Cardiac biomarkers are associated with increased risks of adverse clinical outcomes after ischemic stroke.

BACKGROUND: Impaired cardiac function was suggested to be implicated in the functional recovery after ischemic stroke, but the prognostic value of cardiac biomarkers among ischemic stroke patients remains unclear. We aimed to prospectively explore the associations of serum lactate dehydrogenase (LDH), plasma N-terminal pro-brain natriuretic peptide (NT-proBNP), and plasma high-sensitivity cardiac troponin T (hs-cTnT) with adverse clinical outcomes after ischemic stroke in a large-scale cohort study. METHODS: We measured serum LDH, plasma NT-proBNP, and plasma hs-cTnT levels at baseline among 5056 ischemic stroke patients from the Minhang Stroke Cohort study. All patients were followed up at 3 months after ischemic stroke onset. The primary outcome was composite outcome of death and major disability (modified Rankin Scale [mRS] score ≥ 3) at 3 months after stroke onset, and secondary outcomes included death and ordered 7-level categorical score of the mRS. RESULTS: During 3 months of follow-up, 1584 patients developed the primary outcome. Baseline serum LDH, plasma NT-proBNP, and plasma hs-cTnT were positively associated with the risk of adverse outcomes after ischemic stroke. The multivariable-adjusted odds ratios of primary outcome for the highest versus lowest quartile of LDH, NT-proBNP, and hs-cTnT were 1.37 (95% CI 1.13-1.66; Ptrend = 0.001), 2.51 (95% CI, 2.00-3.16; Ptrend < 0.001), and 2.24 (95% CI 1.77-2.83; Ptrend < 0.001), respectively. Each SD increase of log-transformed cardiac biomarker score was associated with a 49% (95% CI 37-62%; P < 0.001) increased risk of primary outcome. Multivariable-adjusted spline regression analyses showed linear relationships between cardiac biomarkers and the risk of primary outcome (all P for linearity < 0.001). Moreover, adding LDH, NT-proBNP, hs-cTnT, or cardiac biomarker score to conventional risk factors significantly improved the risk reclassification of primary outcome after ischemic stroke (all P < 0.05). CONCLUSION: High LDH, NT-proBNP, hs-cTnT, and cardiac biomarker score were independently associated with increased risks of adverse clinical outcomes among ischemic stroke patients, suggesting that cardiac biomarkers might be potential prognostic biomarkers for ischemic stroke.

Lactate dehydrogenase A (LDHA)-mediated lactate generation promotes pulmonary vascular remodeling in pulmonary hypertension.

BACKGROUND: High levels of lactate are positively associated with prognosis and mortality in pulmonary hypertension (PH). Lactate dehydrogenase A (LDHA) is a key enzyme for the production of lactate. This study is undertaken to investigate the role and molecular mechanisms of lactate and LDHA in PH. METHODS: Lactate levels were measured by a lactate assay kit. LDHA expression and localization were detected by western blot and Immunofluorescence. Proliferation and migration were determined by CCK8, western blot, EdU assay and scratch-wound assay. The right heart catheterization and right heart ultrasound were measured to evaluate cardiopulmonary function. RESULTS: In vitro, we found that lactate promoted proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) in an LDHA-dependent manner. In vivo, we found that LDHA knockdown reduced lactate overaccumulation in the lungs of mice exposed to hypoxia. Furthermore, LDHA knockdown ameliorated hypoxia-induced vascular remodeling and right ventricular dysfunction. In addition, the activation of Akt signaling by hypoxia was suppressed by LDHA knockdown both in vivo and in vitro. The overexpression of Akt reversed the inhibitory effect of LDHA knockdown on proliferation in PASMCs under hypoxia. Finally, LDHA inhibitor attenuated vascular remodeling and right ventricular dysfunction in Sugen/hypoxia mouse PH model, Monocrotaline (MCT)-induced rat PH model and chronic hypoxia-induced mouse PH model. CONCLUSIONS: Thus, LDHA-mediated lactate production promotes pulmonary vascular remodeling in PH by activating Akt signaling pathway, suggesting the potential role of LDHA in regulating the metabolic reprogramming and vascular remodeling in PH.

Elevated lactate dehydrogenase - A red herring in the diagnosis of a sclerosing stromal tumor: A case report.

Sclerosing stromal tumors are a rare type of ovarian tumor in the category of sex cord stromal tumors, which arise from the ovarian connective tissue. This report concerns a case of a sclerosing stromal tumor in a 19-year-old nulliparous woman who presented with the chief complaints of menstrual irregularities and dyspareunia. Preoperative imaging revealed a complex right adnexal mass with blood flow and without associated ascites. Tumor markers were all normal except lactate dehydrogenase, which was elevated. The elevated lactate dehydrogenase, in combination with patient age and menstrual irregularities, initially misdirected the clinicians toward suspicion for dysgerminoma or other malignant germ cell tumor of the ovary. Clinicians should beware of excluding the diagnosis of sex cord stromal tumor on the differential in a young person with an adnexal mass and elevated lactate dehydrogenase.

Effect of Preoperative Serum Lactate Dehydrogenase-to-Albumin Ratio on the Survival of Oral Cancer: A Retrospective Study.

Background: Several studies have investigated the relationship between serum lactate dehydrogenase-to-albumin ratio (LAR) and the prognosis of cancers. However, no studies have explored the association between serum LAR and the survival of oral cancer (OC). This study was aimed to determine the association of serum LAR with the overall survival (OS) of OC. Methods: One hundred and ninety patients with OC were included in this study between January 2018 and December 2019. Log rank test and Kaplan-Meier method were used to compare the survival rate of OC between the low LAR group and the high LAR group. The association between serum LAR and the survival of OC patients was determined via univariate and multivariate Cox regression analyses. Results: Kaplan-Meier analysis and Log rank test indicated that the OS rate in low LAR group was significantly higher than that in high LAR group (P < 0.05). Univariate cox analysis showed that TNM III-IV stage, serum LDH > 162 U/L, and serum LAR > 3.79 were significantly associated with the OS of OC patients. Multivariate Cox analysis suggested that the TNM III-IV stage (HR, 2.317; 95% CI, 1.423-3.774, P = 0.001) and serum LAR > 3.79 (HR, 5.138; 95% CI, 2.245-11.756, P = 0.000) were independently related with poor OS of OC patients. Conclusion: High serum LAR (>3.79) is an independent predictor of adverse prognosis in OC patients. LAR could be used as a promising marker for predicting the OS of OC patients.

Evaluation of the CCL17/CCL22-CCR4 axis in pediatrics with B-cell acute lymphoblastic leukemia before and after a chemotherapy course.

AIMS: Acute lymphoblastic leukemia (ALL) is the most common type of pediatrics cancer. Chemokines exert different roles in leukemia process through leukocyte recruitment and regulation of disease severity. Due to the prominent roles of chemokine/receptor axes, this study aimed to measure the blood expression levels of CCR4 and their ligands in pediatrics with B-cell ALL (B-ALL). We also evaluated the impact of cytotoxic chemotherapy on this axis. MATERIAL AND METHOD: Thirty children suffering from B-ALL were included in the study and followed up for 30 days after completion of a chemotherapy course. The blood sampling was performed before and after chemotherapy. 30 healthy donors have also entered the study as control subjects. The mRNA expression of CCL17, CCL22 and CCR4 genes was determined by quantitative real-time PCR. The frequency of the peripheral blood mononuclear cells expressing CCR4 (CCR4 + PBMCs) was also evaluated by the flow cytometry method. Moreover, we evaluated the association of the CCL17/CCL22-CCR4 axis with some diagnostic, prognostic and predictive biomarkers in ALL patients. RESULTS: There was overexpression of the CCL17/CCL22-CCR4 axis along with lactate dehydrogenase (LDH) in pediatrics with B-ALL compared to healthy controls. After induction of chemotherapy, the blood expression levels of the CCL17/CCL22-CCR4 axis have reached the levels of healthy controls. The findings for the blood expression levels of CCR4 were also confirmed using flow cytometry. CONCLUSION: The CCL17/CCL22-CCR4 axis can be used as a novel predictive and prognostic biomarker in B-ALL.

Changes in serum lactate dehydrogenase as a prognostic factor in patients with head and neck squamous cell carcinoma treated with immune checkpoint inhibitors.

BACKGROUND: Lactate dehydrogenase (LDH) is involved in the Warburg effect. Elevated serum LDH is a prognostic marker for metastatic solid cancer. AIM: To investigate the prognostic impact of serum LDH in patients with head and neck squamous cell carcinoma treated with immune checkpoint inhibitors (ICIs). MATERIALS AND METHODS: This retrospective study included 129 patients treated with ICIs between 2017 and 2023. The effects of pretreatment LDH, LDH at 3 months, and change in LDH during the first 3 months (ΔLDH) on overall survival (OS) and progression-free survival (PFS) were analyzed using the Kaplan-Meier method and Cox regression model. RESULTS: The 1-year PFS and OS rates for high and low groups were 6.0% and 30.1% for pretreatment LDH (p = 0.044), 25.7% and 38.3% for on-treatment LDH (p = 0.079), and 14.3% and 38.7% for ΔLDH (p = 0.008), as well as 42.1% and 60.9% for pretreatment LDH (p = 0.109), 56.0% and 80.5% (p < 0.001) for on-treatment LDH, and 31.0% and 81.0% for ΔLDH (p < 0.001), respectively. ΔLDH was an independent prognostic factor for both PFS and OS. CONCLUSIONS AND SIGNIFICANCE: ΔLDH can be used to predict ICI treatment outcomes and as a marker in deciding to continue ICI therapy.

Metastasis of ovarian dysgerminoma in a postmenopausal patient: a rare case report.

Ovary dysgerminoma is one of the most good prognosis malignant tumor, which has a 5-year overall survival rate exceeding to 90%. Generally, the incidence of ovarian dysgerminoma (OD) is relatively low, accounting for ~0.6% of all ovarian tumors. Usually, it mainly occurs in very young women, about 85% of patients under 30 years old and is rare in middle-aged especially in elderly ones. This ovary dysgerminoma case report presents a 58-year-old menopausal postmenopausal woman which has a poor prognosis. Therefore, there may be differences between the elderly and young women in clinical characteristic that require separate management. This case reports a postmenopausal woman who was diagnosed with ovary dysgerminoma. After surgery, the patient was treated chemotherapy with bleomycin, etoposide, and cisplatin (BEP) according to the treatment guidelines. Unusually, the patient developed bone marrow suppression and lymph node metastasis in final. This report explored the clinical characteristic in postmenopausal woman dysgerminoma. Changes in lactate dehydrogenase (LDH) throughout the course of the disease are closely related to the progression. The patient had a disease progression when treated with the conventional treatment (BEP). The applicability of this treatment protocol to postmenopausal patients requires further research. Postmenopausal woman dysgerminoma is rare but rapid progress. Whether BEP is suitable for OD in middle-aged and elderly people remains to be further validated in the future. LDH may be a potential biomarker for monitoring the progression of OD in the elderly.

Development of human lactate dehydrogenase a inhibitors: high-throughput screening, molecular dynamics simulation and enzyme activity assay.

Lactate dehydrogenase A (LDHA) is highly expressed in many tumor cells and promotes the conversion of pyruvate to lactic acid in the glucose pathway, providing energy and synthetic precursors for rapid proliferation of tumor cells. Therefore, inhibition of LDHA has become a widely concerned tumor treatment strategy. However, the research and development of highly efficient and low toxic LDHA small molecule inhibitors still faces challenges. To discover potential inhibitors against LDHA, virtual screening based on molecular docking techniques was performed from Specs database of more than 260,000 compounds and Chemdiv-smart database of more than 1,000 compounds. Through molecular dynamics (MD) simulation studies, we identified 12 potential LDHA inhibitors, all of which can stably bind to human LDHA protein and form multiple interactions with its active central residues. In order to verify the inhibitory activities of these compounds, we established an enzyme activity assay system and measured their inhibitory effects on recombinant human LDHA. The results showed that Compound 6 could inhibit the catalytic effect of LDHA on pyruvate in a dose-dependent manner with an EC50 value of 14.54 ± 0.83 µM. Further in vitro experiments showed that Compound 6 could significantly inhibit the proliferation of various tumor cell lines such as pancreatic cancer cells and lung cancer cells, reduce intracellular lactic acid content and increase intracellular reactive oxygen species (ROS) level. In summary, through virtual screening and in vitro validation, we found that Compound 6 is a small molecule inhibitor for LDHA, providing a good lead compound for the research and development of LDHA related targeted anti-tumor drugs.

Lactic acid: The culprit behind the immunosuppressive microenvironment in hepatocellular carcinoma.

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.

Association of serum lactate dehydrogenase with prognosis and tumor metabolism in patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab therapy.

PURPOSE: Treatment outcomes are predicted by analyzing peripheral blood markers such as serum lactate dehydrogenase (LDH). We conducted this study to investigate whether serum LDH levels can predict the prognosis of patients treated with atezolizumab plus bevacizumab (ATZ/BEV) therapy for hepatocellular carcinoma (HCC) and whether LDH levels correlate with metabolic changes. METHODS: We enrolled 66 HCC patients treated with ATZ/BEV. Based on the change in serum LDH levels before and after treatment, the patients were divided into two groups, and the prognosis of each group was examined. Moreover, the association of LDH levels with tumor metabolism was analyzed by fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). RESULTS: There were 32 patients categorized as the LDH-decrease group. Kaplan-Meier survival analysis indicated worse progression-free survival (PFS) in the LDH-increase group than in the LDH-decrease group (p = 0.0029). Multivariate analysis showed that an increase in the LDH level was an independent risk factor for worse PFS (p = 0.0045). The baseline LDH level correlated significantly with a high maximum standardized uptake value of 18F-FDG, according to the PET/CT findings. Transcriptomic analyses of specimens resected after ATZ/BEV therapy showed downregulated mitochondria-related pathways. CONCLUSION: Serum LDH levels are a potential prognostic marker and an indicator of tumor metabolism.

Identification of peripheral blood test parameters predicting the response to palbociclib and endocrine therapy for metastatic breast cancer: a retrospective study in a single institution.

PURPOSE: Cyclin-dependent kinase 4/6 inhibitors have been used in endocrine therapy for patients with estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. Although randomized trials have shown that combined therapies prolong progression-free survival (PFS) in comparison to endocrine monotherapy, the predictors of efficacy are unknown. This study aimed to identify the blood test parameters to predict the effects of palbociclib and endocrine therapy. METHODS: Seventy-nine patients treated with palbociclib and endocrine therapy between December 2017 and June 2022 were reviewed. We assessed PFS in patients according to factors evaluated based on patient characteristics and peripheral blood tests. RESULTS: Patients in the C-reactive protein (CRP)-high, lactate dehydrogenase (LDH)-high, and albumin (Alb)-low groups had significantly shorter PFS than those in the normal group. A multivariate analysis revealed that high LDH and low Alb levels were independent factors that affected PFS. The Alb-low group had an inferior disease control rate. Patients in the CRP-high, LDH-high, and Alb-low groups who received these therapies as first- or second-line treatments showed poor PFS. CONCLUSIONS: Several predictors of the efficacy of palbociclib and endocrine therapy were identified in the peripheral blood test parameters of patients with ER-positive and HER2-negative subtypes of metastatic breast cancer.

Electrophysiological and biochemical effect of zinc oxide nanoparticles on heart functions of male Wistar rats.

Zinc oxide nanoparticles (ZnO NPs) are one of the most abundantly used nanomaterials in cosmetics and topical products, and nowadays, they are explored in drug delivery and tissue engineering. Some recent data evidenced that they are responsible for cardiotoxic effects and systemic toxicity. The present study aimed to investigate the toxic effect of ZnO NPs (39 nm) on the heart of Wistar rats and to perform a dose-response relationship using three different dose levels (25, 50, 100 mg/kg bw) of ZnO NPs on the electrocardiogram (ECG) readings, the levels of biochemical function parameters of heart, and the oxidative stress and antioxidant biomarkers. Furthermore, zinc concentration level and histopathological examination of heart tissues were determined. ZnO NPs showed a dose-dependent effect, as the 100 mg/kg bw ZnO NPs treated group showed the most significant changes in ECGs parameters: R-R distance, P-R interval, R and T amplitudes, and increased levels of heart enzymes Creatine Kinase- MB (CK-MB) and Lactate dehydrogenase (LDH). On the other hand, elevated zinc concentration levels, oxidative stress biomarkers MDA and NO, and decreased GSH levels were found also in a dose-dependent manner, the results were supported by impairment in the histopathological structure of heart tissues. While the dose of 100 mg/kg bw of ZnO bulk group showed no significant effects on heart function. The present study concluded that ZnO NPs could induce cardiac dysfunctions and pathological lesions mainly in the high dose.

The role of LDH and ferritin levels as biomarkers for corticosteroid dosage in children with refractory Mycoplasma pneumoniae pneumonia.

BACKGROUND: This study explored the relationship between inflammatory markers and glucocorticoid dosage upon admission. METHODS: We conducted a retrospective analysis of 206 patients with refractory Mycoplasma pneumoniae pneumonia (RMPP) admitted to a Children's Hospital from November 2017 to January 2022. Patients were categorized into three groups based on their methylprednisolone dosage: low-dose (≤ 2 mg/kg/d), medium-dose (2-10 mg/kg/d), and high-dose (≥ 10 mg/kg/d). We compared demographic data, clinical manifestations, laboratory findings, and radiological outcomes. Spearman's rank correlation coefficient was used to assess relationships between variables. RESULTS: The median age was highest in the low-dose group at 7 years, compared to 5.5 years in the medium-dose group and 6 years in the high-dose group (P < 0.001). The body mass index (BMI) was also highest in the low-dose group at 16.12, followed by 14.86 in the medium-dose group and 14.58 in the high-dose group (P < 0.001). More severe radiographic findings, longer hospital stays, and greater incidence of hypoxia were noted in the high-dose group (P < 0.05). Additionally, significant increases in white blood cells, C-reactive protein, procalcitonin, lactate dehydrogenase (LDH), alanine transaminase, aspartate transaminase, ferritin, erythrocyte sedimentation rate, and D-dimer levels were observed in the high-dose group (P < 0.05). Specifically, LDH and ferritin were markedly higher in the high-dose group, with levels at 660.5 U/L and 475.05 ng/mL, respectively, compared to 450 U/L and 151.4 ng/mL in the medium-dose group, and 316.5 U/L and 120.5 ng/mL in the low-dose group. Correlation analysis indicated that LDH and ferritin levels were significantly and positively correlated with glucocorticoid dose (Spearman ρ = 0.672 and ρ = 0.654, respectively; P < 0.001). CONCLUSIONS: Serum LDH and ferritin levels may be useful biomarkers for determining the appropriate corticosteroid dosage in treating children with RMPP.

Accurate evaluation of drug effect on the LDH activity of live cells: dual measurement of live cell number by fluorescent staining of nucleus and LDH activity by formazan.

Effect of drugs on the intracellular activity of lactate dehydrogenase (LDH) has been measured by using water-soluble tetrazolium (WST). Because the assay is usually conducted in the presence of dead cells, net activity of live cells is not evaluated. Here, we reported the assay of the net intracellular LDH activity of live cells by counting the live cells using fluorescent staining of nucleus. By using a deep red fluorescent dye, dual measurements of fluorescence signal of nucleus and absorbance of WST could be conducted with transparent 96-well-plates. We found that conventional assay in the presence of dead cells overestimate the effect of drugs on the LDH activity.

Define Critical Parameters of Trastuzumab-Mediated ADCC Assays via Assay Optimization Processes, Focusing on the Impact of Cryopreserved Effector Cells on Assay Performance.

The mechanisms of mAb-induced ADCC have been well established. However, the ADCC bioassays used to quantify mAb-induced ADCC require continued development/refinement to properly assess and compare the potency of newly developed therapeutic mAbs and biosimilars to meet regulatory requirements. We used trastuzumab and a lactate dehydrogenase (LDH)-based ADCC bioassay as a model to define critical parameters of the ADCC bioassay, describing how several bioassay parameters, including preparation of effector cells, E/T ratio, target cell selection, bioassay media components, and treatment time can influence the data quality of the ADCC activity. We confirm that a 4 to 24 h recovery cultivation is required to restore peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cell activity toward ADCC when using cryopreserved PBMCs. Furthermore, we delineated the cellular mechanisms underlying the restored ADCC activity following the recovery cultivation. We observed that CD69, an early marker of NK cell activation, was upregulated and a new subset CD56dim/CD16dim population was dramatically increased in the recovered NK cells, which led to an increase in expression and secretion of perforin, granzyme B, and cytokine production. This study provides comprehensive technical insights into ADCC bioassay optimization to inform trastuzumab biosimilar development. The knowledge gained from this study can also be leveraged to guide bioassay development for therapeutic mAbs with ADCC as the primary mechanism of action.

Natural flavonoids as promising lactate dehydrogenase A inhibitors: Comprehensive in vitro and in silico analysis.

The inhibitory potential of 17 flavonoids on lactate dehydrogenase A (LDHA), a key enzyme in the downstream process of aerobic glycolysis in cancer cells, is investigated. Fisetin exhibited excellent inhibitory activity (IC50 = 0.066 µM). Quercetin 3-ß-D-glucoside, quercetin 3-galactoside, luteolin, neoeriocitrin, and luteolin 7-O-ß-D-glucoside showed good inhibitory activity (IC50 = 1.397-15.730 µM). Biochanin A, baicalein, quercetin, scutellarein-7-glucuronide, diosmetin, baicalein 7-O-ß-D-glucuronide, and apigenin 7-apioglucoside demonstrated moderate inhibitory activity (IC50 = 33.007-86.643 µM). Eriodictyol, quercetin 7-O-ß-D-glucoside, apigenin 7-O-ß-D-glucoside, and epicatechin were inactive. The Lineweaver-Burk plot showed that fisetin competitively inhibits NADH binding (Ki = 0.024 µM). Ki values for other compounds were calculated using the Cheng-Prusoff equation (Ki = 0.2799-2.1661 µM). The study revealed that the inhibitory effect of flavonoids varies with the number and position of OH groups and bound sugars. Molecular docking analyses indicated that flavonoids exhibited strong interactions with the NADH binding site of LDHA through hydrophobic interactions and hydrogen bonds. Molecular dynamic simulations tested the stability of the fisetin-LDHA complex over 100 ns and showed fisetin's high binding affinity to LDHA, maintaining strong hydrogen bonds. The binding energy of fisetin with LDHA was -33.928 kcal/mol, indicating its effectiveness as an LDHA inhibitor. Consequently, flavonoids identified as strong inhibitors could be potential cancer treatment sources through LDHA inhibition.

HOXC4 promotes proliferation of pancreatic cancer cells by increasing LDHA-mediated glycolysis.

Homeobox C4 (HOXC4) is a member of homeobox family and acts as a transcription factor in regulating morphological development. The current study aimed to determine its role in pancreatic cancer (PC). Bioinformatics analysis was employed to assess the expression and clinical significance of HOXC4 in PC, while the expression of HOXC4 was further confirmed in PC tissues through quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). The impact of HOXC4 on PC cell proliferation was evaluated using various assays including Cell Counting Kit-8, colony formation, apoptosis detection, cell cycle analysis, and subcutaneous tumorigenesis. Extracellular acidification rate, glucose uptake, and lactate production measurements were detected to examine the impact of HOXC4 on glycolysis. The relationship between HOXC4 and lactate dehydrogenase A (LDHA) was investigated using CHIP assay, luciferase reporter assay, and western blot. Notably, there was a substantial increase in HOXC4 expression in PC, and patients with elevated HOXC4 levels exhibited shorter survival durations. HOXC4 knockdown resulted in significantly reduced proliferation and colony formation in PC cells, accompanied by increased apoptosis and G1 phase arrest. The overexpression of HOXC4 resulted in contrasting effects. In vivo, the proliferation of PC cells was diminished upon the knockdown of HOXC4. HOXC4 exhibited an increase in LDHA expression by binding to its promoter. The suppressive effects of HOXC4 knockdown on PC cells were counteracted upon the restoration of LDHA. In conclusion, HOXC4 promoted the proliferation of PC cells by increasing LDHA-mediated glycolysis. HOXC4 can act as a target for PC therapy.

Immunometabolic alteration of CD4+ T cells in the pathogenesis of primary Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is a prevalent autoimmune disorder wherein CD4+ T cells play a pivotal role in its pathogenesis. However, the underlying mechanisms driving the hyperactivity of CD4+ T cells in pSS remain poorly understood. This study aimed to investigate the potential role of immunometabolic alterations in driving the hyperactivity of CD4+ T cells in pSS. We employed Seahorse XF assay to evaluate the metabolic phenotype of CD4+ T cells, conducted flow cytometry to assess the effector function and differentiation of CD4+ T cells and measured the level of intracellular reactive oxygen species (ROS). Additionally, transcriptome sequencing, PCR, and Western blotting were utilized to examine the expression of glycolytic genes. Our investigation revealed that activated CD4+ T cells from pSS patients exhibited elevated aerobic glycolysis, rather than oxidative phosphorylation, resulting in excessive production of IFN-γ and IL-17A. Inhibition of glycolysis by 2-Deoxy-D-glucose reduced the expression of IFN-γ and IL-17A in activated CD4+ T cells and mitigated the differentiation of Th1 and Th17 cells. Furthermore, the expression of glycolytic genes, including CD3E, CD28, PIK3CA, AKT1, mTOR, MYC, LDHA, PFKL, PFKFB3, and PFKFB4, was upregulated in activated CD4+ T cells from pSS patients. Specifically, the expression and activity of LDHA were enhanced, contributing to an increased level of intracellular ROS. Targeting LDHA with FX-11 or inhibiting ROS with N-acetyl-cysteine had a similar effect on reversing the dysfunction of activated CD4+ T cells from pSS patients. Our study unveils heightened aerobic glycolysis in activated CD4+ T cells from pSS patients, and inhibition of glycolysis or its metabolite normalizes the dysfunction of activated CD4+ T cells. These findings suggest that aerobic glycolysis may be a promising therapeutic target for the treatment of pSS.

The association between lactate dehydrogenase to serum albumin ratio and in-hospital mortality in patients with pulmonary embolism: a retrospective analysis of the MIMIC-IV database.

Background: Lactate dehydrogenase (LDH) and albumin (ALB) were found to be significantly correlated with mortality in pulmonary embolism (PE) patients. However, data regarding the LDH/ALB ratio (LAR) in patients with acute PE are scanty. Therefore, the aim of this study was to investigate the association between LAR and the risk of mortality in patients with acute PE. Methods: A retrospective cohort study was conducted on patients with acute PE represented in the Medical Information Mart for Intensive Care IV (MIMIC-IV). A receiver operating characteristic (ROC) curve analysis and calibration curve were used to assess the accuracy of the LAR for predicting mortality in patients with acute PE. We utilized Cox regression analysis to determine adjusted hazard ratios (HR) and 95% confidence interval (CI). Survival curves were used to evaluate a connection between the LAR and prognosis in patients with acute PE. Results: The study comprised 581 patients, and the 30-day all-cause mortality rate was 7.7%. We observed a higher LAR in the non-survival group compared to the surviving group (21.24 ± 21.22 vs. 8.99 ± 7.86, p < 0.0001). The Kaplan-Meier analysis showed that patients with an elevated LAR had a significantly lower likelihood of surviving the 30-day mortality compared to those with a low LAR. Cox regression analysis showed that LAR (HR = 1.04, 95% CI: 1.03-1.05) might have associations with 30-day mortality in patients with acute PE. This result was supported by sensitivity analyses. According to the results of the ROC curve analysis, the LAR's prediction of 30-day mortality in patients with acute PE yielded an area under the ROC curve of 0.73. A calibration curve showed LAR is well calibrated. Conclusion: Our research suggests LAR monitoring may be promising as a prognostic marker among patients with acute PE.

Creatine kinase mitochondrial 2 promotes the growth and progression of colorectal cancer via enhancing Warburg effect through lactate dehydrogenase B.

Background: Mitochondrial creatine kinase (MtCK) plays a pivotal role in cellular energy metabolism, exhibiting enhanced expression in various tumors, including colorectal cancer (CRC). Creatine kinase mitochondrial 2 (CKMT2) is a subtype of MtCK; however, its clinical significance, biological functions, and underlying molecular mechanisms in CRC remain elusive. Methods: We employed immunohistochemical staining to discern the expression of CKMT2 in CRC and adjacent nontumor tissues of patients. The correlation between CKMT2 levels and clinical pathological factors was assessed. Additionally, we evaluated the association between CKMT2 and the prognosis of CRC patients using Kaplan-Meier survival curves and Cox regression analysis. Meanwhile, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the expression levels of CKMT2 in different CRC cell lines. Finally, we explored the biological functions and potential molecular mechanisms of CKMT2 in CRC cells through various techniques, including qRT-PCR, cell culture, cell transfection, western blot, Transwell chamber assays, flow cytometry, and co-immunoprecipitation. Results: We found that CKMT2 was significantly overexpressed in CRC tissues compared with adjacent nontumor tissues. The expression of CKMT2 is correlated with pathological types, tumor size, distant metastasis, and survival in CRC patients. Importantly, CKMT2 emerged as an independent prognostic factor through Cox regression analysis. Experimental downregulation of CKMT2 expression in CRC cell lines inhibited the migration and promoted apoptosis of these cells. Furthermore, we identified a novel role for CKMT2 in promoting aerobic glycolysis in CRC cells through interaction with lactate dehydrogenase B (LDHB). Conclusion: In this study, we found the elevated expression of CKMT2 in CRC, and it was a robust prognostic indicator in CRC patients. CKMT2 regulates glucose metabolism via amplifying the Warburg effect through interaction with LDHB, which promotes the growth and progression of CRC. These insights unveil a novel regulatory mechanism by which CKMT2 influences CRC and provide promising targets for future CRC therapeutic interventions.