Search

Introduction: Salivary Lactate Dehydrogenase (sLDH) levels seem to be higher in patients with Oral Squamous Cell Carcinoma (OSCC) and Oral Potentially Malignant Disorders (OPMD) than a control group (CG)., Methods: Case-control study. Patients with OPMD [oral leukoplakia (OL) and oral lichen planus (OLP)] and OSCC who attended two services in Spain were selected. sLDH in saliva was measured. Epidemiological, periodontal and specific variables related to OPMD and OSCC were collected., Results: A total of 92 patients were included: 12 with OSCC, 51 with OPMD (17 OL and 34 OLP), and 29 controls. sLDH values were higher in the OSCC, followed by the OPMD and CG groups, although no significant differences were observed. In the OSCC group, larger tumor size was associated with higher sLDH levels. In the OLP group, sLDH values were higher in patients with symptomatic lesions than in patients with only white lesions, but not significantly. No associations were observed between sLDH and the type of OL (homogeneous vs. non-homogeneous) and the degree of dysplasia. When analyzing periodontal variables among OSCC, OPMD and CG, periodontal probing depth (PPD) and bleeding on probing were significantly higher in the OSCC group, while the plaque index was higher in OPMD patients. The linear regression model for sLDH in the total group identified age and PPD as significant predictors of sLDH levels., Discussion: Although sLDH values were higher in OSCC and OPMD patients than in a CG, the results do not support the use of sLDH as a reliable prognostic biomarker of malignancy. Future studies need to consider other factors that may influence sLDH levels, such as age and periodontal status., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2025 López-Pintor, González-Serrano, Vallina, Ivaylova Serkedzhieva, Virto, Nuevo, Caponio, Iniesta, Rodríguez Santamarta, Lequerica Fernández, Iglesias Velázquez, Hernández and de Vicente.)

The brain's substantial metabolic requirements, consuming a substantial fraction of the body's total energy despite its relatively small mass, necessitate sophisticated metabolic mechanisms for efficient energy distribution and utilization. The astrocyte-neuron lactate shuttle (ANLS) hypothesis has emerged as a fundamental framework explaining the metabolic cooperation between astrocytes and neurons, whereby astrocyte-derived lactate serves as a crucial energy substrate for neurons. This review synthesizes current understanding of brain energy metabolism, focusing on the dual roles of lactate as both an energy substrate and a signaling molecule. We examine the molecular underpinnings of metabolic compartmentalization, particularly the differential expression of lactate dehydrogenase (LDH) isozymes between astrocytes and neurons, which facilitates directional lactate flux. Recent evidence has challenged aspects of the classical ANLS model, revealing greater metabolic flexibility in neurons than previously recognized, including substantial LDHA expression and direct glucose utilization capabilities. Our recent studies on LDHB-deficient neurons provide new insights into the compensatory mechanisms and limitations of neuronal lactate metabolism, suggesting a more nuanced understanding of the ANLS hypothesis. Furthermore, we discuss lactate's emerging role as a signaling molecule in synaptic plasticity, memory formation, and neuroprotection, particularly in ischemic conditions where elevated lactate levels correlate with enhanced neuronal survival through prostaglandin E2-mediated vasodilation. This comprehensive review integrates classical perspectives with recent advances, providing an updated framework for understanding brain lactate metabolism and its therapeutic implications in neurological disorders.

Objective: To investigate the prognostic value of lactate dehydrogenase (LDH), serum albumin (ALB) and the lactate dehydrogenase/albumin ratio (LAR) in diffuse large B-cell lymphoma (DLBCL) before primary treatment., Methods: The clinical data of 212 primary adult DLBCL patients admitted to the First People's Hospital of Lianyungang from January 2017 to December 2022 were analyzed retrospectively. The optimal cutoff values of LDH, ALB, and LAR were determined using ROC curves. Survival curves of LDH, ALB, and LAR were plotted and analyzed using the Cox regression model and Kaplan-Meier method with the log-rank test., Results: Among the 212 patients admitted, the study derived the optimal cutoff values for ALB, LDH, and LAR as 38, 301, and 6, respectively. The Kaplan-Meier method and log-rank test analysis indicated a significant association between lower ALB levels, elevated LDH levels, elevated LAR levels, and shorter overall survival (OS) and progression-free survival (PFS) ( P  < 0.05). Additionally, the critical values of ALB and LDH were grouped into three categories. The differences in OS and PFS among these three groups were statistically significant ( P  < 0.05). Cox multifactorial analysis revealed that the LAR was an independent factor influencing the prognosis of OS and PFS, with a higher prognostic value than LDH and ALB alone., Conclusion: Decreased ALB levels and elevated LDH and LAR levels at the time of initial diagnosis are indicative of a poor prognosis in DLBCL patients. Furthermore, the study highlighted that the LAR has a higher prognostic value than LDH and ALB alone.

Background: Prostate cancer (PCa) is a serious malignancy. The main causes of PCa aggravation and death are unexplained resistance to chemotherapy and bone metastases., Objective: This study aimed to investigate the molecular mechanisms associated with the dynamic processes of progression, bone metastasis, and chemoresistance in PCa., Methods: Through comprehensive analysis of single-cell RNA sequencing (scRNA-seq) data, Gene Expression Omnibus (GEO) tumor progression and metastasis-related genes were identified. These genes were subjected to lasso regression modeling using the Cancer Genome Atlas (TCGA) database. Tartrate-resistant acid phosphatase (TRAP) staining and real-time quantitative PCR (RT-qPCR) were used to evaluate osteoclast differentiation. CellMiner was used to confirm the effect of LDHA on chemoresistance. Finally, the relationship between LDHA and chemoresistance was verified using doxorubicin-resistant PCa cell lines., Results: 7928 genes were identified as genes related to tumor progression and metastasis. Of these, 7 genes were found to be associated with PCa prognosis. The scRNA-seq and TCGA data showed that the expression of LDHA was higher in tumors and associated with poor prognosis of PCa. In addition, upregulation of LDHA in PCa cells induces osteoclast differentiation. Additionally, high LDHA expression was associated with resistance to Epirubicin, Elliptinium acetate, and doxorubicin. Cellular experiments demonstrated that LDHA knockdown inhibited doxorubicin resistance in PCa cells., Conclusions: LDHA may play a potential contributory role in PCa initiation and development, bone metastasis, and chemoresistance. LDHA is a key target for the treatment of PCa., Competing Interests: Declarations. Ethics approval: Not application. Consent for publication: Not applicable. Competing interests: All authors declare that they have no conflict of interest., (© 2024. The Author(s) under exclusive licence to The Genetics Society of Korea.)

Aerobic glycolysis is involved in the pathogenesis of pulmonary hypertension (PH). The mechanisms by which glycolysis is increased and how it contributes to pulmonary vascular remodelling are not yet fully understood. In this study, we demonstrated that elevated lipocalin-2 (LCN2) in PH significantly enhances aerobic glycolysis in human pulmonary artery smooth muscle cells (PASMCs) by up-regulating LDHA expression. Knockout of Lcn2 or having heterozygous LDHA deficiency in mice significantly inhibits the progression of hypoxic PH. Our study reveals that LCN2 stimulates LDHA expression by activating Akt-HIF-1α signalling pathway. Inhibition of Akt or HIF-1α reduces LDHA expression and proliferation of PASMCs. Both Akt and HIF-1α play critical roles in the development of PH and are suppressed in the pulmonary vessels of hypoxic PH mice lacking LCN2. These findings shed light on the LCN2-Akt-HIF1α-LDHA axis in aerobic glycolysis in PH., (© 2024 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

Abnormal N6-methyladenosine (m6A) methylation in RNA plays a pivotal role in the pathogenesis of many types of tumors by influencing mRNA metabolism, alternative splicing, translocation, stability and translation. However, the specific regulators and underlying mechanisms of m6A modification in the progression of lung adenocarcinoma are not well understood. In this study, we analyzed the RNA-seq transcriptome data downloaded from The Cancer Genome Atlas (TCGA) database, and identified "m6A writer" RNA binding motif protein 15 (RBM15) expression was significantly elevated in lung adenocarcinoma (LUAD) biopsies, and the higher RBM15 levels were correlated with the poorer overall survival (OS) of LUAD patients. Further study confirmed RBM15 was prominently expressed in LUAD tissues and cell lines. Moreover, silencing RBM15 in PC9 and H1299 cells reduced cell proliferation both in vitro and in vivo, while overexpression of RBM15 in A549 cells promoted cell growth. Mechanistically, lactate dehydrogenase A (LDHA) acted as a downstream target of RBM15. RBM15-mediated m6A modification of LDHA mRNA enhanced its stability to exert an oncogenic role in LUAD. Taken together, our findings suggest that the RBM15/LDHA axis might be a novel and promising therapeutic target for LUAD., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

The E3 ubiquitin ligase Tripartite-motif 3 (TRIM3) is known to play a crucial role in tumor suppression in various tumors through different mechanisms. However, its function and mechanism in ovarian cancer have yet to be elucidated. Our study aims to investigate the expression of TRIM3 in ovarian cancer and evaluate its role in the development of the disease. Our findings revealed a significant decrease in TRIM3 mRNA and protein levels in ovarian cancer tissues and cells when compared to normal ovarian epithelial tissues and cells. Furthermore, we observed a negative correlation between the protein level of TRIM3 and the FIGO stage, as well as a positive correlation with the survival of ovarian cancer patients. Using gain and loss of function experiments, we demonstrated that TRIM3 can inhibit cell proliferation, migration and invasion of the ovarian cancer cells in vitro, as well as suppress tumor growth in vivo. Mechanistic studies showed that TRIM3 interacts with lactate dehydrogenase A, a key enzyme in the glycolytic pathway, through its B-box and coiled-coil domains and induces its ubiquitination and proteasomal degradation, leading to the inhibition of glycolytic ability in ovarian cancer cells. RNA-sequencing analysis revealed significant alterations in the phosphatidylinositol signaling pathways upon TRIM3 overexpression. Additionally, overexpression of TRIM3 inhibited the phosphorylation of AKT. In conclusion, our study demonstrated that TRIM3 exerts a tumor-suppressive effect in ovarian cancer, at least partially, by downregulating LDHA and inhibiting the AKT signaling pathway, and thus leading to the inhibition of glycolysis and limiting the growth of ovarian cancer cells., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Decreased nicotinamide adenine dinucleotide (NAD + ) content has been shown to contribute to metabolic dysfunction during aging, including polycystic ovary syndrome (PCOS). However, the effect of NAD + on ovulatory dysfunction in PCOS by regulating glycolysis has not been reported. Based on the observations of granulosa cells (GCs) transcriptome data from the Gene Expression Omnibus (GEO) database, the signal pathways including glycolysis and nicotinate-nicotinamide metabolism were significantly enriched, and most genes of the above pathway like LDHA and SIRT2 were down-regulated in PCOS patients. Therefore, the PCOS rat model was established by combining letrozole with a high-fat diet (HFD), we demonstrate that in vivo supplementation of nicotinamide mononucleotide (NMN) significantly improves the ovulatory dysfunction by facilitating the follicular development, promoting luteal formation, as well the fertility in PCOS rats. Furthermore, target energy metabolomics and transcriptome results showed that NMN supplementation ameliorates the lactate production by activating glycolytic process in the ovary. In vitro, when NAD + synthesis and SIRT2 expression were inhibited, lactate content in KGN cells was decreased and LDHA expression was significantly inhibited. We confirmed that FK866 can enhance the acetylation of LDHA on 293T cells by Co-immunoprecipitation (Co-IP) assay. We also observed that inhibition of NAD + synthesis can reduce the activity and increase the apoptosis of KGN cells. Overall, these benefits of NMN were elucidated and the Nampt/SIRT2/LDHA pathway mediated lactate production in granulosa cells played an important role in the improvement of follicular development disorders in PCOS. This study will provide experimental evidence for the clinical application of NMN in the treatment of PCOS in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

The prevalence and mortality rates of colorectal cancer have been increasing in recent years, driven in part by the reliance of cancerous cells on aerobic glycolysis for growth. Sodium butyrate (NaB) has been shown to impede this process in colorectal cancer cells, although its mechanism of action remains unclear. In this study, we used cobalt chloride (CoCl 2 ) to simulate a hypoxic environment and demonstrated that NaB downregulated hypoxia-inducible factor-1α (HIF-1α) protein levels under both normoxic and hypoxic conditions. By employing cycloheximide (CHX), MG132, and chloroquine (CQ), we investigated whether NaB affects HIF-1α protein levels via the autophagy pathway. Importantly, siRNA-mediated SIRT4 knockdown revealed that NaB promotes HIF-1α autophagic degradation by upregulating SIRT4 expression. This subsequently inhibits HIF-1α-mediated expression of GLUT1 and LDHA, reducing glucose uptake, lactate production, and ATP generation, ultimately suppressing aerobic glycolysis and cell proliferation in colorectal cancer cells. Furthermore, a human colorectal cancer xenograft model confirmed that butyric acid inhibited tumor growth in vivo, correlating with SIRT4 and HIF-1α modulation. In conclusion, our findings indicate that NaB hinders colorectal cancer progression by disrupting aerobic glycolysis mediated by SIRT4/HIF-1α., Competing Interests: Declaration of competing interest The authors declare that there are no conflict of interests, we do not have any possible conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ubiquitin-specific protease 4 (USP4) has been identified as a promising oncogenic factor implicated in various human malignancies. However, the exact biological functions and underlying mechanisms of USP4 in the progression of papillary thyroid carcinoma (PTC) remain elusive. In this study, we observed a marked upregulation of USP4 expression in PTC tumor tissues. Elevated levels of USP4 were significantly correlated with aggressive clinicopathological features and poor prognosis. Functional assays for loss-of-function demonstrated that silencing USP4 hindered the proliferation of PTC cells. Furthermore, our investigation revealed a specific interaction between USP4 and lactate dehydrogenase A (LDHA), wherein USP4 played a crucial role in stabilizing LDHA protein levels via deubiquitination in PTC cells. Notably, this study demonstrated that USP4 promotes PTC proliferation by modulating the MAPK and AKT signaling pathways. In summary, our findings elucidate the critical involvement of the USP4/LDHA axis in driving PTC progression through the modulation of MAPK and AKT pathways, thereby identifying USP4 as a potential therapeutic target for the treatment of PTC.

Objective: Lactate dehydrogenase is dysregulated in several cancer types. However, the mechanism of its dysregulation in lung cancer is not fully understood. We utilized web-based computational databases to conduct gene expression analysis on LDHA, identified its regulator, and explored their role in the prognosis of lung cancer., Methods: We used various web-based computational tools, including the UALCAN, TIMER2.0, ENCORI, TCGA Portal, OncoDB, and GEPIA2 datasets for lung cancer analysis in this study. We also performed survival, biological processes, and metastasis analysis using various computational tools. We also carried out co-expression functional enrichment analysis using the Enrichr and TIMER databases, multivariate analysis of survival and pathological stage, and transcriptional regulation analysis using the ENCORI and OncoDB datasets. Furthermore, LDHA inhibitor binding of withanolides was analyzed using Auto Dock Tools 1.5.6, LigPlot+, and Pymol., Results: The study found that the higher levels of LDHA gene expression were associated with poor prognosis and overall survival in lung cancer patients. We identified 11 key genes co-expressed with LDHA; out of them, two genes, MKI67 and PGK1, showed a strong positive correlation with LDHA and associated poor survival outcomes in LUAD patients. Furthermore, we also identified hsa-let-7c-5p and TMPO-AS1 as potential regulators of LDHA in LUAD. It might be possible that the TMPO-AS1- hsa-let-7c-5p-LDHA ceRNA network could serve as a potential regulator of aerobic glycolysis in LUAD and can serve as prognostic biomarkers. Further, Withanolides can inhibit the activity of LDHA and can be tested as an adjuvant treatment., Conclusion: We conclude that LDHA is overexpressed in LUAD, and the patients with high expression of LDHA exhibit poor prognosis. Further, the TMPO-AS1-hsa-let-7c-5p-LDHA ceRNA network can regulate aerobic glycolysis, thereby facilitating tumor growth in lung cancer.

Escherichia coli small heat-shock protein IbpB (MW: 16 KDa) has holding chaperone activity and is present in cells at 30 °C as two large oligomers of MW 2.0-3.0 MDa and 600-700 KDa. We report here about the presence of two additional oligomers of MW around 400 and 130 KDa in cells under heat-stress at 50 °C. These two smaller oligomers possess the most chaperone activity, as observed from the extent of inhibition of inactivation and aggregation separately, of L-Lactate dehydrogenase in the presence of the individual oligomers at 52 and 60 °C, respectively. It is suggested here that the two larger oligomers act as poorly active storage forms, which under heat stress dissociate partially into smaller oligomers with high holdase activity., (© 2024 Federation of European Biochemical Societies.)

L-Lactate is a commodity chemical used in various fields. Microorganisms have produced L-lactate via lactic fermentation using saccharides derived from crops as carbon sources. Recently, L-lactate production using microalgae, whose carbon source is carbon dioxide, has been spotlighted because the prices of the crops have increased. A red alga Cyanidioschyzon merolae produce L-lactate via lactic fermentation under dark anaerobic conditions. The L-lactate titer of C. merolae is higher than those of other microalgae but lower than those of heterotrophic bacteria. Therefore, an increase in the L-lactate titer is required in C. merolae. L-Lactate dehydrogenase (L-LDH) catalyzes the reduction of pyruvate to L-lactate during lactic fermentation. C. merolae possesses five isozymes of L-LDH. The results of previous transcriptome analysis suggested that L-LDHs are the key enzymes in the lactic fermentation of C. merolae. However, their biochemical characteristics, such as catalytic efficiency and tolerance for metabolites, have not been revealed. We compared the amino acid sequences of C. merolae L-LDHs (CmLDHs) and characterized one of the isozymes, CmLDH1. BLAST analysis revealed that the sequence similarities of CmLDH1 and the other isozymes were above 99%. The catalytic efficiency of CmLDH1 under its optimum conditions was higher than those of L-LDHs of other organisms. ATP decreased the affinity and turnover number of CmLDH1 for NADH. These findings contribute to understanding the characteristics of L-LDHs of microalgae and the regulatory mechanisms of lactic fermentation in C. merolae., (© 2024. The Author(s).)

As a solid tumor with high glycolytic activity, hepatocellular carcinoma (HCC) produces excess lactic acid and increases extracellular acidity, thus forming a unique immunosuppressive microenvironment. L-lactate dehydrogenase (LDH) and monocarboxylate transporters (MCTs) play a very important role in glycolysis. LDH is the key enzyme for lactic acid (LA) production, and MCT is responsible for the cellular import and export of LA. The synergistic effect of the two promotes the formation of an extracellular acidic microenvironment. In the acidic microenvironment of HCC, LA can not only promote the proliferation, survival, transport and angiogenesis of tumor cells but also have a strong impact on immune cells, ultimately leading to an inhibitory immune microenvironment. This article reviews the role of LA in HCC, especially its effect on immune cells, summarizes the progress of LDH and MCT-related drugs, and highlights the potential of immunotherapy targeting lactate combined with HCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: Osteoarthritis (OA) is the most common joint disease. The occurrence and progression of OA are regulated by epigenetics. A large number of studies have shown the important regulatory role of noncoding RNAs in joint diseases. As the largest class of noncoding small RNAs, the importance of piRNAs in many diseases, especially cancer, has been increasingly recognized. However, few studies have explored the role of piRNAs in OA. Our study showed that hsa&#95;piR&#95;019914 decreased significantly in OA. This study aimed to demonstrate the role of hsa&#95;piR&#95;019914 as a potential biological target of OA in chondrocytes., Design: The GEO database and bioinformatics analysis were used for a series of screenings, and the OA model using human articular chondrocytes (C28/I2 cells), SW1353 cells under inflammatory factor stimulation was used to determine that hsa&#95;piR&#95;019914 was significantly downregulated in OA. Overexpression or inhibition of hsa&#95;piR&#95;019914 in C28/I2 cells was achieved by transfecting mimics or inhibitors. The effect of hsa&#95;piR&#95;019914 on the biological function of chondrocytes was verified by qPCR, flow cytometry, and colony formation assays in vitro. The target gene of hsa&#95;piR&#95;019914, lactate dehydrogenase A (LDHA), was screened by small RNA sequencing and quantitative polymerase chain reaction (qPCR), LDHA was knocked out in C28/I2 cells by the transfection of siRNA LDHA, and the relationship between hsa&#95;piR&#95;019914, LDHA, and reactive oxygen species (ROS) production was verified by flow cytometry., Results: The piRNA hsa-piR-019914 was significantly downregulated in osteoarthritis (OA). Hsa-piR-019914 reduced inflammation-mediated chondrocyte apoptosis and maintained cell proliferation and clone formation in vitro. Hsa-piR-019914 reduced the production of LDHA-dependent ROS through targeted regulation of LDHA expression, maintained chondrocyte-specific gene expression of ACAN and COL2, and inhibited the gene expression of MMP3 and MMP13., Conclusions: Collectively, this study showed that hsa&#95;piR&#95;019914 was negatively correlated with the expression of LDHA, which mediates ROS production. Under the stimulation of inflammatory factors, overexpression of hsa&#95;piR&#95;019914 had a protective effect on chondrocytes in vitro, and the absence of hsa&#95;piR&#95;019914 exacerbated the negative effect of inflammation on chondrocytes. Studies on piRNAs provide new therapeutic interventions for OA., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Understanding the heterogeneous nature of breast cancer, including the role of LDHA expression regulation via non-coding RNAs in prognosis, is still unknown, highlighting the need for more research into its molecular roles and diagnostic approaches., Methods: The study utilized various computer tools to analyze the differences between LDHA in tissues and cancer cells. It used data from TIMER 2.0, UALCAN, and TISIDB to study gene expression and survival outcomes in breast cancer patients. The study also used the Breast Cancer Gene Expression Miner to examine the relationship between LDHA gene expression and breast cancer type. Other tools included TCGAPortal, TNMplot, ctcRbase, GSCA, Enrichr, TISIDB, Oncomx, and TANRIC. The study then explored the relationship between tumor-infiltrating immune cells and LDHA formation using the GSCA and TISIDB repositories. We used Auto Dock Tools 1.5.6 to perform ligand binding analysis for LDHA, withanolides, and the known inhibitor LDH-IN-1. LigPlot+ and Pymol were used for visualization of protein-ligand complexes., Results: LDHA overexpression in breast cancer cells, metastatic tissue, and circulating tumor cells leads to shortened recurrence-free survival, overall survival, and distant metastasis-free survival. In invasive breast cell carcinoma, we observed that LDHA/HIF-1α /TMPO-AS1 are overexpressed while miR-383-5p is downregulated. This overexpression is associated with poor prognosis and may lead to Act&#95;DC infiltration into the tumor microenvironment. Withanolides, viz., Withaferine A and Withanolide D, have shown high binding affinity with LDHA, with binding energies of -9.3kcal/mol and -10kcal/mol respectively. These could be attractive choices for small-molecule inhibitor design against LDHA.

Background: Breast cancer manifests as a heterogeneous pathology marked by complex metabolic reprogramming essential to satisfy its energy demands. Oncogenic signals boost the metabolism, modifying fatty acid synthesis and glucose use from the onset to progression and therapy resistant-forms. However, the exact contribution of metabolic dependencies during tumor evolution remains unclear., Methods: In this study, we elucidate the connection between FASN and LDHA, pivotal metabolic genes, and their correlation with tumor grade and therapy response using datasets from public repositories. Subsequently, we evaluated the metabolic and proliferative functions upon FASN and LDHA inhibition in breast cancer models. Lastly, we integrated metabolomic and lipidomic analysis to define the contributions of metabolites, lipids, and precursors to the metabolic phenotypes., Results: Collectively, our findings indicate metabolic shifts during breast cancer progression, unvealling two distinct functional energy phenotypes associated with aggressiveness and therapy response. Specifically, FASN exhibits reduced expression in advance-grade tumors and therapy-resistant forms, whereas LDHA demonstrates higher expression. Additionally, the biological and metabolic impact of blocking the enzymatic activity of FASN and LDHA was correlated with resistant conditions., Conclusions: These observations emphasize the intrinsic metabolic heterogeneity within breast cancer, thereby highlighting the relevance of metabolic interventions in the field of precision medicine., (© 2024. The Author(s).)

Objective: Glioblastoma (GBM) has poor clinical prognosis due to limited treatment options. In addition, the current treatment regimens for GBM may only slightly prolong patient survival. The aim of this study was to assess the role of BMAL1 in the immune microenvironment and drug resistance of GBM., Methods: GBM cell lines with stable BMAL1 knockdown or LDHA overexpression were constructed, and functionally characterized by the CCK8, EdU incorporation, and transwell assays. In vivo GBM model was established in C57BL/6J mice. Flow cytometry, ELISA, immunofluorescence, and RT-qPCR were performed to detect macrophage polarization. Lactate production, pathological changes, and the expression of glycolytic proteins were analyzed by HE staining, immunohistochemistry, biochemical assays, and Western blotting., Results: BMAL1 silencing inhibited the malignant characteristics, lactate production, and expression of glycolytic proteins in GBM cells, and these changes were abrogated by overexpression of LDHA or exogenous lactate supplementation. Furthermore, BMAL1 knockdown induced M1 polarization of macrophages, and inhibited M2 polarization and angiogenesis in GBM cells in conditioned media. Overexpression of LDHA or presence of exogenous lactate inhibited BMAL1-induced M1 polarization and angiogenesis. Finally, BMAL1 silencing and bevacizumab synergistically inhibited glycolysis, angiogenesis and M2 polarization, and promoted M1 polarization in vivo, thereby suppressing GBM growth., Conclusion: BMAL1 silencing can sensitize GBM cells to bevacizumab by promoting M1/M2 polarization through the LDHA/lactate axis., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Lactate dehydrogenase (LDH) from Schistosoma mansoni has peculiar properties for a eukaryotic LDH. Schistosomal LDH (SmLDH) isolated from schistosomes, and the recombinantly expressed protein, are strongly inhibited by ATP, which is neutralized by fructose-1,6-bisphosphate (FBP). In the conserved FBP/anion binding site we identified two residues in SmLDH (Val187 and Tyr190) that differ from the conserved residues in LDHs of other eukaryotes, but are identical to conserved residues in FBP-sensitive prokaryotic LDHs. Three-dimensional (3D) models were generated to compare the structure of SmLDH with other LDHs. These models indicated that residues Val187, and especially Tyr190, play a crucial role in the interaction of FBP with the anion pocket of SmLDH. These 3D models of SmLDH are also consistent with a competitive model of SmLDH inhibition in which ATP (inhibitor) and FBP (activator) compete for binding in a well-defined anion pocket. The model of bound ATP predicts a distortion of the nearby key catalytic residue His195, resulting in enzyme inhibition. To investigate a possible physiological role of this allosteric regulation of LDH in schistosomes we made a kinetic model in which the allosteric regulation of the glycolytic enzymes can be varied. The model showed that inhibition of LDH by ATP prevents fermentation to lactate in the free-living stages in water and ensures complete oxidation via the Krebs cycle of the endogenous glycogen reserves. This mechanism of allosteric inhibition by ATP prevents the untimely depletion of these glycogen reserves, the only fuel of the free-living cercariae. Neutralization by FBP of this ATP inhibition of LDH prevents accumulation of glycolytic intermediates when S. mansoni schistosomula are confronted with the sudden large increase in glucose availability upon penetration of the final host. It appears that the LDH of S. mansoni is special and well suited to deal with the variations in glucose availability the parasite encounters during its life cycle., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Everolimus, a mammalian target of rapamycin inhibitor used as an antineoplastic drug, is associated with a remarkably high incidence of interstitial lung disease (ILD). The clinical and pathological characteristics of ILD caused by everolimus have not been thoroughly investigated; therefore, we aimed to elucidate the features of everolimus-associated ILD., Methods: We retrospectively reviewed the medical records of patients who received everolimus for cancer treatment at our hospital. Patient backgrounds were compared between the ILD and non-ILD groups. Chest computed tomography (CT), changes in biomarkers, and lung histopathological features were analyzed for ILD cases., Results: Sixty-six patients were reviewed, and ILD developed in 19. There were no differences in patient demographics between the ILD and non-ILD groups. The severity of ILD was grade 1 (G1) in 9 and grade 2 (G2) in 10 cases. Chest CT showed organizing pneumonia (OP) or a hypersensitive pneumonia pattern. The levels of lactate dehydrogenase, C-reactive protein, Krebs von den lungen-6, and surfactant protein-D (SP-D) at the onset of ILD were significantly higher than those at baseline. Analysis of G1 and G2 ILD subgroups showed a higher SP-D levels in the G2 subgroup. Five patients underwent lung biopsies; all specimens demonstrated alveolitis with lymphocytic infiltration and granulomatous lesions, and some had OP findings., Conclusions: Everolimus-associated ILD is mild and has a favorable prognosis. Patients with symptomatic ILD were more likely to have higher SP-D levels than those with asymptomatic ILD. Granulomatous lesions are an important pathological feature of everolimus-associated ILD.

Background: Metabolic reprogramming and epigenetic alterations contribute to the aggressiveness of pancreatic ductal adenocarcinoma (PDAC). Lactate-dependent histone modification is a new type of histone mark, which links glycolysis metabolite to the epigenetic process of lactylation. However, the role of histone lactylation in PDAC remains unclear., Methods: The level of histone lactylation in PDAC was identified by western blot and immunohistochemistry, and its relationship with the overall survival was evaluated using a Kaplan-Meier survival plot. The participation of histone lactylation in the growth and progression of PDAC was confirmed through inhibition of histone lactylation by glycolysis inhibitors or lactate dehydrogenase A (LDHA) knockdown both in vitro and in vivo. The potential writers and erasers of histone lactylation in PDAC were identified by western blot and functional experiments. The potential target genes of H3K18 lactylation (H3K18la) were screened by CUT&Tag and RNA-seq analyses. The candidate target genes TTK protein kinase (TTK) and BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B) were validated through ChIP-qPCR, RT-qPCR and western blot analyses. Next, the effects of these two genes in PDAC were confirmed by knockdown or overexpression. The interaction between TTK and LDHA was identified by Co-IP assay., Results: Histone lactylation, especially H3K18la level was elevated in PDAC, and the high level of H3K18la was associated with poor prognosis. The suppression of glycolytic activity by different kinds of inhibitors or LDHA knockdown contributed to the anti-tumor effects of PDAC in vitro and in vivo. E1A binding protein p300 (P300) and histone deacetylase 2 were the potential writer and eraser of histone lactylation in PDAC cells, respectively. H3K18la was enriched at the promoters and activated the transcription of mitotic checkpoint regulators TTK and BUB1B. Interestingly, TTK and BUB1B could elevate the expression of P300 which in turn increased glycolysis. Moreover, TTK phosphorylated LDHA at tyrosine 239 (Y239) and activated LDHA, and subsequently upregulated lactate and H3K18la levels., Conclusions: The glycolysis-H3K18la-TTK/BUB1B positive feedback loop exacerbates dysfunction in PDAC. These findings delivered a new exploration and significant inter-relationship between lactate metabolic reprogramming and epigenetic regulation, which might pave the way toward novel lactylation treatment strategies in PDAC therapy., (© 2024. The Author(s).)

Herein, we present a paper-based POCT sensor based on lactate dehydrogenase-mediated alginate gelation combined with visual distance reading and smartphone-assisted colorimetric dual-signal analysis to determine the concentration of L-lactate in yogurt samples. In this research, L-lactate was transformed into pyruvate by lactate dehydrogenase. Pyruvate then triggered the gelation of a sol mixture, increasing the viscosity ( η s ) of the mixture, which was shown as a decrease in the diffusion diameter on the paper-based sensor. In addition, protons from pyruvate accelerated the degradation of Rhodamine B, causing color fading of the mixture, which was analyzed using RGB analysis application software. Under optimal experimental conditions, the linear ranges of visual distance reading and smartphone-assisted colorimetric analysis were 0.1-15 μM and 0.3-15 μM and the detection limits were 0.03 μM and 0.07 μM, respectively. As a proof-of-concept application, we exploited the paper-based sensor to determine the concentration of L-lactate in yogurt samples. The results from the dual-signal paper-based sensor were consistent with the ones from HPLC analysis. In short, this study developed a simple, convenient, cost-effective, and feasible method for the quantitative detection of L-lactate in real samples.

Meningioma is one of the most common primary neoplasms in the central nervous system, but no specific molecularly targeted therapy has been approved for the clinical treatment of aggressive meningiomas. There is hence an urgent demand to decrypt the biological and molecular landscape of malignant meningioma. Here, through the in-silica prescreening and 10-year follow-up studies of 445 meningioma patients, we uncovered that CBX7 expression progressively decreases with malignancy grade and neoplasia stage in meningioma, and a high CBX7 expression level predicts a favorable prognosis in meningioma patients. CBX7 restoration significantly induces cell cycle arrest and inhibits meningioma cell proliferation. iTRAQ-based proteomics analysis indicated that CBX7 restoration triggers the metabolic shift from glycolysis to oxidative phosphorylation. The mechanistic study demonstrated that CBX7 promotes the proteasome-dependent degradation of c-MYC protein by transcriptionally inhibiting the expression of a c-MYC deubiquitinase, USP44, consequently attenuates c-MYC-mediated transactivation of LDHA transcripts, and further inhibits glycolysis and subsequent cell proliferation. More importantly, the functional role of CBX7 was further confirmed in subcutaneous and orthotopic meningioma xenograft mouse models and meningioma patients. Altogether, our results shed light on the critical role of CBX7 in meningioma malignancy progression and identify the CBX7/USP44/c-MYC/LDHA axis as a promising therapeutic target against meningioma progression., (© The Author(s) (2023). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, CEMCS, CAS.)

Objectives: To describe real-world use/effectiveness of pegcetacoplan (PEG) in paroxysmal nocturnal haemoglobinuria (PNH)., Methods: Data were drawn from the Adelphi PNH Disease Specific Programme™, a cross-sectional survey conducted in France, Italy, Germany, Spain and the United States from January to November 2022. Patients had a confirmed PNH diagnosis and received PEG for ≥1 month. Physicians reported patient characteristics, treatment use/satisfaction and their perception of patients' fatigue and health-related quality of life (HRQoL). Patients reported treatment satisfaction and completed questionnaires assessing fatigue, HRQoL and productivity. Descriptive statistics were reported., Results: Overall, 14 physicians provided data for 61 patients who had received 1080 mg/dose PEG for 1.3-14.8 months. At data collection compared to PEG initiation: haemoglobin was 2.5 g/dL higher on average; proportion of patients with lactate dehydrogenase (LDH) ≥1.5 × upper limit of normal was reduced by 27.4%; physician-perceived fatigue was lower and HRQoL better. Physician- and patient-reported treatment satisfaction was high for >90% of patients. Physicians and patients were more satisfied with PEG than previously prescribed C5 complement inhibitors. Mean work impairment and activity impairment in the 7 days prior to data collection were 32.9% and 22.4%, respectively., Conclusions: These real-world data support the effectiveness of PEG through positive effects on haemoglobin, LDH, fatigue and HRQoL., (© 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Pretreatment serum lactate dehydrogenase (LDH) levels have been associated with poor prognosis in several types of cancer, including metastatic colorectal cancer (mCRC). However, very few models link survival to longitudinal LDH measured repeatedly over time during treatment. We investigated the prognostic value of on-treatment LDH dynamics in mCRC. Using data from two large phase III studies (2L and 3L+ mCRC settings, n = 824 and 210, respectively), we found that integrating longitudinal LDH data with baseline risk factors significantly improved survival prediction. Current LDH values performed best, enhancing discrimination ability (area under the receiver operating characteristic curve) by 4.5~15.4% and prediction accuracy (Brier score) by 3.9~15.0% compared with baseline variables. Combining all longitudinal LDH markers further improved predictive performance. After controlling for baseline covariates and other longitudinal LDH indicators, current LDH levels remained a significant risk factor in mCRC, increasing mortality risk by over 90% (P < 0.001) in 2L patients and 60-70% (P < 0.01) in 3L+ patients per unit increment in current log (LDH). Machine-learning techniques, like functional principal component analysis (FPCA), extracted informative features from longitudinal LDH data, capturing over 99% of variability and allowing prediction of survival. Unsupervised clustering based on the extracted FPCA features stratified patients into three groups with distinct LDH dynamics and survival outcomes. Hence, our approaches offer a valuable and cost-effective way for risk stratification and improves survival prediction in mCRC using LDH trajectories., (© 2023 The Authors. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics.)

Background: To examine standardized uptake value max of the primary lesion (pSUVmax) and tumor markers (TMs) for clinically predicting distant metastasis in novo lung adenocarcinoma., Methods: The current retrospective observational study examined individuals diagnosed with de novo lung adenocarcinoma at Shanxi Cancer Hospital between February 2015 and December 2019., Results: Totally, 532 de novo lung adenocarcinoma cases were included. They were aged 60.8 ± 9.7 years and comprised 224 women and 268 patients with distant metastasis. The areas under the curves (AUCs) of pSUVmax, lactate dehydrogenase (LDH), carcinoembryonic antigen (CEA), cytokeratin-19 fragment (CYFRA21-1), carbohydrate antigen 125 (CA125), and Grade of TMs for predicting distant metastasis were 0.742, 0.601, 0.671, 0.700, 0.736, and 0.745, respectively. The combination of pSUVmax, LDH, CEA, CYFRA21-1, CA125, and grade of TMs in predicting distant metastasis had an AUC value of 0.816 (95%CI: 0.781-0.851), with sensitivity of 89.2%, specificity of 58.7%, positive predictive value of 73.7%, and negative predictive value of 79.7%, respectively., Conclusions: pSUVmax combined with serum levels of LDH, CEA, CYFRA21-1, CA125, and the grade of TMs may have good performance in predicting distant metastasis of de novo lung adenocarcinoma., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Growth differentiation factor 15 (GDF-15) is a stress-induced cytokine associated with acute and chronic inflammatory states. This prospective observational study aimed to investigate the prognostic roles of GDF-15 and routine clinical laboratory parameters in COVID-19 patients. Upon the admission of 95 adult hospitalized COVID-19 patients in Croatia, blood analysis was performed, and medical data were collected. The patients were categorized based on survival, ICU admission, and hospitalization duration. Logistic regression and ROC curve methods were employed for the statistical analysis. Logistic regression revealed two independent predictors of negative outcomes: CURB-65 score (OR = 2.55) and LDH (OR = 1.005); one predictor of ICU admission: LDH (OR = 1.004); and one predictor of prolonged hospitalization: the need for a high-flow nasal cannula (HFNC) upon admission (OR = 4.75). The ROC curve showed diagnostic indicators of negative outcomes: age, CURB-65 score, LDH, and GDF-15. The largest area under the curve (AUC = 0.767, specificity = 65.6, sensitivity = 83.9) was represented by GDF-15, with a cutoff value of 3528 pg/mL. For ICU admission, significant diagnostic indicators were LDH, CRP, and IL-6. Significant diagnostic indicators of prolonged hospitalization were CK, GGT, and oxygenation with an HFNC upon admission. This study reaffirms the significance of the commonly used laboratory parameters and clinical scores in evaluating COVID-19. Additionally, it introduces the potential for a new diagnostic approach and research concerning GDF-15 levels in this widespread disease.

Introduction: The coronavirus disease 2019 (COVID-19) pandemic has affected billions of people worldwide, and the lessons learned need to be concluded to get better prepared for the next pandemic. Early identification of high-risk patients is important for appropriate treatment and distribution of medical resources. A generalizable and easy-to-use COVID-19 severity stratification model is vital and may provide references for clinicians., Methods: Three COVID-19 cohorts (one discovery cohort and two validation cohorts) were included. Longitudinal peripheral blood mononuclear cells were collected from the discovery cohort (n = 39, mild = 15, critical = 24). The immune characteristics of COVID-19 and critical COVID-19 were analyzed by comparison with those of healthy volunteers (n = 16) and patients with mild COVID-19 using mass cytometry by time of flight (CyTOF). Subsequently, machine learning models were developed based on immune signatures and the most valuable laboratory parameters that performed well in distinguishing mild from critical cases. Finally, single-cell RNA sequencing data from a published study (n = 43) and electronic health records from a prospective cohort study (n = 840) were used to verify the role of crucial clinical laboratory and immune signature parameters in the stratification of COVID-19 severity., Results: Patients with COVID-19 were determined with disturbed glucose and tryptophan metabolism in two major innate immune clusters. Critical patients were further characterized by significant depletion of classical dendritic cells (cDCs), regulatory T cells (Tregs), and CD4 + central memory T cells (Tcm), along with increased systemic interleukin-6 (IL-6), interleukin-12 (IL-12), and lactate dehydrogenase (LDH). The machine learning models based on the level of cDCs and LDH showed great potential for predicting critical cases. The model performances in severity stratification were validated in two cohorts (AUC = 0.77 and 0.88, respectively) infected with different strains in different periods. The reference limits of cDCs and LDH as biomarkers for predicting critical COVID-19 were 1.2% and 270.5 U/L, respectively., Conclusion: Overall, we developed and validated a generalizable and easy-to-use COVID-19 severity stratification model using machine learning algorithms. The level of cDCs and LDH will assist clinicians in making quick decisions during future pandemics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 He, Cui, Zhao, Wu, Zhang, Xue, Zhang, Ge and Leng.)

Objective: To explore potential predictors of refractory Mycoplasma pneumoniae pneumonia (RMPP) in early stage. Methods: The prospective multicenter study was conducted in Zhejiang, China from May 1 st , 2019 to January 31 st , 2020. A total of 1 428 patients with fever >48 hours to <120 hours were studied. Their clinical data and oral pharyngeal swab samples were collected; Mycoplasma pneumoniae DNA in pharyngeal swab specimens was detected. Patients with positive Mycoplasma pneumoniae DNA results underwent a series of tests, including chest X-ray, complete blood count, C-reactive protein, lactate dehydrogenase (LDH), and procalcitonin. According to the occurrence of RMPP, the patients were divided into two groups, RMPP group and general Mycoplasma pneumoniae pneumonia (GMPP) group. Measurement data between the 2 groups were compared using Mann-Whitney U test. Logistic regression analyses were used to examine the associations between clinical data and RMPP. Receiver operating characteristic (ROC) curves were used to analyse the power of the markers for predicting RMPP. Results: A total of 1 428 patients finished the study, with 801 boys and 627 girls, aged 4.3 (2.7, 6.3) years. Mycoplasma pneumoniae DNA was positive in 534 cases (37.4%), of whom 446 cases (83.5%) were diagnosed with Mycoplasma pneumoniae pneumonia, including 251 boys and 195 girls, aged 5.2 (3.3, 6.9) years. Macrolides-resistant variation was positive in 410 cases (91.9%). Fifty-five cases were with RMPP, 391 cases with GMPP. The peak body temperature before the first visit and LDH levels in RMPP patients were higher than that in GMPP patients (39.6 (39.1, 40.0) vs. 39.2 (38.9, 39.7) ℃, 333 (279, 392) vs. 311 (259, 359) U/L, both P <0.05). Logistic regression showed the prediction probability π=exp (-29.7+0.667×Peak body temperature (℃)+0.004×LDH (U/L))/(1+exp (-29.7+0.667×Peak body temperature (℃)+0.004 × LDH (U/L))), the cut-off value to predict RMPP was 0.12, with a consensus of probability forecast of 0.89, sensitivity of 0.89, and specificity of 0.67; and the area under ROC curve was 0.682 (95% CI 0.593-0.771, P <0.01). Conclusion: In MPP patients with fever over 48 to <120 hours, a prediction probability π of RMPP can be calculated based on the peak body temperature and LDH level before the first visit, which can facilitate early identification of RMPP.

Plasmodium vivax lactate dehydrogenase (PvLDH) is an essential enzyme in the glycolytic pathway of P. vivax. It is widely used as a diagnostic biomarker and a measure of total-body parasite biomass in vivax malaria. However, the dynamics of PvLDH remains poorly understood. Here, we developed mathematical models that capture parasite and matrix PvLDH dynamics in ex vivo culture and the human host. We estimated key biological parameters characterising in vivo PvLDH dynamics based on longitudinal data of parasitemia and PvLDH concentration collected from P. vivax-infected humans, with the estimates informed by the ex vivo data as prior knowledge in a Bayesian hierarchical framework. We found that the in vivo accumulation rate of intraerythrocytic PvLDH peaks at 10-20 h post-invasion (late ring stage) with a median estimate of intraerythrocytic PvLDH mass at the end of the life cycle to be 9.4 × 10 -3 ng. We also found that the median estimate of in vivo PvLDH half-life was approximately 21.9 h. Our findings provide a foundation with which to advance our quantitative understanding of P. vivax biology and will facilitate the improvement of PvLDH-based diagnostic tools., (© 2024. The Author(s).)

Objective: This study aims to investigate the association between lactate dehydrogenase (LDH) and the risk of diabetic kidney disease (DKD) in patients with type 2 diabetes (T2D)., Methods: The study enrolled patients with diagnosis of T2D between 2009 and 2018 from the National Nutrition and Health Examination Survey (NHANES) database. Demographic information, laboratory test, and diagnostic data were collected. Restricted cubic spline (RCS) plots were used to assess the dose-effect relationship between LDH levels and the risk of DKD in patients with T2D. Based on LDH levels, individuals were divided into higher and lower groups using dichotomy, and multivariate logistic regression analysis was conducted to explore the relationship between different LDH levels and the risk of DKD in T2D patients. Stratified analysis was performed to assess the consistency of the result., Results: A total of 4888 patients were included in the study, with 2976 (60.9%) patients without DKD and 1912 (39.1%) patients with DKD. RCS plots showed that the risk of DKD increased with increasing LDH levels. Multifactorial logistic regression analysis revealed that T2D patients with higher LDH levels had a 45% increased risk of DKD compared to those with lower LDH levels (OR=1.45; 95% CI: 1.11-1.89). Furthermore, each standard deviation increase in LDH level was associated with a 24% increase in DKD incidence among T2D patients (OR=1.24; 95% CI: 1.07-1.44). Stratified analysis consistently supported these findings., Conclusions: LDH can serve as a valuable biomarker for screening DKD in patients with T2D., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Tang, Yang, Ma, Zhou, Peng, Xie, Liang, Wu, Gao, Yu, Deng, Dai, Mao and Xiao.)

Background: Coronavirus disease 2019 (COVID-19) is frequntly accompanied by venous thromboembolism (VTE), and its mechanism may be related to the abnormal inflammation and immune status of COVID-19 patients. It has been proved that interleukin-6 (IL-6), ferritin and lactate dehydrogenase (LDH) may play an important role in the occurrence of VTE in COVID-19 infection. But whether they can server as predictors for VTE in COVID-19 is still unclear. In this study, we performed a systematic review and meta-analysis to compare IL-6, ferritin and LDH in VTE and non-VTE COVID-19 patients in order to shed light on the prevention and treatment of VTE., Methods: Related literatures were searched in PubMed, Embase, Web of Science, Google Scholar, China National Knowledge Infrastructure (CNKI), WANGFANG. COVID-19 patients were divided into VTE group and non-VTE group. Meta-analysis was then conducted to compare levels of IL-6, ferritin and LDH between the two groups., Results: We finally included and analyzed 17 literatures from January 2019 to October 2022. There was a total of 7,035 COVID-19 patients, with a weighted mean age of 60.01 years. Males accounted for 62.64% and 61.34% patients were in intensive care unit (ICU). Weighted mean difference (WMD) of IL-6, ferritin and LDH was 31.15 (95% CI: 9.82, 52.49), 257.02 (95% CI: 51.70, 462.33) and 41.79 (95% CI: -19.38, 102.96), respectively. The above results indicated that than compared with non-VTE group, VTE group had significantly higher levels of IL-6 and ferritin but similar LDH., Conclusion: This systematic review and meta-analysis pointed out that elevated levels of IL-6 and ferritin were significantly possitive associated with VTE, thus could be used as biological predictive indicators of VTE among COVID-19 patients. However, no association was found between level of LDH and VTE. Therefore, close monitoring of changes in IL-6 and ferritin concentrations is of great value in assisting clinicans to rapidly identify thrombotic complications among COVID-19 patients, hence facilitating the timely effective managment. Further studies are required in terms of the clinical role of cytokines in the occurrence of VTE among COVID-19 infection, with more reliable systematic controls and interventional trials., (© 2024. The Author(s).)

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder caused by uncontrolled terminal complement activation, which leads to intravascular hemolysis (IVH), thromboembolism (TE), renal failure, and premature mortality., Methods: We performed a secondary analysis of data collected from patients enrolled in the Korean National PNH Registry to assess the relative importance of risk factors, specifically lactate dehydrogenase (LDH) and hemoglobin (Hb), in predicting the incidence of TE, impaired renal function, and death in complement inhibitor-naïve patients with PNH., Results: Multivariate regression modeling indicated that LDH ≥ 1.5 × upper limit of normal (ULN), male sex, and pain were associated with increased risk of TE ( P = 0.016, 0.045, and 0.033, respectively), hemoglobinuria and pain were associated with an increased risk of impaired renal function ( P = 0.034 and 0.022, respectively), and TE was associated with an increased incidence of death ( P < 0.001). Hb < 8 g/dL was not a predictor of TE, impaired renal function, or death in multivariate regression analyses. Standardized mortality ratio analysis indicated that LDH ≥ 1.5 × ULN ( P < 0.001), Hb < 8 g/dL ( P < 0.001), and Hb ≥ 8 g/dL ( P = 0.004) were all risk factors for death; in contrast, patients with LDH < 1.5 × ULN had similar mortality to the general population., Conclusion: In complement inhibitor-naïve patients with PNH, LDH ≥ 1.5 × ULN was a significant predictor of TE, and TE was a significant predictor of death. Hb was not a significant predictor of TE, impaired renal function, or death. Therefore, controlling IVH will improve clinical outcomes for patients with PNH., Competing Interests: Jun Ho Jang has no conflicts of interest to declare. Jin Seok Kim has received fees from Alexion, AstraZeneca Rare Disease. Cindy Thiow Koon Lim is an employee of IQVIA. Nora J. Kleinman is an employee of IQVIA. Karl-Johan Myren is an employee of and shareholder in Alexion, AstraZeneca Rare Disease. Alice Wang was an employee of and shareholder in Alexion, AstraZeneca Rare Disease at the time of study completion. Yogesh Patel is an employee of and shareholder in Alexion, AstraZeneca Rare Disease. Jong Wook Lee has received grants and fees from Alexion, AstraZeneca Rare Disease, and has served as a member of an advisory board for Alexion, AstraZeneca Rare Disease., (© 2024 The Korean Academy of Medical Sciences.)

At the individual cow level, suboptimum fertility, mastitis, negative energy balance, and ketosis are major issues in dairy farming. These problems are widespread on dairy farms and have an important economic impact. The objectives of this study were (1) to assess the potential of milk mid-infrared (MIR) spectra to predict key biomarkers of energy deficit (citrate, isocitrate, glucose-6 phosphate [glucose-6P], free glucose), ketosis (β-hydroxybutyrate [BHB] and acetone), mastitis (N-acetyl-β-d-glucosaminidase activity [NAGase] and lactate dehydrogenase), and fertility (progesterone); (2) to test alternative methodologies to partial least squares (PLS) regression to better account for the specific asymmetric distribution of the biomarkers; and (3) to create robust models by merging large datasets from 5 international or national projects. Benefiting from this international collaboration, the dataset comprised a total of 9,143 milk samples from 3,758 cows located in 589 herds across 10 countries and represented 7 breeds. The samples were analyzed by reference chemistry for biomarker contents, whereas the MIR analyses were performed on 30 instruments from different models and brands, with spectra harmonized into a common format. Four quantitative methodologies were evaluated to address the strongly skewed distribution of some biomarkers. Partial least squares regression was used as the reference basis, and compared with a random modification of distribution associated with PLS (random-downsampling-PLS), an optimized modification of distribution associated with PLS (KennardStone-downsampling-PLS), and support vector machine (SVM). When the ability of MIR to predict biomarkers was too low for quantification, different qualitative methodologies were tested to discriminate low versus high values of biomarkers. For each biomarker, 20% of the herds were randomly removed within all countries to be used as the validation dataset. The remaining 80% of herds were used as the calibration dataset. In calibration, the 3 alternative methodologies outperform the PLS performances for the majority of biomarkers. However, in the external herd validation, PLS provided the best results for isocitrate, glucose-6P, free glucose, and lactate dehydrogenase (coefficient of determination in external herd validation [R 2 v] = 0.48, 0.58, 0.28, and 0.24, respectively). For other molecules, PLS-random-downsampling and PLS-KennardStone-downsampling outperformed PLS in the majority of cases, but the best results were provided by SVM for citrate, BHB, acetone, NAGase, and progesterone (R 2 v = 0.94, 0.58, 0.76, 0.68, and 0.15, respectively). Hence, PLS and SVM based on the entire dataset provided the best results for normal and skewed distributions, respectively. Complementary to the quantitative methods, the qualitative discriminant models enabled the discrimination of high and low values for BHB, acetone, and NAGase with a global accuracy around 90%, and glucose-6P with an accuracy of 83%. In conclusion, MIR spectra of milk can enable quantitative screening of citrate as a biomarker of energy deficit and discrimination of low and high values of BHB, acetone, and NAGase, as biomarkers of ketosis and mastitis. Finally, progesterone could not be predicted with sufficient accuracy from milk MIR spectra to be further considered. Consequently, MIR spectrometry can bring valuable information regarding the occurrence of energy deficit, ketosis, and mastitis in dairy cows, which in turn have major influences on their fertility and survival., (The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

The bacterial determinants that facilitate Mycobacterium tuberculosis (Mtb) adaptation to the human host environment are poorly characterized. We have sought to decipher the pressures facing the bacterium in vivo by assessing Mtb genes that are under positive selection in clinical isolates. One of the strongest targets of selection in the Mtb genome is lldD2, which encodes a quinone-dependent L-lactate dehydrogenase (LldD2) that catalyzes the oxidation of lactate to pyruvate. Lactate accumulation is a salient feature of the intracellular environment during infection and lldD2 is essential for Mtb growth in macrophages. We determined the extent of lldD2 variation across a set of global clinical isolates and defined how prevalent mutations modulate Mtb fitness. We show the stepwise nature of lldD2 evolution that occurs as a result of ongoing lldD2 selection in the background of ancestral lineage-defining mutations and demonstrate that the genetic evolution of lldD2 additively augments Mtb growth in lactate. Using quinone-dependent antibiotic susceptibility as a functional reporter, we also find that the evolved lldD2 mutations functionally increase the quinone-dependent activity of LldD2. Using 13C-lactate metabolic flux tracing, we find that lldD2 is necessary for robust incorporation of lactate into central carbon metabolism. In the absence of lldD2, label preferentially accumulates in dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (G3P) and is associated with a discernible growth defect, providing experimental evidence for accrued lactate toxicity via the deleterious buildup of sugar phosphates. The evolved lldD2 variants increase lactate incorporation to pyruvate while altering triose phosphate flux, suggesting both an anaplerotic and detoxification benefit to lldD2 evolution. We further show that the mycobacterial cell is transcriptionally sensitive to the changes associated with altered lldD2 activity which affect the expression of genes involved in cell wall lipid metabolism and the ESX- 1 virulence system. Together, these data illustrate a multifunctional role of LldD2 that provides context for the selective advantage of lldD2 mutations in adapting to host stress., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Stanley et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Since 2010, malaria rapid diagnostic tests (RDTs) are widely used to detect malaria. The Indian Council of Medical Research-National Institute of Malaria Research performed lot testing (LT) according to WHO procedures since 2016. Lot testing is performed to evaluate the lot-to-lot variation in performance of malaria RDTs. Four sets of positive quality control (QC) panels for P. falciparum (Pf) and P. vivax (Pv) and 10 negative panels tested RDTs. RDTs were reported as pass, failed, or deferred on the basis of WHO criteria. In the past 5 years, 275 lots containing 15,488 RDT kits for malaria diagnosis were subjected to LT. The monovalent RDTs (n = 1,216), based on either Pf histidine rich protein 2 (HRP2) or Pan-Plasmodium lactate dehydrogenase (Pan-pLDH) antigens, showed 90.4% sensitivity and 100% specificity, whereas RDTs based on HRP2 + Pan-pLDH or HRP2 + pLDH (n = 13,924) had sensitivity 95.6% and specificity 99.5%, respectively. RDTs based on PfHRP2 + Pv-pLDH + Pan-pLDH (n = 348) had 100% sensitivity and specificity. In a comparison between HRP2 + pLDH or HRP2 + Pan-pLDH to HRP2 + pLDH + Pan-pLDH RDTs, it was found that the sensitivity of PfHRP2 with Pan-pLDH RDTs (n = 2,382) was only 83%. Of the 275 lots analyzed, 15 lots of PfHRP2 with Pan-pLDH were deferred. The QC panel for Pf revealed a faint Pan band in the tested lots, which is a cause for concern. The results of deferred lots were reported to concerned government agencies. Quality-compromised RDTs may lead to an incorrect diagnosis. It is critical to have a QC system in place for effective malaria management.

Objective: To analyze the expression of MCP-1 and CCR2 in newly diagnosed diffuse large B-cell lymphoma (DLBCL), and to evaluate their correlation with clinicopathological features and prognosis., Methods: A total of 141 patients with DLBCL diagnosed and treated in the Department of Hematology, the First Affiliated Hospital of Bengbu Medical College from January 2017 to May 2022 were retrospectively collected. The clinical characteristics, pathological data and prognostic factors of the patients were collected. Immunohistochemical staining was used to detect the expression of MCP-1 and CCR2 in the tissues of newly treated DLBCL patients, and to analyze the relationship between MCP-1 and clinical characteristics, prognosis and survival of patients., Results: The expression of MCP-1 and CCR2 were correlated with Ann Arbor stage, IPI score, lactate dehydrogenase (LDH), Ki-67 index and therapeutic effect. There were no significant correlation between the expression of MCP-1 or CCR2 and other clinical histopathological parameters such as gender, age, β 2 -microglobulin, BCL-2, BCL-6, Hans classification, initial location, B symptoms, bone marrow involvement. There was a statistical difference in OS and PFS between the MCP-1 or CCR2 positive group and the negative group, which was associated to poor prognosis.Univariate Cox regression analysis showed that β 2 -microglobulin, Ki-67 index, IPI score, MCP-1, CCR2 expression levels and disease remission affected the PFS and OS of DLBCL patients ( P < 0.05). Gender, age, LDH, BCL-2, BCL-6, Hans classification, primary tumor site, B symptoms, bone marrow involvement, Ann Arbor stage had no effect on PFS and OS ( P >0.05). Multivariate analysis showed that β 2 -microglobulin, Ki-67 index, IPI score, MCP-1, CCR2 expression levels and disease remission were independent influencing factors of patients ( P < 0.05)., Conclusion: The expression rate of MCP-1 or CCR2 in newly treated DLBCL is high, and it is correlated with the clinical features of poor prognosis such as stage and LDH of DLBCL patients, which is a poor prognostic factor affecting PFS and OS.

Unstructured biological macromolecules have attracted attention as protein aggregation inhibitors in living cells. Some are characterized by their free structural configuration, highly charged, and water-soluble. However, the importance of these properties in inhibiting protein aggregation remains unclear. In this study, we investigated the effect of charged poly (amino acids), which mimic these properties, on aggregation of l-lactate dehydrogenase (LDH) and compared their effects to monomeric amino acids and folded proteins. LDH was stable and active at a neutral pH (~7) but formed inactive aggregates at acidic pH (< 6). Adding cationic polyelectrolytes of poly-l-lysine and poly-l-arginine suppressed the acid-induced aggregation and inactivation of LDH under acidic pH values. Adding monomeric amino acids and cationic folded proteins also prevented LDH aggregation but with lower efficacy than cationic polyelectrolytes. These results indicate that unstructured polyelectrolytes effectively stabilize unstable enzymes because they interact flexibly and multivalently with them. Our findings provide a simple method for stabilizing enzymes under unstable conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Infectious specimens containing viruses like Ebola require sample manipulation to ensure the safety of laboratory staff, which may negatively impact biochemistry test results. We evaluated the impact of viral inactivation methods on 25 biochemistry analytes in plasma, and seven biochemistry analytes in urine., Methods: Fifteen lithium heparinized plasma specimens with and without gel underwent the following viral inactivation methods: 1) untreated, 2) Triton X-100 treatment, 2) heated for 60 min then Triton X-100 treatment, 3) heated for 60 min, 4) heated for 75 min, and 5) heated for 90 min. Electrolytes, protein, enzymes, glucose, as well as hepatic and renal markers were measured on the Roche Cobas e601, c502 or c702. Urinalysis analytes were measured on the Siemens CLINITEK. Acceptable recovery was based on Institute for Quality Management in Healthcare 2021 guidelines or ± 1 for urinalysis., Results: Potassium and lactate dehydrogenase were impacted by the presence of gel. Viral inactivation with Triton X-100 had minimal impact on the biochemistry results. Heat inactivation resulted in significant negative bias in alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, creatinine, total protein, amylase, lactate dehydrogenase and creatine kinase. Positive bias in phosphate, aspartate transaminase, total bilirubin, and uric acid were observed after heat inactivation., Conclusion: Reliable results for commonly measured electrolytes, enzymes and proteins can be obtained after viral inactivation by Triton X-100 treatment at room temperature. However, heat inactivation has significant negative impact on routine biochemistry enzymes and alternative testing processes should be explored., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JT receives in-kind funding from Roche for an independent and unrelated project., (Copyright © 2024. Published by Elsevier Inc.)

Background: Lactate dehydrogenase (LDHs) is an enzyme involved in anaerobic glycolysis, including LDHA, LDHB, LDHC and LDHD. Given the regulatory role in the biological progression of certain tumors, we analyzed the role of LDHs in pan-cancers., Methods: Cox regression, Kaplan-Meier curves, Receiver Operating Characteristic (ROC) curves, and correlation of clinical indicators in tumor patients were used to assess the prognostic significance of LDHs in pan-cancer. The TCGA, HPA, TIMER, UALCAN, TISIDB, and Cellminer databases were used to investigate the correlation between the expression of LDHs and immune subtypes, immune checkpoint genes, methylation levels, tumor mutational load, microsatellite instability, tumor-infiltrating immune cells and drug sensitivity. The cBioPortal database was also used to identify genomic abnormalities of LDHs in pan-cancer. A comprehensive assessment of the biological functions of LDHs was performed using GSEA. In vitro, HepG2 and Huh7 cells were transfected with LDHD siRNA and GFP-LDHD, the proliferation capacity of cells was examined using CCK-8, EdU, and colony formation assays; the migration and invasion of cells was detected by wound healing and transwell assays; western blotting was used to detect the levels of MMP-2, MMP-9, E-cadherin, N-cadherin and Akt phosphorylation., Results: LDHs were differentially expressed in a variety of human tumor tissues. LDHs subtypes can act as pro-oncogenes or anti-oncogenes in different types of cancer and have an impact on the prognosis of patients with tumors by influencing their clinicopathological characteristics. LDHs were differentially expressed in tumor immune subtypes and molecular subtypes. In addition, LDHs expression correlated with immune checkpoint genes, tumor mutational load, and microsatellite instability. LDHD was identified to play an important role in the prognosis of HCC patients, according to a comprehensive analysis of LDHs in pan-cancer. In HepG2 and Huh7 cells, knockdown of LDHD promoted cell proliferation, migration, and invasion, promoted the protein expression levels of MMP-2, MMP-9, N-cadherin, and Akt phosphorylation, but inhibited the protein expression level of E-cadherin. In addition, LDHD overexpression showed the opposite changes., Conclusion: LDHs subtypes can be used as potential prognostic markers for certain cancers. Prognostic and immunotherapeutic analysis indicated that LDHD plays an important role in the prognosis of HCC patients. In vitro experiments revealed that LDHD can affect HCC proliferation, migration, and invasion by regulating MMPs expression and EMT via Akt signaling pathway, which provides a new perspective on the anti-cancer molecular mechanism of LDHD in HCC., (© 2024. The Author(s).)

Cannabis sativa is a well-known plant for its psychoactive effects; however, its many derivatives, such as Cannabidiol (CBD), contain several therapeutic applications. Tetrahydrocannabinol (THC) is the main cannabis derivative responsible for psychoactive properties, while CBD is non-psychotropic. For this reason, CBD has been more exploited in the last decade. CBD has been connected to multiple anticancer properties, and when combined with photodynamic therapy (PDT), it is possible to eradicate tumors more effectively. In this study, CBD was utilized to treat MCF-7 breast cancer cells, followed by in vitro PDT combination therapy. Conventional breast cancer treatment modalities such as chemotherapy, radiotherapy, etc. have been reported for inducing a number of undesirable side effects, recurrence of the disease, and low quality of life. In this study, cells were exposed to varying concentrations of CBD (i.e., 1.25, 2.5, 5, 10, and 20 μg/mL) and incubated 12 and 24 h after treatment. The optimal doses were then used in combination therapy. Morphology and biochemical assays, including lactate dehydrogenase (LDH) for membrane integrity, adenosine triphosphate (ATP) for viability, and trypan blue exclusion assay for viability, were used to examine cellular responses after treatments. The optimal concentration was then utilized in Hypericin-Gold nanoparticles mediated PDT combination. The results revealed that, in a dose-dependent manner, conventional morphological characteristics of cell death, such as vacuolization, blebbing, and floating were observed in treated cells. The biochemical responses demonstrated an increase in LDH, a decrease in ATP, and a reduction in viability. This study demonstrated that CBD induces cell death in MCF-7 breast cancer cells cultured in vitro. The immunofluorescence results of combination therapy indicated that cell death occurred via apoptosis. In conclusion, this study proposes that the CBD and PDT combination therapy is effective in killing MCF-7 breast cancer cells in vitro by induction of apoptosis.

Objective: This study analyzes the levels of peripheral blood placental growth factor (PLGF), body mass index (BMI), decorin (DCN), lactate dehydrogenase (LDH), uric acid (UA), and clinical indicators of patients with preeclampsia (PE), and establishes a predictive risk model of PE, which can provide a reference for early and effective prediction of PE., Methods: 81 cases of pregnant women with PE who had regular prenatal checkups and delivered in Jinshan Branch of Shanghai Sixth People's Hospital from June 2020 to December 2022 were analyzed, and 92 pregnant women with normal pregnancies who had their antenatal checkups and delivered at the hospital during the same period were selected as the control group. Clinical data and peripheral blood levels of PLGF, DCN, LDH, and UA were recorded, and the two groups were subjected to univariate screening and multifactorial logistic regression analysis. Based on the screening results, the diagnostic efficacy of PE was evaluated using the receiver operating characteristic (ROC) curve. Risk prediction nomogram model was constructed using R language. The Bootstrap method (self-sampling method) was used to validate and produce calibration plots; the decision curve analysis (DCA) was used to assess the clinical benefit rate of the model., Results: There were statistically significant differences in age, pre-pregnancy BMI, gestational weight gain, history of PE or family history, family history of hypertension, gestational diabetes mellitus, and history of renal disease between the two groups (P < 0.05). The results of multifactorial binary logistic stepwise regression revealed that peripheral blood levels of PLGF, DCN, LDH, UA, and pre-pregnancy BMI were independent influences on the occurrence of PE (P < 0.05). The area under the curve of PLGF, DCN, LDH, UA levels and pre-pregnancy BMI in the detection of PE was 0.952, with a sensitivity of 0.901 and a specificity of 0.913, which is better than a single clinical diagnostic indicator. The results of multifactor analysis were constructed as a nomogram model, and the mean absolute error of the calibration curve of the modeling set was 0.023, suggesting that the predictive probability of the model was generally compatible with the actual value. DCA showed the predictive model had a high net benefit in the range of 5% to 85%, suggesting that the model has clinical utility value., Conclusion: The occurrence of PE is related to the peripheral blood levels of PLGF, DCN, LDH, UA and pre-pregnancy BMI, and the combination of these indexes has a better clinical diagnostic value than a single index. The nomogram model constructed by using the above indicators can be used for the prediction of PE and has high predictive efficacy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhou, Xiao and Yang.)

Background: The Zarudny's spur-thighed tortoise or Iranian tortoise (Testudo graeca zarudnyi) has just been reported from Iran so far. Therefore, the purpose of this study was to determine the effects of season and gender on serum biochemical parameters of this valuable species in Iran., Results: This study was performed on 20 clinically healthy adult Zarudny's spur-thighed tortoises. Blood samples were collected from the jugular vein and then serum biochemical parameters and body weight were measured in autumn and winter. The following biochemical parameters were measured: total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein, total protein, creatinine, urea, glucose, calcium, inorganic phosphorus, total bilirubin, uric acid, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and lactate dehydrogenase. Urea concentration increased significantly at emergence from hibernation. Also, in winter, total protein, phosphorous, creatinine, total bilirubin concentrations and alkaline phosphatase activity decreased significantly compared to autumn, but aspartate aminotransferase and lactate dehydrogenase activities were significantly higher than in autumn. There was no significant difference for the parameters mentioned above by gender, except for phosphorous. Phosphorous concentration in females was significantly higher than that of males in autumn. Cholesterol and low-density lipoprotein cholesterol levels in females were significantly higher than males in autumn and winter., Conclusions: The present study is the first study that monitors the serum biochemical parameters of adult Zarudny's spur-thighed tortoises based on season and gender. Seasonal reference intervals should be used for biochemical parameters in this valuable species. Also, sex-specific reference intervals for phosphate and cholesterol are necessary., (© 2024. The Author(s).)

Background: Lactate dehydrogenase (LDH) has emerged as a promising biomarker for cancer. However, the current understanding of LDH and circulating LDH expression in thymic epithelial tumour (TET) is lacking., Methods: A comprehensive literature review and meta-analysis were performed to evaluate the clinical significance of circulating LDH levels in patients with TET. Circulating LDH levels were measured using a laboratory analyser (Cobas8000, Roche, Basel, Switzerland). The maximum standardised uptake value (SUVmax) was determined in patients who underwent whole-body 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). Multiplex immunohistochemistry (IHC) was performed using a commercially available kit (Opal 6-plex Detection Kit, Akoya Biosciences, Marlborough, MA, USA) and slide scanner (Slideview VS200, Olympus, Tokyo, Japan). All statistical analyses were performed using SPSS (IBM Corp., Armonk, NY, USA) and Prism version 9.0 (GraphPad Inc., San Diego, CA, USA). Differences with p < 0.05 were considered to be statistically significant., Results: Meta-analysis revealed that elevated circulating serum levels of LDH predicted poor prognosis in patients with TET. Circulating levels of LDH were analysed in the serum of 313 patients with TET and 87 with benign mediastinal mass. The mean circulating LDH level in patients with thymic carcinoma (TC) was significantly higher than that in those with thymoma (TM) and the benign group (p < 0.001). Expression levels of circulating LDH were significantly reduced in postoperative samples compared with that in preoperative samples (p < 0.05). Receiver operating characteristic (ROC) curve analysis for diagnosing TC yielded an area under the curve of 0.74, with a sensitivity of 54 % and specificity of 86 %. Furthermore, patients with TC exhibited higher 18F-FDG PET/CT SUVmax values compared to those with TM. Correlation analysis demonstrated a positive association between SUVmax values and circulating LDH levels. In addition, the percentages of LDH-positive cells in TC and type B1 TM tissues were higher than those in other subtypes of TM, and a significant positive correlation between the percentages of LDH-positive and CD20-positive cells was detected in patients with TET (p < 0.05)., Conclusion: Circulating serum LDH level may serve as a non-invasive biomarker for the diagnosis and prognosis of TET. The relationship between LDH expression and immune cell infiltration merits further regarding its application in companion diagnosis for immunotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: The purpose of our investigation is to evaluate the level of relationship between lactate dehydrogenase (LDH) and the occurrence of diabetic retinopathy (DR) in adults with diabetes mellitus (DM)., Methods: The investigation involved an analysis of five sectional data cycles acquired from the National Health and Nutrition Examination Survey from 2009 to 2018. The present study involved the selection of DM samples from a complex multistage probability sample. These samples were subsequently classified into two distinct groups, namely the No DR (NDR) and DR groups. The present study comprehensively investigated the biological and social risk factors associated with DR. The biological factors examined in this investigation included blood pressure, blood routine, hemoglobin A1c, blood glucose, and comorbidities. The social dimensions encompass education and sex., Results: After considering all factors, multivariate regression models indicated a significant relationship between DR and increased LDH (adjusted odds ratio = 1.007, 95% confidence interval: 1.003-1.011). The subgroup analysis revealed that the effect size of LDH on the existence of DR in the subgroups remained consistent, as indicated by all p values greater than .05. A statistically significant relationship was identified between elevated LDH levels > 134 U/L and a raised risk of DR in people with DM., Conclusion: LDH concentrations were connected with an increased prevalence of DR in participants with DM. Our study highlights that patients with LDH > 134 U/L are distinguishably related to DM complicated by DR. DR is more common in diabetic individuals with coronary heart disease., (© 2023 The Authors. Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background: The prognostic role of lactate dehydrogenase (LDH) has been confirmed in many malignant tumors, but the role of serum LDH in primary central nervous system germ cell tumor (GCT) remains unknown. This study aimed to assess the prognostic value of LDH in GCT patients and develop a nomogram to predict prognosis in patients undergoing chemoradiotherapy., Methods: A total of 161 patients with GCT were included in this study. Using a restricted cubic spline (RCS) model, the optimal cutoff point for LDH was determined to be 217 U/L. The survival of GCT patients was evaluated using the Kaplan-Meier method and log-rank test to analyze the effects of LDH levels. Univariate Cox regression, multivariate Cox regression, and LASSO Cox regression were conducted to identify prognostic factors, which were incorporated into a nomogram for predicting overall survival (OS). The predictive accuracy of the nomogram was assessed using the C-index, calibration curve, area under the time-dependent receiver operating characteristic curve (time-dependent AUC), and risk group stratification. The net benefits of the nomogram at different threshold probabilities were quantified using decision curve analysis (DCA)., Results: The high-LDH group had significantly shorter OS compared to the low-LDH group (P = 0.016). Based on the SYSUCC cohort, three variables were shown to be significant factors for OS and were incorporated in the nomogram: LDH, histopathology, and dissemination. It showed good discrimination ability, with C-index of 0.789 (95% CI, 0.671-0.907). Additionally, the clinical usefulness of the nomogram was confirmed by calibration curves and time-dependent AUC. DCA further highlighted the potential of the nomogram to guide clinical treatment strategies for patients. Moreover, there was a significant difference in OS among patients categorized into different risk groups (P < 0.001)., Conclusion: LDH levels may serve as a reliable predictor for assessing the therapeutic effect of chemoradiotherapy in GCT. The developed nomogram exhibits high accuracy in predicting survival outcomes, aiding in the classification of prognostic groups, and supporting informed clinical decision-making., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: This study aims to evaluate the lactate dehydrogenase to albumin ratio and mortality at 28 days in patients with sepsis., Methods: Data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database were used for this retrospective cohort analysis. The level of the lactate dehydrogenase to albumin ratio was recovered at admission and the outcome index was mortality at 28 days. Multivariate Cox regression, survival curve analysis, and subgroup analysis were used to study the relationship between lactate dehydrogenase to albumin ratio and 28-day mortality in sepsis patients., Results: This study included a total of 4,265 patients with sepsis, with a 28-day mortality rate of 51.9%. After conducting multivariable COX regression analysis and adjusting for all potential confounding factors, we observed that compared to the LDH/ALB (Q1) group, the Q2 group had a 1.34-fold higher risk of 28-day mortality (HR = 1.34, 95% CI: 1.20 - 1.49, p < 0.001), while the Q3 group had a 1.90-fold higher risk (HR = 1.90, 95% CI: 1.69 - 2.14, p < 0.001). Furthermore, the survival analysis curve indicated a gradual increase in the 28-day mortality rate of septic patients as LDH/ALB levels increased. In addition, the ROC curve demonstrated that the area under the curve for LDH/ALB was 0.6507 (95% CI: 63.4991% - 66.6368%), which was higher than that of LDH (AUC = 0.6434), ALB (AUC = 0.55), and SOFA SCORE (AUC = 0.5564). Finally, subgroup analysis revealed no significant interaction between LDH/ALB and the various subgroups., Conclusions: The LDH/ALB ratio is significantly correlated with mortality at 28 days in patients with sepsis, which is of significant clinical importance and deserves further study.

Endothelial pyroptosis is a pathological mechanism of atherosclerosis (AS). Circular RNAs (circRNAs) are vital in AS progression by regulating endothelial cell functions. The study aimed to explore whether circ-USP9× regulated pyroptosis of endothelial cell to involve in AS development and the molecular mechanism. Pyroptosis was determined using lactate dehydrogenase (LDH) assay, enzyme linked immunosorbent assay (ELISA), flow cytometry, propidium iodide (PI) staining assay, and western blot. The mechanism of circ-USP9× was determined using RNA pull-down and RNA binding protein immunoprecipitation (RIP) assays. Results showed that circ-USP9× was upregulated in AS and oxidized low-density lipoprotein (ox-LDL)-treated human umbilical vein endothelial cells (HUVECs). Knockdown of circ-USP9× suppressed ox-LDL induced pyroptosis of HUVECs. Mechanically, circ-USP9× could bind to EIF4A3 in the cytoplasm. Moreover, EIF4A3 was bound to GSDMD and further affects GSDMD stability. Overexpression of EIF4A3 rescued cell pyroptosis induced by circ-USP9× depletion. In short, circ-USP9× interacted with EIF4A3 to enhance GSDMD stability, thus further promoting ox-LDL-induced pyroptosis of HUVECs. These findings suggested that circ-USP9× participates in AS progression and may be a potential therapeutic target for AS.

Background and Objectives : Given the wide spectrum of clinical and laboratory manifestations of the coronavirus disease 2019 (COVID-19), it is imperative to identify potential contributing factors to patients' outcomes. However, a limited number of studies have assessed how the different waves affected the progression of the disease, more so in Portugal. Therefore, our main purpose was to study the clinical and laboratory patterns of COVID-19 in an unvaccinated population admitted to the intensive care unit, identifying characteristics associated with death, in each of the first three waves of the pandemic. Materials and Methods : This study included 337 COVID-19 patients admitted to the intensive care unit of a single-center hospital in Lisbon, Portugal, between March 2020 and March 2021. Comparisons were made between three COVID-19 waves, in the second ( n = 325) and seventh ( n = 216) days after admission, and between discharged and deceased patients. Results : Deceased patients were considerably older ( p = 0.021) and needed greater ventilatory assistance ( p = 0.023), especially in the first wave. Differences between discharged and deceased patients' biomarkers were minimal in the first wave, on both analyzed days. In the second wave significant differences emerged in troponins, lactate dehydrogenase, procalcitonin, C-reactive protein, and white blood cell subpopulations, as well as platelet-to-lymphocyte and neutrophil-to-lymphocyte ratios (all p < 0.05). Furthermore, in the third wave, platelets and D-dimers were also significantly different between patients' groups (all p < 0.05). From the second to the seventh days, troponins and lactate dehydrogenase showed significant decreases, mainly for discharged patients, while platelet counts increased (all p < 0.01). Lymphocytes significantly increased in discharged patients (all p < 0.05), while white blood cells rose in the second (all p < 0.001) and third (all p < 0.05) waves among deceased patients. Conclusions : This study yields insights into COVID-19 patients' characteristics and mortality-associated biomarkers during Portugal's first three COVID-19 waves, highlighting the importance of considering wave variations in future research due to potential significant outcome differences.