THAP3 recruits SMYD3 to OXPHOS genes and epigenetically promotes mitochondrial respiration in hepatocellular carcinoma.

Mitochondria harbor the oxidative phosphorylation (OXPHOS) system to sustain cellular respiration. However, the transcriptional regulation of OXPHOS remains largely unexplored. Through the cancer genome atlas (TCGA) transcriptome analysis, transcription factor THAP domain-containing 3 (THAP3) was found to be strongly associated with OXPHOS gene expression. Mechanistically, THAP3 recruited the histone methyltransferase SET and MYND domain-containing protein 3 (SMYD3) to upregulate H3K4me3 and promote OXPHOS gene expression. The levels of THAP3 and SMYD3 were altered by metabolic cues. They collaboratively supported liver cancer cell proliferation and colony formation. In clinical human liver cancer, both of them were overexpressed. THAP3 positively correlated with OXPHOS gene expression. Together, THAP3 cooperates with SMYD3 to epigenetically upregulate cellular respiration and liver cancer cell proliferation.

Interaction between HTR2A rs3125 and negative life events in suicide attempts among patients with major depressive disorder: a cross-sectional study.

BACKGROUND: Both genetic and environmental factors play crucial roles in the development of major depressive disorder (MDD) and suicide attempts (SA). However, the interaction between both items remains unknown. This study aims to explore the interactions between the genetic variants of the serotonin 2 A receptor (HTR2A) and the nitric oxide synthase 1 (NOS1) and environmental factors in patients who experience MDD and SA. METHODS: A total of 334 patients with MDD and a history of SA (MDD-SA) were recruited alongside 518 patients with MDD with no history of SA (MDD-NSA), and 716 healthy controls (HC). The demographic data and clinical characteristics were collected. Sequenom mass spectrometry was used to detect eight tag-single nucleotide polymorphisms (tagSNPs) in HTR2A (rs1328683, rs17068986, and rs3125) and NOS1 (rs1123425, rs2682826, rs3741476, rs527590, and rs7959232). Generalized multifactor dimensionality reduction (GMDR) was used to analyze the gene-environment interactions. RESULTS: Four tagSNPs (rs17068986, rs3125, rs527590, and rs7959232) exhibited significant differences between the three groups. However, these differences were not significant between the MDD-SA and MDD-NSA groups after Bonferroni correction. A logistic regression analysis revealed that negative life events (OR = 1.495, 95%CI: 1.071-2.087, P = 0.018), self-guilt (OR = 2.263, 95%CI: 1.515-3.379, P < 0.001), and negative cognition (OR = 2.252, 95%CI: 1.264-4.013, P = 0.006) were all independently associated with SA in patients with MDD. Furthermore, GMDR analysis indicated a significant interaction between HTR2A rs3125 and negative life events. Negative life events in conjunction with the HTR2A rs3125 CG + GG genotype were associated with a higher SA risk in patients with MDD when compared to the absence of negative life events in conjunction with the CC genotype (OR = 2.547, 95% CI: 1.264-5.131, P = 0.009). CONCLUSION: Several risk factors and a potential interaction between HTR2A rs3125 and negative life events were identified in patients with SA and MDD. The observed interaction likely modulates the risk of MDD and SA, shedding light on the pathogenesis of SA in patients with MDD.

SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression.

Mitochondria are cellular powerhouses that generate energy through the electron transport chain (ETC). The mitochondrial genome (mtDNA) encodes essential ETC proteins in a compartmentalized manner, however, the mechanism underlying metabolic regulation of mtDNA function remains unknown. Here, we report that expression of tricarboxylic acid cycle enzyme succinate-CoA ligase SUCLG1 strongly correlates with ETC genes across various TCGA cancer transcriptomes. Mechanistically, SUCLG1 restricts succinyl-CoA levels to suppress the succinylation of mitochondrial RNA polymerase (POLRMT). Lysine 622 succinylation disrupts the interaction of POLRMT with mtDNA and mitochondrial transcription factors. SUCLG1-mediated POLRMT hyposuccinylation maintains mtDNA transcription, mitochondrial biogenesis, and leukemia cell proliferation. Specifically, leukemia-promoting FMS-like tyrosine kinase 3 (FLT3) mutations modulate nuclear transcription and upregulate SUCLG1 expression to reduce succinyl-CoA and POLRMT succinylation, resulting in enhanced mitobiogenesis. In line, genetic depletion of POLRMT or SUCLG1 significantly delays disease progression in mouse and humanized leukemia models. Importantly, succinyl-CoA level and POLRMT succinylation are downregulated in FLT3-mutated clinical leukemia samples, linking enhanced mitobiogenesis to cancer progression. Together, SUCLG1 connects succinyl-CoA with POLRMT succinylation to modulate mitochondrial function and cancer development.

Heat shock induces HuR-dependent MKP-1 posttranslational regulation through the p38 MAPK signaling cascade.

Previous studies demonstrated that phosphatases play a pivotal role in modulating inflammation-associated signal transduction, particularly in the context of heat shock, where Mitogen-Activated Protein Kinase Phosphatase-1 (MKP-1) appears to have a central role. Recently, Human Antigen R (HuR) has also been identified as a factor that enhances stress-response protein MKP-1 levels. Consequently, we have directed our interest towards elucidating the mechanisms by which heat shock induces MKP-1 mRNA stabilization, dependent on HuR via the p38 MAPK Signaling Cascade. In this study, we subjected Mouse Embryonic Fibroblast (Mef) cells to heat shock treatment, resulting in a potent stabilization MKP-1 mRNA. The RNA-binding protein HuR, known to influence mRNA, was observed to bind to the MKP-1 AU-rich 3 ´untranslated region. Transfection of p38 wild-type Mef cells with a flag-HuR plasmid resulted in a significant increase in MKP-1 mRNA stability. Interestingly, transfection of the siRNA for HuR into Mef cells resulted in diminished MKP-1 mRNA stability following heat shock, inhibition of p38 MAPK activity effectively curtailed heat shock-mediated MKP-1 mRNA stability. Immunofluorescence analyses further revealed that the translocation of HuR was contingent on p38 MAPK Signaling Cascade. Collectively, these findings underscore the regulatory role of heat shock in MKP-1 gene expression at posttranscriptional levels. The mechanisms underlying the observed increased MKP-1 mRNA stability are shown to be partially dependent on HuR through the p38 MAPK Signaling Cascade.

Diurnal switches in diazotrophic lifestyle increase nitrogen contribution to cereals.

Uncoupling of biological nitrogen fixation from ammonia assimilation is a prerequisite step for engineering ammonia excretion and improvement of plant-associative nitrogen fixation. In this study, we have identified an amino acid substitution in glutamine synthetase, which provides temperature sensitive biosynthesis of glutamine, the intracellular metabolic signal of the nitrogen status. As a consequence, negative feedback regulation of genes and enzymes subject to nitrogen regulation, including nitrogenase is thermally controlled, enabling ammonia excretion in engineered Escherichia coli and the plant-associated diazotroph Klebsiella oxytoca at 23 °C, but not at 30 °C. We demonstrate that this temperature profile can be exploited to provide diurnal oscillation of ammonia excretion when variant bacteria are used to inoculate cereal crops. We provide evidence that diurnal temperature variation improves nitrogen donation to the plant because the inoculant bacteria have the ability to recover and proliferate at higher temperatures during the daytime.

Identification of cpxS mutational resistome in Pseudomonas aeruginosa.

Pseudomonas aeruginosa easily produces drug-resistant mutants. A large number of mutational resistome genes exist in the genome of P. aeruginosa. In this study, whole genome sequencing analysis of a multidrug-resistant P. aeruginosa strain isolated by in vitro antibiotic treatment showed a mutation in the cpxS gene. Random mutagenesis of cpxS was conducted and introduced into the PA14ΔcpxS strain. Numerous CpxS mutants, including 14 different single amino acid substitutions, were identified, which led to reduced antibiotic susceptibility. Moreover, some of them were also present in the published genomes of P. aeruginosa isolates. Around cpxS, a gene coding for a putative sensor kinase, the nearest gene coding for a response regulator is cpxR in the genome of P. aeruginosa. Deletion of cpxR restored antibiotic susceptibility in the above cpxS mutant strains. As an extension of our previous work, where the expression of the mexAB-oprM operon is directly activated by CpxR in P. aeruginosa, in this study, we showed that the expression of the mexA promoter was increased in the above cpxS mutant strains in a cpxR-dependent manner, and mexA is prerequisite for the reduced antibiotic susceptibility. Therefore, we propose that the putative sensor kinase CpxS, together with CpxR, comprises a two-component regulatory system regulating the expression of the mexAB-oprM operon in P. aeruginosa. Our work indicates that cpxS, as a novel member of mutational resistome, plays important roles on the development of multidrug resistance in P. aeruginosa.

Synthesis of α-Hydroxyl and α-Amino Pyridinyl Esters via Photoreductive Dual Radical Cross-Coupling.

A method for the synthesis of α-hydroxyl and α-amino pyridinyl esters via photoreductive dual radical cross-coupling catalyzed by the super-organoreductant CBZ6 has been developed. A wide range of 2-pyridinylation and 4-pyridinylation of either α-ketoesters or imine derivatives has been achieved. The applications in the synthesis of pyridinyl amino-hydroxyl acids as well as a new chiral oxazoline ligand have also been accomplished.

Organelle-dependent polyprotein designs enable stoichiometric expression of nitrogen fixation components targeted to mitochondria.

Introducing nitrogen fixation (nif  ) genes into eukaryotic genomes and targeting Nif components to mitochondria or chloroplasts is a promising strategy for engineering nitrogen-fixing plants. A prerequisite for achieving nitrogen fixation in crops is stable and stoichiometric expression of each component in organelles. Previously, we designed a polyprotein-based nitrogenase system depending on Tobacco Etch Virus protease (TEVp) to release functional Nif components from five polyproteins. Although this system satisfies the demand for specific expression ratios of Nif components in Escherichia coli, we encountered issues with TEVp cleavage of polyproteins targeted to yeast mitochondria. To overcome this obstacle, a version of the Nif polyprotein system was constructed by replacing TEVp cleavage sites with minimal peptide sequences, identified by knowledge-based engineering, that are susceptible to cleavage by the endogenous mitochondrial-processing peptidase. This replacement not only further reduces the number of genes required, but also prevents potential precleavage of polyproteins outside the target organelle. This version of the polyprotein-based nitrogenase system achieved levels of nitrogenase activity in E. coli, comparable to those observed with the TEVp-based polyprotein nitrogenase system. When applied to yeast mitochondria, stable and balanced expression of Nif components was realized. This strategy has potential advantages, not only for transferring nitrogen fixation to eukaryotic cells, but also for the engineering of other metabolic pathways that require mitochondrial compartmentalization.

Emerging therapies in cancer metabolism.

Metabolic reprogramming in cancer is not only a biological hallmark but also reveals treatment vulnerabilities. Numerous metabolic molecules have shown promise as treatment targets to impede tumor progression in preclinical studies, with some advancing to clinical trials. However, the intricacy and adaptability of metabolic networks hinder the effectiveness of metabolic therapies. This review summarizes the metabolic targets for cancer treatment and provides an overview of the current status of clinical trials targeting cancer metabolism. Additionally, we decipher crucial factors that limit the efficacy of metabolism-based therapies and propose future directions. With advances in integrating multi-omics, single-cell, and spatial technologies, as well as the ability to track metabolic adaptation more precisely and dynamically, clinicians can personalize metabolic therapies for improved cancer treatment.

Simultaneous determination of multiple constituents, serum composition, and tissue distribution of Qingshen granule using ultra-high performance liquid chromatography-quadrupole-orbitrap high-resolution mass spectrometry.

Qingshen granule, composed of 14 herbal drugs, is primarily used as the assistant therapy for chronic kidney disease. Qingshen granule chemical composition was complex, but its chemical constituents and the pharmacodynamic material basis remain unreported. Ultra-high-performance liquid chromatography (UHPLC)-quadrupole-orbitrap high-resolution mass spectrometry was applied to recognize the chemical constituents of Qingshen granule. The analysis was performed using the ACQUITY UHPLC BEH C18 column (2.1 × 50 mm, 1.7 µm) with acetonitrile-0.1% formic acid as the mobile phase for gradient elution. The data were collected using heated electrospray ionization in positive and negative ion modes. This study successfully applied the UPHLC-quadrupole-orbitrap high-resolution mass spectrometry technique with the Compound Discoverer 3.3 platform to analyze Qingshen granule chemical composition. A total of 127 and 42 chemical components were identified in Qingshen granule in vitro and in vivo, respectively. In the tissue distribution of Qingshen granule, 9, 10, 11, 10, and 18 prototype components were detected in the heart, liver, spleen, lungs, and kidneys, respectively. Qingshen granule chemical constituents were characterized rapidly for the first time in this study, laying a foundation for further research on the substance basis and quality control of Qingshen granule in treating chronic kidney disease.

Enhanced Optical Response of SnS/SnS2 Layered Heterostructure.

The SnS/SnS2 heterostructure was fabricated by the chemical vapor deposition method. The crystal structure properties of SnS2 and SnS were characterized by X-ray diffraction (XRD) pattern, Raman spectroscopy, and field emission scanning electron microscopy (FESEM). The frequency dependence photoconductivity explores its carrier kinetic decay process. The SnS/SnS2 heterostructure shows that the ratio of short time constant decay process reaches 0.729 with a time constant of 4.3 × 10-4 s. The power-dependent photoresponsivity investigates the mechanism of electron-hole pair recombination. The results indicate that the photoresponsivity of the SnS/SnS2 heterostructure has been increased to 7.31 × 10-3 A/W, representing a significant enhancement of approximately 7 times that of the individual films. The results show the optical response speed has been improved by using the SnS/SnS2 heterostructure. These results indicate an application potential of the layered SnS/SnS2 heterostructure for photodetection. This research provides valuable insights into the preparation of the heterostructure composed of SnS and SnS2, and presents an approach for designing high-performance photodetection devices.

Higher frequencies of anemia, vitamin B12 deficiency, and gastric parietal cell antibody positivity in folic acid-deficient Taiwanese male oral submucous fibrosis patients.

Background/purpose: Oral submucous fibrosis (OSF) is a progressive fibrotic oral mucosal disease associated with betel quid chewing. This study evaluated whether Taiwanese male OSF patients with folic acid (FA) deficiency (the serum FA level ≤6 ng/mL, so-called FA-deficient OSF patients) had high frequencies of blood hemoglobin (Hb) and serum iron and vitamin B12 deficiencies, and serum gastric parietal cell antibody (GPCA) positivity. Materials and methods: The blood Hb and serum iron, vitamin B12, FA, and GPCA concentrations in 59 Taiwanese male FA-deficient OSF patients were measured and compared with the corresponding data in 118 age-matched healthy male control subjects. Results: We found that 3 (5.1%), 35 (59.3%), and 7 (11.9%) of the 59 FA-deficient OSF patients had blood Hb (<13 g/dL) and serum vitamin B12 (≤450 pg/mL) deficiencies, and serum GPCA positivity, respectively. Furthermore, 59 FA-deficient OSF patients had significantly higher frequencies of serum vitamin B12 deficiency and serum GPCA positivity than 118 healthy control subjects (all P-values <0.05). Of the 3 anemic FA-deficient OSF patients, one had macrocytic anemia and the other two had thalassemia trait-induced anemia. Conclusion: We conclude that Taiwanese male FA-deficient OSF patients have high frequencies of serum vitamin B12 deficiency and GPCA positivity than healthy control subjects. The vitamin B12 and FA deficiencies in FA-deficient OSF patients are more likely due to OSF symptoms and signs-caused insufficient intake, difficulty in chewing and swallowing, and malabsorption of food fragment-bound vitamin B12 and FA rather than the GPCA positivity in these OSF patients.

LncRNA-PEAK1 promotes neuronal apoptosis after intracerebral hemorrhage by miR-466i-5p/caspase 8 axis.

Background: At present, the treatment of intracerebral hemorrhage (ICH)-induced secondary brain injury (ISB) is limited, and the curative effect is not good. Long noncoding RNAs (lncRNAs) have been reported to play a role in ISB after ICH. We preliminarily monitored the induction effect of lncRNA-pseudopodium-enriched atypical kinase 1 (PEAK1) on neuronal cell apoptosis after ICH through our previous study and further experimental verification. However, the specific role and mechanism of lncRNA-PEAK1 in neuronal cell apoptosis after ICH have not been reported. Methods: ICH cell models were established with hemin. Pro-inflammatory cytokines, cell proliferation, and apoptosis were evaluated by enzyme-linked immunosorbent assay, Cell Counting Kit-8 assay, flow cytometry, and terminal deoxynucleotidyl transferase dUTP nick end labeling, respectively. Moreover, lncRNA expression associated with apoptosis was confirmed by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The biological functions of lncRNA-PEAK1, miR-466i-5p, and caspase8 were conducted in vitro. Further, we used bioinformatics, a dual-luciferase reporter assay, and rescue experiments to understand the mechanisms of competitive endogenous RNAs. Results: qRT-PCR revealed that lncRNA-PEAK1 was markedly upregulated in ICH cell models. LncRNA-PEAK1 knockdown decreased the interleukin-1ß and tumor necrosis factor-alpha levels, promoted cell proliferation, weakened cell apoptosis, and downregulated the key molecular protein levels involved in the cell apoptosis pathway. Bioinformatics analysis and dual-luciferase reporter assay revealed that lncRNA bound to miR-466i-5p, and caspase 8 was a target of miR-466i-5p. The mechanistic analysis demonstrated that lncRNA-PEAK1/miR-466i-5p promoted neuronal cell apoptosis by activating the apoptosis pathway through caspase8 after ICH. Conclusion: Collectively, our investigation identified that the lncRNA-PEAK1/miR-446i-5p/caspase8 axis is closely related to neuronal cell apoptosis after ICH. Additionally, lncRNA-PEAK1 may be a potential target for ICH intervention.

The functional change of the P2X7R containing the Ala348 to Thr polymorphism is associated with the pathogenesis of gout.

Our previous study has shown that ATP action on P2X7R could be the second signal to induce the onset of gouty arthritis. However, the functional changes of P2X7R single nucleotide polymorphisms (SNPs) on the effects of ATP-P2X7R-IL-1ß signaling pathway and uric acid remained unknown. We aimed to investigate the association between the functional change of P2X7R containing the Ala348 to Thr polymorphisms (rs1718119) and the pathogenesis of gout. First, 270 gout patients and 70 hyperuricemic patients (without gout attack history in recent 5 years) were recruited for genotyping. In addition, the changes of ATP-induced pore formation were assessed in HEK-293T cells overexpressing different mutants in P2RX7, and the effects on P2X7R-NLRP3-IL-1ß pathway activation were explored in P2RX7 overexpression THP-1 cells. The risk allele for gout was A at rs1718119, and the AA and AG genotypes exhibited a higher risk of gout. Furthermore, Ala348 to Thr mutants increased P2X7-dependent ethidium+ bromide uptake, upregulated IL-1ß and NLRP3 levels as compared to the wild-type. We suggest that genetic polymorphisms of P2X7R containing the Ala348 to Thr are associated with the increased risk of gout, showing an enhanced gain-of-function effect on the development of this disease.

Vapor-Induced Pore-Forming Atmospheric-Plasma-Sprayed Zinc-, Strontium-, and Magnesium-Doped Hydroxyapatite Coatings on Titanium Implants Enhance New Bone Formation-An In Vivo and In Vitro Investigation.

OBJECTIVES: Titanium implants are regarded as a promising treatment modality for replacing missing teeth. Osteointegration and antibacterial properties are both desirable characteristics for titanium dental implants. The aim of this study was to create zinc (Zn)-, strontium (Sr)-, and magnesium (Mg)-multidoped hydroxyapatite (HAp) porous coatings, including HAp, Zn-doped HAp, and Zn-Sr-Mg-doped HAp, on titanium discs and implants using the vapor-induced pore-forming atmospheric plasma spraying (VIPF-APS) technique. METHODS: The mRNA and protein levels of osteogenesis-associated genes such as collagen type I alpha 1 chain (COL1A1), decorin (DCN), osteoprotegerin (TNFRSF11B), and osteopontin (SPP1) were examined in human embryonic palatal mesenchymal cells. The antibacterial effects against periodontal bacteria, including Porphyromonas gingivalis and Prevotella nigrescens, were investigated. In addition, a rat animal model was used to evaluate new bone formation via histologic examination and micro-computed tomography (CT). RESULTS: The ZnSrMg-HAp group was the most effective at inducing mRNA and protein expression of TNFRSF11B and SPP1 after 7 days of incubation, and TNFRSF11B and DCN after 11 days of incubation. In addition, both the ZnSrMg-HAp and Zn-HAp groups were effective against P. gingivalis and P. nigrescens. Furthermore, according to both in vitro studies and histologic findings, the ZnSrMg-HAp group exhibited the most prominent osteogenesis and concentrated bone growth along implant threads. SIGNIFICANCE: A porous ZnSrMg-HAp coating using VIPF-APS could serve as a novel technique for coating titanium implant surfaces and preventing further bacterial infection.

Factors affecting the accuracy of anti-BRAF V600E immunohistochemistry results in ameloblastomas.

BACKGROUND: There are still some controversies about the results of anti-BRAF V600E-specific antibody immunohistochemistry in ameloblastomas. This study aimed to examine the accuracy of V600E-specific antibody immunohistochemistry in detection of BRAF V600E mutation in ameloblastoma tissue sections of different ages. METHODS: The BRAF V600E status of 64 ameloblastoma specimens was assessed using both Sanger sequencing and V600E-specific antibody immunohistochemistry, and the sensitivity, specificity, positive predictive value, and negative predictive value were calculated. The difference in V600E-specific antibody immunohistochemistry staining intensity among the three groups of ameloblastoma tissue blocks of different ages was evaluated by chi-square test. The consistency between V600E-specific antibody immunohistochemistry and DNA sequencing results and the V600E-specific antibody immunohistochemistry staining intensity of 15 paired newly-cut and 3-month storage sections of the same 15 ameloblastomas were also compared. RESULTS: For detection of BRAF V600E mutation, the V600E-specific antibody immunohistochemistry had high sensitivity (98.21% 55/56), specificity (87.5% 7/8), positive predictive value (98.21% 55/56), and negative predictive value (87.5% 7/8). Heterogeneity of the staining intensity was observed in the same tissue section, but all or none expression pattern was noticed in the solid tumor nests. The storage time of paraffin tissue blocks ranging from 2 to 14 years did not affect the V600E-specific antibody-positive staining intensity. However, the three-month storage sections showed a significant diminishment of V600E-specific antibody-positive staining signals. CONCLUSIONS: The BRAF V600E-specific antibody immunohistochemistry is suitable for routine detection of BRAF V600E mutation in ameloblastomas. The all or none expression pattern suggests the BRAF V600E mutation may be an early event in the pathogenesis of ameloblastoma.

High frequencies of vitamin B12 and folic acid deficiencies and hyperhomocysteinemia in Taiwanese male patients with oral submucous fibrosis.

Background: /purpose: Oral submucous fibrosis (OSF) is a betel quid chewing-caused oral mucosal disease with progressive collagen deposition. This study evaluated whether Taiwanese male OSF patients had high frequencies of vitamin B12 and folic acid deficiencies, hyperhomocysteinemia, and serum gastric parietal cell antibody (GPCA) positivity. Materials and methods: The blood hemoglobin (Hb), serum iron, vitamin B12, folic acid, homocysteine, and GPCA concentrations in 62 male OSF patients were measured and compared with the corresponding data in 124 age-matched male healthy control subjects. Results: We found that 5 (8.1%), 12 (19.4%), 32 (51.6%), 31 (50.0%), 22 (35.5%), and 6 (9.7%) of the 62 male OSF patients had Hb (<13 g/dL), iron (≤70 µg/dL), vitamin B12 (≤450 pg/mL), and folic acid (≤6 ng/mL) deficiencies, hyperhomocysteinemia (>12 µM), and serum GPCA positivity, respectively. Furthermore, OSF patients had significantly higher frequencies of Hb (P = 0.006), vitamin B12 (P < 0.001), and folic acid (P < 0.001) deficiencies, hyperhomocysteinemia (P < 0.001), and serum GPCA positivity (P = 0.030) than 124 healthy control subjects. Of the 22 OSF patients with hyperhomocysteinemia, 4 had vitamin B12 deficiency only, 7 had folic acid deficiency only, and 11 had both vitamin B12 and folic acid deficiencies. Conclusion: We conclude that Taiwanese male OSF patients have high frequencies of vitamin B12 and folic acid deficiencies, hyperhomocysteinemia, and serum GPCA positivity. The hyperhomocysteinemia in our OSF patients is predominantly due to deficiencies of either vitamin B12 or folic acid or both.

Higher frequencies of anemia, hematinic deficiencies, and gastric parietal cell antibody positivity in vitamin B12-deficient Taiwanese male oral submucous fibrosis patients.

Abstract Background/purpose: Oral submucous fibrosis (OSF) is a progressive fibrotic oral mucosal disease associated with betel quid chewing. This study evaluated whether Taiwanese male OSF patients with vitamin B12 deficiency (the serum vitamin B12 level ≤ 450 pg/mL, B12-deficient OSF patients) had high frequencies of blood hemoglobin (Hb) and serum iron and folic acid deficiencies, and serum gastric parietal cell antibody (GPCA) positivity. Materials and methods: The blood Hb and serum iron, vitamin B12, folic acid, and GPCA concentrations in 66 Taiwanese male B12-deficient OSF patients were measured and compared with the corresponding data in 132 age-matched healthy male control subjects. Results: We found that 6 (9.1%), 19 (28.8%), 35 (53.0%), and 9 (13.6%) of the 66 B12-deficient OSF patients had blood Hb (<13 g/dL) and serum iron (≤70 µg/dL), and folic acid (≤6 ng/mL) deficiencies, and serum GPCA positivity, respectively. Furthermore, 66 OSF patients had significantly higher frequencies of blood Hb and serum iron and folic acid deficiencies, and serum GPCA positivity than 132 healthy control subjects (all P-values < 0.05). Of the 6 anemic B12-deficient OSF patients, one had macrocytic anemia, two normocytic anemia, and three thalassemia trait-induced anemia. Conclusion: Taiwanese male B12-deficient OSF patients have high frequencies of blood Hb, serum iron and folic acid deficiencies, and serum GPCA positivity. The anemia and hematinic deficiencies in B12-deficient OSF patients are likely due to OSF symptoms and signs-caused insufficient intake, poor chewing, and malabsorption of hematinic elements from ingested food stuffs rather than the GPCA positivity.

Ferroptosis heterogeneity in triple-negative breast cancer reveals an innovative immunotherapy combination strategy.

Treatment of triple-negative breast cancer (TNBC) remains challenging. Deciphering the orchestration of metabolic pathways in regulating ferroptosis will provide new insights into TNBC therapeutic strategies. Here, we integrated the multiomics data of our large TNBC cohort (n = 465) to develop the ferroptosis atlas. We discovered that TNBCs had heterogeneous phenotypes in ferroptosis-related metabolites and metabolic pathways. The luminal androgen receptor (LAR) subtype of TNBC was characterized by the upregulation of oxidized phosphatidylethanolamines and glutathione metabolism (especially GPX4), which allowed the utilization of GPX4 inhibitors to induce ferroptosis. Furthermore, we verified that GPX4 inhibition not only induced tumor ferroptosis but also enhanced antitumor immunity. The combination of GPX4 inhibitors and anti-PD1 possessed greater therapeutic efficacy than monotherapy. Clinically, higher GPX4 expression correlated with lower cytolytic scores and worse prognosis in immunotherapy cohorts. Collectively, this study demonstrated the ferroptosis landscape of TNBC and revealed an innovative immunotherapy combination strategy for refractory LAR tumors.