Gene replacement therapies for inherited disorders of neurotransmission: Current progress in succinic semialdehyde dehydrogenase deficiency.

Neurodevelopment is a highly organized and complex process involving lasting and often irreversible changes in the central nervous system. Inherited disorders of neurotransmission (IDNT) are a group of genetic disorders where neurotransmission is primarily affected, resulting in abnormal brain development from early life, manifest as neurodevelopmental disorders and other chronic conditions. In principle, IDNT (particularly those of monogenic causes) are amenable to gene replacement therapy via precise genetic correction. However, practical challenges for gene replacement therapy remain major hurdles for its translation from bench to bedside. We discuss key considerations for the development of gene replacement therapies for IDNT. As an example, we describe our ongoing work on gene replacement therapy for succinic semialdehyde dehydrogenase deficiency, a GABA catabolic disorder.

Risk stratification of synchronous gastric cancers including alcohol-related genetic polymorphisms.

BACKGROUND AND AIM: We previously identified that ever-smoking and severe gastric atrophy in pepsinogen are risk factors for synchronous gastric cancers (SGCs). This study aimed to determine the association of alcohol drinking status or alcohol-related genetic polymorphism with SGCs and also stratify their risk. METHODS: This multi-center prospective cohort study included patients who underwent endoscopic submucosal dissection for the initial early gastric cancers at 22 institutions in Japan. We evaluated the association of alcohol drinking status or alcohol dehydrogenase 1B (ADH1B) and acetaldehyde dehydrogenase 2 (ALDH2) genotypes with SGCs. We then stratified the risk of SGCs by combining prespecified two factors and risk factors identified in this study. RESULTS: Among 802 patients, 130 had SGCs. Both the ADH1B Arg and ALDH2 Lys alleles demonstrated a significant association with SGCs on multivariate analysis (odds ratio, 1.77), although alcohol drinking status showed no association. The rates of SGCs in 0-3 risk factors in the combined evaluation of three risk factors (ever-smoking, severe gastric atrophy in pepsinogen, and both the ADH1B Arg and ALDH2 Lys alleles) were 7.6%, 15.0%, 22.0%, and 32.1%, respectively. The risk significantly increased from 0 to 3 risk factors on multivariate analysis (P for trend <0.001). CONCLUSIONS: Both the ADH1B Arg and ALDH2 Lys alleles were at high risk for SGCs. The risk stratification by these three factors may be a less invasive and promising tool for predicting their risk.

Colorectal Cancer Stem Cell Biomarkers: Biological Traits and Prognostic Insights.

Due to self-renewal, differentiation, and limitless proliferation properties, Cancer Stem Cells (CSCs) increase the probability of tumor development. These cells are identified by using CSC markers, which are highly expressed proteins on the cell surface of CSCs. Recently, the therapeutic application of CSCs as novel biomarkers improved both the prognosis and diagnosis outcome of colorectal Cancer. In the present review, we focused on a specific panel of colorectal CSC markers, including LGR5, ALDH, CD166, CD133, and CD44, which offers a targeted and comprehensive analysis of their functions. The selection criteria for these markersCancer were based on their established significance in Colorectal Cancer (CRC) pathogenesis and clinical outcomes, providing novel insights into the CSC biology of CRC. Through this approach, we aim to elevate understanding and stimulate further research for developing effective diagnostic and therapeutic strategies in CRC.

Characteristic phenotypes of ADH5/ALDH2 deficiency during childhood.

ADH5/ALDH2 deficiency is a rare inherited syndrome characterized by short stature, microcephaly, delayed mental development, and hematopoietic dysfunction and has recently been proposed as a disease paradigm. Acute and severe presentations include aplastic anemia, myelodysplastic syndrome, or leukemia, requiring bone marrow transplantation during childhood. Conversely, non-hematological manifestations may exhibit a prolonged and nonspecific clinical trajectory, with growth failure and developmental delay, most of which are often overlooked, particularly in patients with milder symptoms. Here, we describe the clinical course of a girl with a wide spectrum of clinical presentations, including nonspecific hematopoietic disorders, growth retardation, mild developmental delay, amblyopia, hemophagocytic lymphohistiocytosis, and verruca vulgaris, culminating in a genetic diagnosis of AMeD syndrome at 12 years of age. We also summarized the clinical manifestations of previously reported cases of AMeD syndrome. Cumulatively, 13 females and 5 males have been documented, with a cardinal triad of symptoms, aplastic anemia, short stature, and intellectual disability. Additional characteristic observations included pigmentary deposition in approximately half of the cases and skeletal difficulties in one-quarter. We propose that early diagnosis of patients who exhibit relatively mild phenotypes of skin or skeletal lesions is important for managing and improving the quality of life of patients with AMeD syndrome.

The ALDH2 gene rs671 polymorphism is associated with cardiometabolic risk factors in East Asian population: an updated meta-analysis.

Introduction: Acetaldehyde dehydrogenase 2 (ALDH2) had reported as a prominent role in the development of cardiometabolic diseases among Asians. Our study aims to investigate the relationship between ALDH2 polymorphism and cardiometabolic risk factors in East Asian population. Method: We searched databases of PubMed, Web of Science, and Embase updated to Oct 30th, 2023. We extracted data of BMI, Hypertension, SBP, DBP, T2DM, FBG, PPG, HbA1c, TG, TC, LDL-C and HDL-C. Result: In total, 46 studies were finally included in our meta-analysis, containing, 54068 GG and, 36820 GA/AA participants. All outcomes related to blood pressure revealed significant results (hypertension OR=0.83 [0.80, 0.86]; SBP MD=-1.48 [-1.82, -1.14]; DBP MD=-1.09 [-1.58, -0.61]). FBG showed a significant difference (MD=-0.10 [-0.13, -0.07]), and the lipid resulted significantly in some outcomes (TG MD=-0.07 [-0.09, -0.04]; LDL-C MD=-0.04 [-0.05, -0.02]). As for subgroups analysis, we found that in populations without severe cardiac-cerebral vascular diseases (CCVDs), GG demonstrated a significantly higher incidence of T2DM (T2DM OR=0.88 [0.79, 0.97]), while the trend was totally opposite in population with severe CCVDs (T2DM OR=1.29 [1.00, 1.66]) with significant subgroup differences. Conclusion: Our updated meta-analysis demonstrated that ALDH2 rs671 GG populations had significantly higher levels of BMI, blood pressure, FBG, TG, LDL-C and higher risk of hypertension than GA/AA populations. Besides, to the best of our knowledge, we first report GG had a higher risk of T2DM in population without severe CCVDs, and GA/AA had a higher risk of T2DM in population with severe CCVDs.Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO, identifier CRD42023389242.

Synergistic eradicating impact of 5-fluouracil with FeO nanoparticles-diethyldithiocarbamate in colon cancer spheroids.

Background: Cancer stem cells' (CSCs) resistance to 5-fluorouracil (Fu), which is the main obstacle in treating colon cancer (CC), can be overcome by ferroptosis. The latter, herein, can be triggered by FeO nanoparticles (inducer of iron accumulation) and diethyldithiocarbamate-inhibited glutathione system and aldehyde dehydrogenase (ALDH1A1-maintained stemness, therapeutic resistance and metastasis). Materials & methods: Nanocomplex of FeO nanoparticles and diethyldithiocarbamate (FD) was used in combination with Fu to investigate its potential synergistic anti-CSC influence using CC spheroid models. Results: In Fu + FD-treated spheroids, the strongest growth inhibition, the highest cell death percentage, and the lowest CD133+-CSCs percentage and stemness gene expressions (e.g., drug efflux transporter), and the strongest antimetastatic effect were recorded with high synergistic indexes. Conclusion: Fu + FD represents effective combination therapy for chemoresistant CC cells.

Biological evaluation of levofloxacin and its thionated derivatives: antioxidant activity, aldehyde dehydrogenase enzyme inhibition, and cytotoxicity on A549 cell line.

Levofloxacin (LVX) is among the fluoroquinolones antibiotics that has also been studied in vitro and in vivo for its anticancer effects. In this study, we used LVX and novel LVX thionated derivatives; compounds 2 and 3, to evaluate their antioxidant activity, aldehyde dehydrogenase (ALDH) enzymes activity inhibition, and anticancer activity. Combination treatments with doxorubicin (DOX) were investigated as well. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay was used to determine the antioxidant activity. The NADH fluorescence spectrophotometric activity assay was used to determine the ALDH inhibitory effects. Resazurin dye method was applied for cell viability assays. Molecular Operating Environment software was used for the molecular docking experiments. Compared to ascorbic acid, DPPH assay showed that compound 3 had the highest antioxidant activity among the tested compounds with approximately 35% scavenging activity. On ALDH enzymes, compound 3 showed a significant ALDH activity inhibition compared to compound 2 at 200 µM. The IC50 values for the tested compounds were approximately 100 µM on A549 cell line, a non-small cell lung cancer (NSCLC) cell line. However, significant enhancement of cytotoxicity and reduction of IC50 values were observed by combining DOX and synergism was achieved with LVX with a combination index value of 0.4. The molecular docking test showed a minimum binding energy with a good affinity for compound 3 towards ALDH enzymes. Thionated LVX derivatives, may be repurposed for NSCLC therapy in combination with DOX, taking into account the antioxidant activity, ALDH activity inhibition, and the molecular docking results of compound 3.

Asian flush is a potential protective factor against COVID-19: a web-based retrospective survey in Japan.

BACKGROUND: Coronavirus disease 2019 (COVID-19), first reported in December 2019, spread worldwide in a short period, resulting in numerous cases and associated deaths; however, the toll was relatively low in East Asia. A genetic polymorphism unique to East Asians, Aldehyde dehydrogenase 2 rs671, has been reported to confer protection against infections. METHOD: We retrospectively investigated the association between the surrogate marker of the rs671 variant, the skin flushing phenomenon after alcohol consumption, and the timing of COVID-19 incidence using a web-based survey tool to test any protective effects of rs671 against COVID-19. RESULTS: A total of 807 valid responses were received from 362 non-flushers and 445 flushers. During the 42 months, from 12/1/2019 to 5/31/2023, 40.6% of non-flushers and 35.7% of flushers experienced COVID-19. Flushers tended to have a later onset (Spearman's partial rank correlation test, p = 0.057, adjusted for sex and age). Similarly, 2.5% of non-flushers and 0.5% of flushers were hospitalized because of COVID-19. Survival analysis estimated lower risks of COVID-19 and associated hospitalization among flushers (p = 0.03 and <0.01, respectively; generalized Wilcoxon test). With the Cox proportional hazards model covering 21 months till 8/31/2021, when approximately half of the Japanese population had received two doses of COVID-19 vaccine, the hazard ratio (95% confidence interval) of COVID-19 incidence was estimated to be 0.21 (0.10-0.46) for flusher versus non-flusher, with adjustment for sex, age, steroid use, and area of residence. CONCLUSIONS: Our study suggests an association between the flushing phenomenon after drinking and a decreased risk of COVID-19 morbidity and hospitalization, suggesting that the rs671 variant is a protective factor. This study provides valuable information for infection control and helps understand the unique constitutional diversity of East Asians.

Low-Dose Sorafenib Promotes Cancer Stem Cell Expansion and Accelerated Tumor Progression in Soft Tissue Sarcomas.

The cancer stem cell (CSC) hypothesis postulates that heterogeneous human cancers harbor a population of stem-like cells which are resistant to cytotoxic therapies, thus providing a reservoir of relapse following conventional therapies like chemotherapy and radiation (RT). CSCs have been observed in multiple human cancers, and their presence has been correlated with worse clinical outcomes. Here, we sought to evaluate the impact of drug dosing of the multi-tyrosine kinase inhibitor, sorafenib, on CSC and non-CSCs in soft tissue sarcoma (STS) models, hypothesizing differential effects of sorafenib based on dose and target cell population. In vitro, human cancer cell lines and primary STS from surgical specimens were exposed to escalating doses of sorafenib to determine cell viability and expression of CSC marker aldehyde dehydrogenase (ALDH). In vivo, ALDHbright CSCs were isolated, exposed to sorafenib, and xenograft growth and survival analyses were performed. We observed that sarcoma CSCs appear to paradoxically respond to the tyrosine kinase inhibitor sorafenib at low doses with increased proliferation and stem-like function of CSCs, whereas anti-viability effects dominated at higher doses. Importantly, STS patients receiving neoadjuvant sorafenib and RT on a clinical trial (NCT00864032) showed increased CSCs post therapy, and higher ALDH scores post therapy were associated with worse metastasis-free survival. These data suggest that low-dose sorafenib may promote the CSC phenotype in STS with clinically significant effects, including increased tumor growth and higher rates of metastasis formation in sarcoma patients.

Aldehyde Dehydrogenase 2 (ALDH2): A novel sorafenib target in hepatocellular carcinoma unraveled by the proteome-wide cellular thermal shift assay.

Sorafenib is a multikinase inhibitor indicated for first-line treatment of unresectable hepatocellular carcinoma. Despite its widespread use in the clinic, the existing knowledge of sorafenib mode-of-action remains incomplete. To build upon the current understanding, we used the Cellular Thermal Shift Assay (CETSA) coupled to Mass Spectrometry (CETSA-MS) to monitor compound binding to its target proteins in the cellular context on a proteome-wide scale. Among the potential sorafenib targets, we identified aldehyde dehydrogenase 2 (ALDH2), an enzyme that plays a major role in alcohol metabolism. We validated the interaction of sorafenib with ALDH2 by orthogonal methods using pure recombinant protein, proving that this interaction is not mediated by other cellular components. Moreover, we showed that sorafenib inhibits ALDH2 activity, supporting a functional role for this interaction. Finally, we were able to demonstrate that both ALDH2 protein expression and activity were reduced in sorafenib-resistant cells compared to the parental cell line. Overall, our study allowed the identification of ALDH2 as a novel sorafenib target and sheds light on its potential role in both hepatocellular carcinoma and sorafenib resistance condition.

A functional variant of ALDH1A2 is associated with hand osteoarthritis in the Chinese population.

Genome-wide association study identified common variants within the ALDH1A2 gene as the susceptible loci of hand osteoarthritis (HOA) in UK and Iceland populations. Located in chromosome 15, ALDH1A2 encodes aldehyde dehydrogenase family 1 member A2, which is an enzyme that catalyses the synthesis of retinoic acid from retinaldehyde. Our purposes were to replicate the association of functional variant in ALDH1A2 with the development of HOA in the Chinese population. Variant rs12915901 of ALDH1A2 was genotyped in 872 HOA patients and 1223 healthy controls. Subchondral bone samples were collected from 40 patients who had undergone a trapeziectomy, and the tissue expression of ALDH1A2 was analysed. The chi-square analysis was used to compare the frequency of genotype and risk allele between the HOA cases and controls. The Student t test was used to compare the mRNA expression of ALDH1A2 between patients with genotype AA/AG and those with genotype GG. The frequency of genotype AA was significantly higher in HOA patients than in the controls (7.6% vs. 5.1%, p = .01). The frequency of allele A was significantly higher in the patients than in the controls (28.9% vs. 24.6%, p = .005). The mRNA expression of ALDH1A2 was 1.31-folds higher in patients with genotype GG than in the patients with genotype AA/AG (0.000617 ± 0.000231 vs. 0.000471 ± 0.000198, p = .04). Variant rs12915901 of ALDH1A2 contributed to the susceptibility of HOA in the Chinese population. Allele A of rs12915901 can add to the risk of HOA possibly via down-regulation of ALDH1A2 expression.

ALDH Activity Assay: A Method for Cancer Stem Cell (CSC) Identification and Isolation.

Cancer stem cells (CSCs) are a small tumor cell subpopulation, driving cancer initiation, progression, multidrug resistance, and metastasis. Several methods are used to detect and isolate CSCs by flow cytometry. Among these, measurement of aldehyde dehydrogenase (ALDH) activity within the cell is an assay widely used to identify and isolate CSCs from different types of solid tumors. The aldehyde dehydrogenase (ALDH) is a polymorphic enzyme responsible for the oxidation of aldehydes to carboxylic acids, overexpressed both in normal and cancer stem cells. In this chapter, it is described how CSCs are detected and isolated by using ALDH activity assay.

Neutrophil ALDH2 is a new therapeutic target for the effective treatment of sepsis-induced ARDS.

Acetaldehyde dehydrogenase 2 (ALDH2) mutations are commonly found in a subgroup of the Asian population. However, the role of ALDH2 in septic acute respiratory distress syndrome (ARDS) remains unknown. Here, we showed that human subjects carrying the ALDH2rs671 mutation were highly susceptible to developing septic ARDS. Intriguingly, ALDH2rs671-ARDS patients showed higher levels of blood cell-free DNA (cfDNA) and myeloperoxidase (MPO)-DNA than ALDH2WT-ARDS patients. To investigate the mechanisms underlying ALDH2 deficiency in the development of septic ARDS, we utilized Aldh2 gene knockout mice and Aldh2rs671 gene knock-in mice. In clinically relevant mouse sepsis models, Aldh2-/- mice and Aldh2rs671 mice exhibited pulmonary and circulating NETosis, a specific process that releases neutrophil extracellular traps (NETs) from neutrophils. Furthermore, we discovered that NETosis strongly promoted endothelial destruction, accelerated vascular leakage, and exacerbated septic ARDS. At the molecular level, ALDH2 increased K48-linked polyubiquitination and degradation of peptidylarginine deiminase 4 (PAD4) to inhibit NETosis, which was achieved by promoting PAD4 binding to the E3 ubiquitin ligase CHIP. Pharmacological administration of the ALDH2-specific activator Alda-1 substantially alleviated septic ARDS by inhibiting NETosis. Together, our data reveal a novel ALDH2-based protective mechanism against septic ARDS, and the activation of ALDH2 may be an effective treatment strategy for sepsis.

The Capacity of Drug-Metabolising Enzymes in Modulating the Therapeutic Efficacy of Drugs to Treat Rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is a rare soft tissue sarcoma (STS) that predominantly affects children and teenagers. It is the most common STS in children (40%) and accounts for 5-8% of total childhood malignancies. Apart from surgery and radiotherapy in eligible patients, standard chemotherapy is the only therapeutic option clinically available for RMS patients. While survival rates for this childhood cancer have considerably improved over the last few decades for low-risk and intermediate-risk cases, the mortality rate remains exceptionally high in high-risk RMS patients with recurrent and/or metastatic disease. The intensification of chemotherapeutic protocols in advanced-stage RMS has historically induced aggravated toxicity with only very modest therapeutic gain. In this review, we critically analyse what has been achieved so far in RMS therapy and provide insight into how a diverse group of drug-metabolising enzymes (DMEs) possess the capacity to modify the clinical efficacy of chemotherapy. We provide suggestions for new therapeutic strategies that exploit the presence of DMEs for prodrug activation, targeted chemotherapy that does not rely on DMEs, and RMS-molecular-subtype-targeted therapies that have the potential to enter clinical evaluation.

Are embryonic stem cell markers and ALDH1A1 relevant in the context of breast cancer estrogen positivity?

BACKGROUND: Embryonic pluripotency markers are recognized for their role in ER- BC aggressiveness, but their significance in ER+ BC remains unclear. This study aims to investigate the prevalence of expression of pluripotency markers in ER+ BC and their effect on survival and prognostic indicators. METHODS: We analyzed data of ER+ BC patients from three large cancer datasets to assess the expression of three pluripotency markers (NANOG, SOX-2, and OCT4), and the stem cell marker ALDH1A1. Additionally, we investigated associations between gene expression, through mRNA-Seq analysis, and overall survival (OS). The prevalence of mutational variants within these genes was explored. Using immunohistochemistry (IHC), we examined the expression and associations with clinicopathologic prognostic indicators of the four markers in 81 ER+ BC patients. RESULTS: Through computational analysis, NANOG and ALDH1A1 genes were significantly upregulated in ER+ BC compared to ER- BC patients (p < 0.001), while POU5F1 (OCT4) was downregulated (p < 0.001). NANOG showed an adverse impact on OS whereas ALDH1A1 was associated with a highly significant improved survival in ER+ BC (p = 4.7e-6), except for the PR- and HER2+ subgroups. Copy number alterations (CNAs) ranged from 0.4% to 1.6% in these genes, with the highest rate detected in SOX2. In the IHC study, approximately one-third of tumors showed moderate to strong expression of each of the four markers, with 2-4 markers strongly co-expressed in 56.8% of cases. OCT-4 and ALDH1A1 showed a significant association with a high KI-67 index (p = 0.009 and 0.008, respectively), while SOX2 showed a significant association with perinodal fat invasion (p = 0.017). CONCLUSION: Pluripotency markers and ALDH1A1 are substantially expressed in ER+ BC tumors with different, yet significant, associations with prognostic and survival outcomes. This study suggests these markers as targets for prospective clinical validation studies of their prognostic value and their possible therapeutic roles.

Exploring patterns of alcohol use and alcohol use disorder among Asian Americans with a finer lens.

BACKGROUND: National survey data suggest Asian Americans (AA) are less likely to consume alcohol and develop AUD than Americans in other groups. However, it is common for AA to be born outside of the US and carry gene variants that alter alcohol metabolism, both of which can lead to lower levels of alcohol involvement. The current study examined differences in alcohol use and AUD between AA and other groups before and after controlling for birth location and gene variants. DESIGN: Past year alcohol measures were examined from adults 18+ (N=22,848) in the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions III before and after controlling for birth location (inside or outside of the US) and gene variants (ALDH2*2 and ADH1B*2/ADH1B*3). Gender gaps in alcohol measures also were assessed. RESULTS: Before adjustments, AA were less likely than White Americans to drink in the previous year (OR=0.50, 95% CI 0.41-0.62), binge (OR=0.68, 95% CI 0.52-0.88), engage in frequent heavy drinking (OR=0.55, 95% CI 0.42-0.73), and reach criteria for AUD (OR=0.71, 95% CI 0.53-0.94). After controlling for birth location and gene variants, AA remained less likely to drink in the past year (OR=0.54, 95% CI 0.41-0.70) but all other differences disappeared. Gender gaps were only observed for AA born outside of the US, highlighting the importance of experience rather than racial category per se. CONCLUSIONS: Findings indicate that heterogeneity among AA leads to spurious generalizations regarding alcohol use and AUD and challenge the model minority myth.

Inhibiting apoptosis and GSDME-mediated pyroptosis attenuates hepatic injury in septic mice.

BACKGROUND: Sepsis is characterized by severe inflammation and organ dysfunction resulting from a dysregulated organismal response to infection. Although pyroptosis has been presumably shown to be a major cause of multiple organ failure and septic death, whether gasdermin E (GSDME)-mediated pyroptosis occurs in septic liver injury and whether inhibiting apoptosis and GSDME-mediated pyroptosis can attenuate septic liver injury remain unclear. This study investigated the role of apoptosis and GSDME-mediated pyroptosis in septic liver injury. METHODS: Adult male C57BL/6 mice were randomly divided into four groups: sham, cecal ligation puncture (CLP), CLP + Z-DEVD-FMK (a caspase-3 inhibitor, 5 mg/kg), and CLP + Ac-DMLD-CMK (a GSDME inhibitor, 5 mg/kg). Sepsis severity was assessed using the murine sepsis score (MSS). Hepatic tissue damage was observed by the hematoxylin-eosin staining method, the activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), the levels of malondialdehyde (MDA), the concentrations of interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) were measured according to the related kits, and the changes in the hepatic tissue reactive oxygen species (ROS) levels were detected by immunofluorescence (IF). The protein expression levels of cleaved caspase-3, GSDME-N, IL-1ß, B-cell lymphoma-2 (Bcl-2), cytochrome C (Cyt-c), and acetaldehyde dehydrogenase 2 (ALDH2) were detected using western blotting. GSDME expression was detected by immunohistochemistry. RESULTS: Compared with the Sham group, CLP mice showed high sepsis scores and obvious liver damage. However, in the CLP + Z-DEVD-FMK and CLP + Ac-DMLD-CMK groups, the sepsis scores were reduced and liver injury was alleviated. Compared with the Sham group, the serum ALT and AST activities, MDA and ROS levels, and IL-1ß and TNF-α concentrations were increased in the CLP group, as well as the protein expression of cleaved caspase-3, GSDME-N, IL-1ß, Cyt-c, and GSDME positive cells (P < 0.05). However, the expression levels of Bcl-2 and ALDH2 protein were decreased (P < 0.05). Compared with the CLP group, the CLP + Z-DEVD-FMK and CLP + Ac-DMLD-CMK groups showed low sepsis scores, ALT and AST activities, MDA and ROS levels, decreased IL-1ß and TNF-α concentrations, and decreased expression of cleaved caspase-3, GSDME-N, IL-1ß protein expression, and GSDME positive cells (P < 0.05). The expression levels of Bcl-2 and ALDH2 protein were increased (P < 0.05). CONCLUSION: Apoptosis and GSDME-mediated pyroptosis are involved in the development of sepsis-induced hepatic injury. Inhibition of apoptosis and GSDME-mediated pyroptosis attenuates injury. ALDH2 plays a protective role by inhibiting apoptosis and pyroptosis.

Potential clinical significance of ALDH3B1 in auxiliary diagnosis of gastric cancer.

Objective: This research aimed to explore a diagnostic method based on serum ALDH3B1 and to evaluate the clinical diagnostic efficacy in gastric cancer (GC) by comparing it with the traditional GC diagnostic method, the carcinoembryonic protein (CEA) assay. Methods: Serum samples were collected from 70 healthy volunteers and various patients (GC: 76, benign gastric lesions: 20, postoperative: 37, recurrence: 56). The diagnostic efficacy of serum ALDH3B1, CEA and the co-diagnosis were evaluated by receiver operating characteristic curve. ALDH3B1 protein levels were evaluated by western blot. Results: The co-diagnosis of ALDH3B1 and CEA had the highest diagnostic efficacy (area under the curve = 0.841). Conclusion: Serum ALDH3B1 may be used as an auxiliary diagnostic biomarker for GC, and its co-diagnosis with CEA can improve diagnostic efficacy.

Utility and limitations of EEG in the diagnosis and management of ALDH7A1-related pyridoxine-dependent epilepsy. A retrospective observational study.

Purpose: Pyridoxine-dependent epilepsy due to ALDH7A1 variants (PDE-ALDH7A1) is a rare disorder, presenting typically with severe neonatal, epileptic encephalopathy. Early diagnosis is imperative to prevent uncontrolled seizures. We have explored the role of EEG in the diagnosis and management of PDE. Methods: A total of 13 Norwegian patients with PDE-ALDH7A1 were identified, of whom five had reached adult age. Altogether 163 EEG recordings were assessed, 101 from the 1st year of life. Results: Median age at seizure onset was 9 h (IQR 41), range 1 h-6 days. Median delay from first seizure to first pyridoxine injection was 2 days (IQR 5.5). An EEG burst suppression pattern was seen in eight patients (62%) during the first 5 days of life. Eleven patients had recordings during pyridoxine injections: in three, immediate EEG improvement correlated with seizure control, whereas in six, no change of epileptiform activity occurred. Of these six, one had prompt clinical effect, one had delayed effect (< 1 day), one had no effect, one had uncertain effect, and another had more seizures. A patient without seizures at time of pyridoxine trial remained seizure free for 6 days. Two patients with prompt clinical effect had increased paroxysmal activity, one as a conversion to burst suppression. Autonomic seizures in the form of apnoea appeared to promote respiratory distress and were documented by EEG in one patient. EEG follow-up in adult age did not show signs of progressing encephalopathy. Conclusion: A neonatal burst suppression EEG pattern should raise the suspicion of PDE-ALDH7A1. Respiratory distress is common; isolated apnoeic seizures may contribute. EEG responses during pyridoxine trials are diverse, often with poor correlation to immediate clinical effect. Reliance on single trials may lead to under-recognition of this treatable condition. Pyridoxine should be continued until results from biomarkers and genetic testing are available.

Effect of ALDH1A1 and CD44 on Survival and Disease Recurrence in Patients With Osteosarcoma.

PURPOSE: Emerging evidence suggests that osteosarcoma stem cells (OSCs) may be responsible for tumor initiation propagation, recurrence, and resistance to therapy. We set out to evaluate the relationship between the abundance of ALDH1A1 and CD44-positive cells in biopsy and resection samples on disease recurrence and overall survival. METHODS: A retrospective review of 20 patients, including biopsy and resection samples, was performed at a comprehensive cancer center. Additionally, we queried the publicly available TARGET dataset of osteosarcoma patients. RESULTS: Neither the percentages of ALDH1A1-positive cells nor CD44-positive cells were significantly associated with overall mortality or disease recurrence in either biopsy or resection samples. Unlike our institutional data, overall survival was significantly correlated to higher ALDH1A1 expression in the TARGET dataset both in univariate and age-adjusted analyses. CONCLUSIONS: ADLH1 and CD44, potential markers of OSCs, were not found to be reliable clinical immunohistochemical prognostic markers for osteosarcoma patient survival, specifically disease-free survival. Osteosarcoma patients with high ALDH1A1 RNA expression showed improved overall survival in examining a national genomic database of osteosarcoma patients but again no association with disease-free survival. The potential of CD44 and ALDH1A1 as cellular-specific prognostic markers of survival, and as possible molecular targets, may be limited in osteosarcoma.