal immunochemical tests for haemoglobin (FIT).
Piggott C, Thelen M, Jones S … +5 more , Kocna P, Frasa M, van der Hagen EAE, Benton SC, International Federation of Clinical Chemistry Faecal Immunochemical Test Working Group (IFCC FIT-WG)
Clin Chim Acta · 2026 Jun · PMID 42288274 · Publisher ↗
Immunochemical assays for faecal haemoglobin (FIT) are used in colorectal cancer (CRC) screening programmes and for patients with symptoms suggestive of CRC. External quality assessment schemes (EQAS) for FIT have been e...
Immunochemical assays for faecal haemoglobin (FIT) are used in colorectal cancer (CRC) screening programmes and for patients with symptoms suggestive of CRC. External quality assessment schemes (EQAS) for FIT have been established, however although there are ISO standards for EQAS with the ideal aim of establishing Category 1 schemes, there are no criteria to guide schemes for FIT. The aim of this study was to gather information by survey from EQAS FIT programmes, to find out the current similarities and differences, and to work towards establishing what ideal FIT EQAS look like to assist EQA schemes to make improvements. 24 schemes were identified worldwide; 16 responded to the survey. Programmes cover different testing environments and different patient groups. The number of sample distributions per year ranged from 1-12; most schemes did not provide faecal-based samples (69%), and for those that do, they mostly did not indicate if samples were provided in the assay manufacturers' sample buffer (88%). 69% of respondents provided information on reporting units and 31% use the recommended reporting units (μg Hb/g faeces); several methods were described for assigning target values, performance criteria and reporting performance. This survey indicates that large differences exist between the current FIT EQA schemes.
Microfluidic biosensors for early detection of ovarian cancer.
Zafarjanovna KM, Erkinovna SL, Khaydarov N … +10 more , Kobilova S, Dilovar K, Ravshanovna AG, Sabirovna VK, Akabirovich BA, Jurabek B, Shahzoda I, Islomov S, Qodirjanovna QN, Uktam T
Clin Chim Acta · 2026 Jun · PMID 42288273 · Publisher ↗
Ovarian cancer remains the most lethal gynecological malignancy, primarily because of the absence of reliable early detection methods. Microfluidic biosensors have emerged as promising platforms for rapid, sensitive, and...
Ovarian cancer remains the most lethal gynecological malignancy, primarily because of the absence of reliable early detection methods. Microfluidic biosensors have emerged as promising platforms for rapid, sensitive, and minimally invasive detection of ovarian cancer biomarkers. This review provides a comprehensive analysis of recent advances in microfluidic biosensing technologies for early ovarian cancer detection. We systematically examine various detection modalities, including electrochemical, optical, and mass-based sensors, with an emphasis on their integration with microfluidic platforms for point-of-care applications. Key biomarkers, including CA125, HE4, circulating tumor cells, exosomes, and circulating tumor DNA, are discussed in the context of multiplexed detection strategies. The review highlights critical performance metrics such as sensitivity, specificity, limit of detection, and clinical validation status. Furthermore, we address current challenges, including sample preparation, standardization, and clinical translation barriers. Our analysis revealed that integrated microfluidic platforms combining multiple biomarker detection methods with advanced nanomaterials and machine learning algorithms demonstrated the greatest promise for transforming ovarian cancer screening. Future directions toward clinical implementation require standardized validation protocols, large-scale prospective studies, and regulatory pathway clarification to realize the full potential of these innovative diagnostic technologies.
Multi-omic biomarkers in cardiovascular disease: Discovery to clinical translation.
AlRamadneh TN, Abdulsahib WK, Gajjar TB … +7 more , Hanumanthayya M, Shukla SK, Panigrahi R, Bainsal N, Rizaev J, Abduvoyitov B, Polatova D
Clin Chim Acta · 2026 Jun · PMID 42288272 · Publisher ↗
Cardiovascular disease (CVD) remains the leading cause of mortality worldwide, necessitating improved risk stratification and early detection strategies. Multiomics approaches that integrate genomics, transcriptomics, pr...
Cardiovascular disease (CVD) remains the leading cause of mortality worldwide, necessitating improved risk stratification and early detection strategies. Multiomics approaches that integrate genomics, transcriptomics, proteomics, metabolomics, and epigenomics offer unprecedented opportunities for biomarker discovery and precision medicine in cardiovascular care. This narrative review examines the current landscape of multiomics biomarkers for CVD, tracing their evolution from discovery to clinical translation. We synthesize evidence from recent studies evaluating the clinical utility of integrated omics approaches across diverse cardiovascular conditions, including atherosclerotic cardiovascular disease, heart failure, and atrial fibrillation. High-throughput proteomics has identified novel protein signatures that enhance cardiovascular risk prediction beyond traditional risk factors. Metabolomics has revealed pathway-specific biomarkers, including trimethylamine N-oxide and lipid species, associated with atherogenesis. Polygenic risk scores derived from genomic data demonstrate incremental value when combined with clinical risk scores. Multiomics biomarkers represent a transformative approach to cardiovascular risk assessment and disease management.
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