In situ turning defects of exfoliated Ti3C2 MXene into Fenton-like catalytic active sites.

Controllable in situ formation of nanoclusters with discrete active sites is highly desirable in heterogeneous catalysis. Herein, a titanium oxide-based Fenton-like catalyst is constructed using exfoliated Ti3C2 MXene as a template. Theoretical calculations reveal that a redox reaction between the surface Ti-deficit vacancies of the exfoliated Ti3C2 MXene and H2O2 molecules facilitates the in situ conversion of surface defects into titanium oxide nanoclusters anchoring on amorphous carbon (TiOx@C). The presence of mixed-valence Tiδ+ (δ = 0, 2, 3, and 4) within TiOx@C is confirmed by X-ray photoelectron spectroscopy (XPS) and X-ray absorption fine structure (XAFS) characterizations. The abundant surface defects within TiOx@C effectively promote the generation of reactive oxygen species (ROS) leading to superior and stable Fenton-like catalytic degradation of atrazine, a typical agricultural herbicide. Such an in situ construction of Fenton-like catalysts through defect engineering also applies to other MXene family materials, such as V2C and Nb2C.

Structure and biochemical characterization of l-2-hydroxyglutarate dehydrogenase and its role in the pathogenesis of l-2-hydroxyglutaric aciduria.

l-2-hydroxyglutarate dehydrogenase (L2HGDH) is a mitochondrial membrane-associated metabolic enzyme, which catalyzes the oxidation of l-2-hydroxyglutarate (l-2-HG) to 2-oxoglutarate (2-OG). Mutations in human L2HGDH lead to abnormal accumulation of l-2-HG, which causes a neurometabolic disorder named l-2-hydroxyglutaric aciduria (l-2-HGA). Here, we report the crystal structures of Drosophila melanogaster L2HGDH (dmL2HGDH) in FAD-bound form and in complex with FAD and 2-OG and show that dmL2HGDH exhibits high activity and substrate specificity for l-2-HG. dmL2HGDH consists of an FAD-binding domain and a substrate-binding domain, and the active site is located at the interface of the two domains with 2-OG binding to the re-face of the isoalloxazine moiety of FAD. Mutagenesis and activity assay confirmed the functional roles of key residues involved in the substrate binding and catalytic reaction and showed that most of the mutations of dmL2HGDH equivalent to l-2-HGA-associated mutations of human L2HGDH led to complete loss of the activity. The structural and biochemical data together reveal the molecular basis for the substrate specificity and catalytic mechanism of L2HGDH and provide insights into the functional roles of human L2HGDH mutations in the pathogeneses of l-2-HGA.

Dynamic reversibility of α-synuclein serine-129 phosphorylation is impaired in synucleinopathy models.

α-Synuclein phosphorylation at serine-129 (pS129) is a widely used surrogate marker of pathology in Parkinson's disease and other synucleinopathies. However, we recently demonstrated that phosphorylation of S129 is also a physiological activator of synaptic transmission. In a feed-forward fashion, neuronal activity triggers reversible pS129. Here, we show that Parkinson's disease-linked missense mutations in SNCA impact activity-dependent pS129. Under basal conditions, cytosol-enriched A30P, H50Q, and G51D mutant forms of α-synuclein exhibit reduced pS129 levels in rat primary cortical neurons. A53T pS129 levels are similar to wild-type, and E46K pS129 levels are higher. A30P and E46K mutants show impaired reversibility of pS129 after stimulation. For the engineered profoundly membrane-associated α-synuclein mutant "3K" (E35K + E46K + E61K), de-phosphorylation was virtually absent after blocking stimulation, implying that reversible pS129 is severely compromised. Importantly, pS129 excess resulting from proteasome inhibition is also associated with reduced reversibility by neuronal inhibition, kinase inhibition, or phosphatase activation. Our findings suggest that perturbed pS129 dynamics are probably a shared characteristic of pathology-associated α-synuclein, with possible implications for synucleinopathy treatment and diagnosis.

Celastrol alleviates atopic dermatitis by regulating Ezrin-mediated mitochondrial fission and fusion.

Celastrol, a bioactive molecule extracted from the plant Tripterygium wilfordii Hook F., possesses anti-inflammatory, anti-obesity and anti-tumour properties. Despite its efficacy in improving erythema and scaling in psoriatic mice, the specific therapeutic mechanism of celastrol in atopic dermatitis (AD) remains unknown. This study aims to examine the role and mechanism of celastrol in AD using TNF-α-stimulated HaCaT cells and DNCB-induced Balb/c mice as in vitro and in vivo AD models, respectively. Celastrol was found to inhibit the increased epidermal thickness, reduce spleen and lymph node weights, attenuate inflammatory cell infiltration and mast cell degranulation and decrease thymic stromal lymphopoietin (TSLP) as well as various inflammatory factors (IL-4, IL-13, TNF-α, IL-5, IL-31, IL-33, IgE, TSLP, IL-17, IL-23, IL-1ß, CCL11 and CCL17) in AD mice. Additionally, celastrol inhibited Ezrin phosphorylation at Thr567, restored mitochondrial network structure, promoted translocation of Drp1 to the cytoplasm and reduced TNF-α-induced cellular reactive oxygen species (ROS), mitochondrial ROS (mtROS) and mitochondrial membrane potential (MMP) production. Interestingly, Mdivi-1 (a mitochondrial fission inhibitor) and Ezrin-specific siRNAs lowered inflammatory factor levels and restored mitochondrial reticular formation, as well as ROS, mtROS and MMP production. Co-immunoprecipitation revealed that Ezrin interacted with Drp1. Knocking down Ezrin reduced mitochondrial fission protein Drp1 phosphorylation and Fis1 expression while increasing the expression of fusion proteins Mfn1 and Mfn2. The regulation of mitochondrial fission and fusion by Ezrin was confirmed. Overall, celastrol may alleviate AD by regulating Ezrin-mediated mitochondrial fission and fusion, which may become a novel therapeutic reagent for alleviating AD.

Multiconfigurational Character of Repulsive A2Σg+ State Leaves Strong Signature in the Photodissociation Spectrum of Zn2.

For the excitation to a repulsive state of a diatomic molecule, one expects a single broad peak in the photodissociation spectrum. For Zn2+, however, two peaks for the spin- and symmetry-allowed A2Σg+ ← X2Σu+ transition are observed. A detailed quantum-chemical analysis reveals pronounced multiconfigurational character of the A2Σg+ state. The σg(4s)2σg(4p) configuration with bond order 1.5 dominates at short distances, while the repulsive σg(4s)σu*(4s)2 configuration with bond order -0.5 wins over with increasing bond length. The two excited-state configurations contribute with opposite signs to the transition dipole moment, which reaches zero near the equilibrium distance. This local minimum of the oscillator strength is responsible for the pronounced dip in the photodissociation spectrum, which is thus the spectroscopic signature of the multiconfigurational character of the A2Σg+ state.

Methionine redox regulation of actin-interacting proteins primarily governs antioxidative signaling and response to the salvianolic acid B treatment in EA.hy926 cells.

Actin-interacting proteins are important molecules for filament assembly and cytoskeletal signaling within vascular endothelium. Disruption in their interactions causes endothelial pathogenesis through redox imbalance. Actin filament redox regulation remains largely unexplored, in the context of pharmacological treatment. This work focused on the peptidyl methionine (M) redox regulation of actin-interacting proteins, aiming at elucidating its role on governing antioxidative signaling and response. Endothelial EA.hy926 cells were subjected to treatment with salvianolic acid B (Sal B) and tert-butyl-hydroperoxide (tBHP) stimulation. Mass spectrometry was employed to characterize redox status of proteins, including actin, myosin-9, kelch-like erythroid-derived cap-n-collar homology-associated protein 1 (Keap1), plastin-3, prelamin-A/C and vimentin. The protein redox landscape revealed distinct stoichiometric ratios or reaction site transitions mediated by M sulfoxide reductase and reactive oxygen species. In comparison with effects of tBHP stimulation, Sal B treatment prevented oxidation at actin M325, myosin-9 M1489/1565, Keap1 M120, plastin-3 M592, prelamin-A/C M187/371/540 and vimentin M344. For Keap1, reaction site was transitioned within its scaffolding region to the actin ring. These protein M oxidation regulations contributed to the Sal B cytoprotective effects on actin filament. Additionally, regarding the Keap1 homo-dimerization region, Sal B preventive roles against M120 oxidation acted as a primary signal driver to activate nuclear factor erythroid 2-related factor 2 (Nrf2). Transcriptional splicing of non-POU domain-containing octamer-binding protein was validated during the Sal B-mediated overexpression of NAD(P)H dehydrogenase [quinone] 1. This molecular redox regulation of actin-interacting proteins provided valuable insights into the phenolic structures of Sal B analogs, showing potential antioxidative effects on vascular endothelium.

From Wilson's Disease to Neurodevelopmental Disorder with Involuntary Movements, Different Genetic Interpretations in a Female Patient.

BACKGROUND: A 19-year-old female patient presented at 2 years of age with dysarthria, incoherent speech, and unsteady ambulation. She is prone to leaning backward when walking and has involuntary movements of the whole body. Besides, she has poor numeracy skills. She has been diagnosed with Wilson's disease (WD) in China and Japan. OBJECTIVE: The objective of this study was to further clarify the diagnosis of this patient. METHODS: The patient and her parents were detected with whole-exome sequencing. RESULTS: Based on the genetic test results, genetic analyses, and clinical manifestations, a diagnosis of WD in this patient was ruled out. The patient was eventually diagnosed with neurodevelopmental disorder with involuntary movements. CONCLUSIONS: This study reinterprets the genetic test results of a young female patient and leads to reflections on the genetic diagnostic criteria for WD: the Leipzig score is suitable for the diagnosis of most WD patients, and the genetic testing section of the score is of great diagnostic value. However, in some special cases, the proband and their first-degree relatives should further complete cosegregation analysis to determine the origin of the lesion gene and to verify the reliability of the genetic test. In addition, this study suggests that further improving the scoring rules of the gene testing part of the Leipzig scoring system may be more helpful in achieving an accurate diagnosis of WD. © 2024 International Parkinson and Movement Disorder Society.

Effects of Connectivity Isomerization on Electron Transport Through Thiophene Heterocyclic Molecular Junction.

Connectivity isomerization of the same aromatic molecular core with different substitution positions profoundly affects electron transport pathways and single-molecule conductance. Herein, we designed and synthesized all connectivity isomers of a thiophene (TP) aromatic ring substituted by two dihydrobenzo[b]thiophene (BT) groups with ethynyl spacers (m,n-TP-BT, (m,n = 2,3; 2,4; 2,5; 3,4)), to systematically probe how connectivity contributes to single-molecule conductance. Single-molecule conductance measurements using a scanning tunneling microscopy break junction (STM-BJ) technique show ∼12-fold change in conductance values, which follow an order of 10-4.83 G0 (2,4-TP-BT) < 10-4.78 G0 (3,4-TP-BT) < 10-4.06 G0 (2,3-TP-BT) < 10-3.75 G0 (2,5-TP-BT). Electronic structure analysis and theoretical simulations show that the connectivity isomerization significantly changes electron delocalization and HOMO-LUMO energy gaps. Moreover, the connectivity-dependent molecular structures lead to different quantum interference (QI) effects in electron transport, e.g., a strong destructive QI near E = EF leads the smallest conductance value for 2,4-TP-BT. This work proves a clear relationship between the connectivity isomerization and single-molecule conductance of thiophene heterocyclic molecular junctions for the future design of molecular devices.

Osthole exhibits the remedial potential for polycystic ovary syndrome mice through Nrf2-Foxo1-GSH-NF-κB pathway.

Polycystic ovary syndrome (PCOS) is the primary cause of female infertility with a lack of universal therapeutic regimen. Although osthole exhibits numerous pharmacological activities in treating various diseases, its therapeutic effect on PCOS is undiscovered. The present study found that application of osthole improved the symptoms of PCOS mice through preventing ovarian granulosa cells (GCs) production of more estrogen and alleviating the liberation of pro-inflammatory cytokine interleukin (IL)-1ß, IL-6, and tumor necrosis factor alpha. Meanwhile, osthole enhanced ovarian antioxidant capacity and alleviated intracellular reactive oxygen species (ROS) accumulation with a concurrent attenuation for oxidative stress, while intervention of antioxidant enzymic activity and glutathione (GSH) synthesis neutralized the salvation of osthole on GCs secretory disorder and chronic inflammation. Further analysis revealed that osthole restored the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and forkhead box O 1 (Foxo1) whose repression antagonized the amelioration of osthole on the insufficiency of antioxidant capacity and accumulation of ROS. Moreover, Nrf2 served as an intermedium to mediate the regulation of osthole on Foxo1. Additionally, osthole restricted the phosphorylation of IκBα and nuclear factor kappa B (NF-κB) subunit p65 by DHEA and weakened the transcriptional activity of NF-κB, but this effectiveness was abrogated by the obstruction of Nrf2 and Foxo1, whereas adjunction of GSH renewed the redemptive effect of osthole on NF-κB whose activation caused an invalidation of osthole in rescuing the aberration of GCs secretory function and inflammation response. Collectively, osthole might relieve the symptoms of PCOS mice via Nrf2-Foxo1-GSH-NF-κB pathway.

Evaluation of the safety, immunogenicity and protective effect of an attenuated Pseudomonas plecoglossicida strain ΔgacS as the live vaccine for the large yellow croaker (Larimichthys crocea).

Pseudomonas plecoglossicida is one of most important pathogenic bacterial species in large yellow croaker and several other commercially valuable fish species. In our previous study, a GacS deficient mutant (ΔgacS) was constructed and its virulence showed substantially attenuated. In present study, the safety, immunogenicity and protective effect of the ΔgacS were evaluated in large yellow croaker as a live-attenuated vaccine candidate. It was shown that the ΔgacS strain exhibited good safety to large yellow croaker and there was no mortality or clinical symptoms observed in all fish that infected by ΔgacS strain with the doses range from 2 × 105～107 CFU per fish via intraperitoneal injection (IP) or immersion (IM), and almost all bacteria were cleaned up in the spleen of the fish at 14-day post infection. Specific antibodies could be detected at 7-day and 14-day post infection by direct agglutination method, and the valences of antibodies and bactericidal activities of the serum were significant increased with vaccination doses and vaccination time. Moreover, the expressions of some molecules and cytokines involved in specific immune responses were detected in the ΔgacS strain immunization group and control group. After challenged by the wild-type (WT) strain XSDHY-P, the relative percentage survival (RPS) showed highly correlated with the immunized dosage regardless of vaccination methods. It showed that the RPS of the IP groups were 39.47 %, 57.89 %, 71.05 % with the immune dosage in a descending order, respectively, and the RPS of the IM groups were 26.31 %, 36.84 %, 76.31 % with the immune dosage in a descending order, respectively. In summary, the ΔgacS strain exhibited safety and good protective effect to large yellow croaker and was a potential live vaccine candidate.

Symmetry reduction induced by argon tagging gives access to low-lying excited states of FeH+ in the overtone region of the Fe-H stretching mode.

Iron is the most abundant transition metal in the interstellar medium (ISM), and is thought to be involved in a variety of astrochemical processes. Here, we present the infrared multiple photon dissociation (IRMPD) spectra of Ar1,2FeH+ and their deuterated isotopologues in the region of 2240-14 000 cm-1. The Fe-H overtone stretching mode in ArFeH+ and Ar2FeH+ is observed at 3636 ± 28 cm-1 and 3659 ± 13 cm-1, respectively. Deuteration shifts these bands to 2618 ± 31 cm-1 and 2650 ± 14 cm-1 in ArFeD+ and Ar2FeD+, respectively. Additionally, the spectra of Ar2FeH+ and Ar2FeD+ feature broad transitions at ∼2200-4000 cm-1 and ∼4500-6500 cm-1. We assign these bands to electronic transitions from the thermally populated X5A2/X'5A1 ground state manifold into the A'5B2 and B5A1 states, which we model with multi-reference quantum chemical calculations including spin-orbit coupling. The calculations show that these transitions are symmetry forbidden in FeH+ and in the equilibrium geometry of ArFeH+/ArFeD+, while the zero-point oscillation of the bending mode of the triatomic molecule leads to some oscillator strength. Upon addition of the second argon atom, the transitions become weakly allowed in the equilibrium geometry of Ar2FeH+/Ar2FeD+ due to symmetry reduction from C∞v to C2v.

Mechanism of CO2 in promoting the hydrogenation of levulinic acid to γ-valerolactone catalyzed by RuCl3 in aqueous solution.

A Ru-containing complex shows good catalytic performance toward the hydrogenation of levulinic acid (LA) to γ-valerolactone (GVL) with the assistance of organic base ligands (OBLs) and CO2. Herein, we report the competitive mechanisms for the hydrogenation of LA to GVL, 4-oxopentanal (OT), and 2-methyltetrahydro-2,5-furandiol (MFD) with HCOOH or H2 as the H source catalyzed by RuCl3 in aqueous solution at the M06/def2-TZVP, 6-311++G(d,p) theoretical level. Kinetically, the hydrodehydration of LA to GVL is predominant, with OT and MFD as side products. With HCOOH as the H source, initially, the OBL (triethylamine, pyridine, or triphenylphosphine) is responsible for capturing H+ from HCOOH, leading to HCOO- and [HL]+. Next, the Ru3+ site is in charge of sieving H- from HCOO-, yielding [RuH]2+ hydride and CO2. Alternatively, with H2 as the H source, the OBL stimulates the heterolysis of H-H bond with the aid of Ru3+ active species, producing [RuH]2+ and [HL]+. Toward the [RuH]2+ formation, H2 as the H source exhibits higher activity than HCOOH as the H source in the presence of an OBL. Thereafter, H- in [RuH]2+ gets transferred to the unsaturated C site of ketone carbonyl in LA. Afterwards, the Ru3+ active species is capable of cleaving the C-OH bond in 4-hydroxyvaleric acid, yielding [RuOH]2+ hydroxide and GVL. Subsequently, CO2 promotes Ru-OH bond cleavage in [RuOH]2+, forming HCO3- and regenerating the Ru3+-active species owing to its Lewis acidity. Lastly, between the resultant HCO3- and [HL]+, a neutralization reaction occurs, generating H2O, CO2, and OBLs. Thus, the present study provides insights into the promotive roles of additives such as CO2 and OBLs in Ru-catalyzed hydrogenation.

Theoretical comparison of fructose with methylglucoside for the production of formate and levulinate catalyzed by Brønsted acids in a methanol solution.

For the conversion of fructose/methylglucoside (MG) into both methyl formate (MF) and methyl levulinate (MLev), the C-source of formate [HCOO]- remains unclear at the molecular level. Herein, reaction mechanisms catalyzed by [CH3OH2]+ in a methanol solution were theoretically investigated at the PBE0/6-311++G(d,p) level. For the conversion of fructose into MF and MLev, the formate [HCOO]- comes from the C1-atom of fructose, in which the rate-determining step lies in the reaction of 5-hydroxymethylfurfural (HMF) with CH3OH to yield MF and MLev. The reaction of fructose with CH3OH kinetically tends to generate HMF intermediates rather than yield (MF + MLev). When MG is dissolved in a methanol solution, its O2, O3, and O4 atoms are closer to the first layer of the solvent than O1, O5, and O6 atoms. For the dehydration of MG with methanol into MF and MLev, the formate [HCOO]- stems from the dominant C1- and secondary C3-atoms of MG. Kinetically, MG is ready to yield (MF + MLev), whereas fructose can induce the reaction to remain at the HMF intermediate, inhibiting the further conversion of HMF with CH3OH into MF and MLev. If MG isomerizes into fructose, the reaction will be more preferable for yielding HMF rather than (MF + MLev).

Iron Complexes as Potential Carriers of Diffuse Interstellar Bands: The Photodissociation Spectrum of Fe+(H2O) at Optical Wavelengths.

The fullerene ion C60+ is the only carrier of diffuse interstellar bands (DIBs) identified so far. Transition-metal compounds feature electronic transitions in the visible and near-infrared regions, making them potential DIB carriers. Since iron is the most abundant transition metal in the cosmos, we here test this idea with Fe+(H2O). Laboratory spectra were obtained by photodissociation spectroscopy at 80 K. Spectra were modeled with the reflection principle. A high-resolution spectrum of the DIB standard star HD 183143 served as an observational reference. Two broad bands were observed from 4120 to 6800 Å. The 4120-4800 Å band has sharp features emerging from the background, which have the width of DIBs but do not match the band positions of the reference spectrum. Calculations show that the spectrum arises from a d-d transition at the iron center. While no match was found for Fe+(H2O) with known DIBs, the observation of structured bands with line widths typical for DIBs shows that small molecules or molecular ions containing iron are promising candidates for DIB carriers.

Serum cytokines and creatinine/cystatin C ratio as prognostic biomarkers in advanced cancer patients treated with anti-PD-1/PD-L1 therapy.

OBJECTIVE: Immune checkpoint inhibitors (ICIs), specifically targeting the programmed cell death protein-1 or its ligand (PD-1/PD-L1), have been extensively used in the treatment of a spectrum of malignancies, although the predictive biomarkers remain to be elucidated. This study aims to investigate the association between baseline circulating levels of cytokines and the creatinine/cystatin C ratio (CCR) with the treatment outcomes of ICIs in patients with advanced cancer. METHODS: The pre-treatment circulating levels of 10 cytokines (PD-L1, CTLA4, CXCL10, LAG3, HGF, CCL2, MIG, GRANB, IL-18, and IL-6) were measured via automated capillary-based immunoassay platform in the serum of 65 advanced cancer patients treated with anti-PD-1/PD-L1-based systemic therapy and 10 healthy volunteers. The levels of cytokines and CCR were quantified and categorized into high and low groups based on the median value. The associations of serum cytokines and CCR with response to treatment, survival, and immune-related adverse events were assessed. RESULTS: Elevated circulating levels of 6 cytokines (PD-L1, CXCL10, HGF, CCL2, MIG, and IL-6) were observed in cancer patients compared with that in healthy volunteers. The correlation coefficients between cytokines, CCR and nutritional risk index were also calculated. In the cancer cohort (N = 65), low circulating HGF (P = 0.023, P = 0.029), low IL-6 (P = 0.002, P < 0.001), and high CCR (P = 0.031, P = 0.008) were associated with significantly improved progression-free survival (PFS) and overall survival (OS). Multi-variable COX analyses adjusted for clinicopathological factors revealed that low HGF, low IL-6, and high CCR were independent favorable prognostic factors for PFS (P = 0.028, P = 0.010, and P = 0.015, respectively) and OS (P = 0.043, P = 0.003, and P = 0.026, respectively). Grade 2 irAEs occurred more frequently in patients with low levels of circulating CCL2 and LAG3. CONCLUSIONS: Pre-treatment circulating levels of serum IL-6, HGF, and CCR may serve as independent predictive and prognostic biomarkers in advanced cancer patients treated with ICIs-based systemic therapy. These findings might help to identify potential patients who would benefit from these therapies.

A chorea-acanthocytosis patient with novel mutations in the VPS13A gene without acanthocyte.

Chorea-acanthocytosis (ChAc) is a rare clinical genetic disorder of the nervous system, which is characterized by choreiform movement disorder, cognitive decline, and psychiatric disorders. ChAc is mostly diagnosed based on its typical clinical manifestations and the increased number of acanthocytes in peripheral blood smears. Here, we report a patient, who has the characteristic clinical manifestations of ChAc with limb choreiform movements, involuntary lip and tongue bites, seizures, and emotional instability. However, her blood smear was negative for acanthocytes with scanning electron microscopy. We later identified two novel pathogenic mutations in the patient's vacuolar protein sorting homolog 13 A (VPS13A) on chromosome 9q21 by targeted gene sequencing, and she was definitively diagnosed with "ChAc." After treatment with carbamazepine, haloperidol, the patient's symptoms gradually improved. We consider that an acanthocyte negative blood smear cannot rule out ChAC diagnosis, and genetic testing is the "gold standard" for the diagnosis. Through a review of previous research, it is rare for a patient to have a clear diagnosis of ChAc by genetic testing, but whose blood smear is negative for acanthocytes with electron microscopy. In addition, in this report, we discovered two novel pathogenic mutations, which have not been reported previously, and extended the genetic characteristics of ChAc.

Teratoma combined with struma ovarii and sarcomatoid carcinoma: a case report and review of the literature.

This is a rare case of struma ovarii combined with sarcomatoid carcinoma. Because struma ovarii and ovarian sarcomatoid carcinoma have an extremely low incidence, this may be the first case of a combined occurrence of both. Therefore, this report describes its clinical manifestations, diagnosis, and treatment, analyzes the pathogenesis, and summarizes the previous literature in the hope that it can be helpful to other tumor-related medical personnel and provide material support for the formation of guidelines for this disease.

ALDH3A1 upregulation inhibits neutrophils N2 polarization and halts oral cancer growth.

OBJECTIVES: Tumor-associated neutrophils (TANs) are among the most abundant inflammatory cells in tumor microenvironment (TME). Aldehyde dehydrogenase 3A1 (ALDH3A1) is significantly reduced in oral squamous cell carcinoma (OSCC), ALDH3A1 overexpression suppresses tumorigenesis by inhibiting inflammation. This study investigated the relationship and mechanisms underlying the crosstalk between ALDH3A1 and TANs in OSCC. MATERIALS AND METHODS: Immunohistochemistry and immunofluorescence were performed to investigate the abundance of TANs and the expression of ALDH3A1. dHL-60 were induced with tumor-conditioned media and recombinant IL-6/IL-8. The expression of key proteins in PI3K/AKT/NF-κB pathway were detected by RT-PCR and western blot. A xenograft model was utilized to examine the effect of ALDH3A1 on tumorigenicity and polarization of TANs. RESULTS: In patients with OSCC, TANs significantly increased and were associated with a worse prognosis. Additionally, ALDH3A1 negatively correlated with TANs infiltration and especially the N2 phenotype which was the prominent part in OSCC. Furthermore, our study demonstrated that tumor-derived IL-8 drives ALDH3A1-mediated TANs N2 polarization in the TME through PI3K/AKT/NF-κB pathway in vitro and in vivo. CONCLUSION: Our results indicate that TANs can serve as a prognostic biomarker and ALDH3A1 could be a promising therapeutic target for regulating TANs N2 polarization in antitumor therapy.

Effect of neutrophil to lymphocyte ratio on prognosis of elderly patients with severe sepsis combined with diabetes mellitus.

BACKGROUND: To investigate the predictive value of neutrophil-to-lymphocyte ratio (NLR) in the short-term prognosis of elderly patients with severe sepsis combined with diabetes mellitus (DM). METHODS: The clinical data of 162 elderly patients with severe sepsis combined with DM from January 2018 to December 2022 were retrospectively collected. These patients were divided into a survival group (n = 104) and a death group (n = 58) according to 90-day prognosis. The number of neutrophils, lymphocytes, and NLR were compared. The optimal cut-off value for NLR to predict 90-day prognosis in elderly patients with severe sepsis combined with DM was determined using Receiver Operator Characteristic (ROC) curves, and the patients were divided into high and low NLR groups depending on the optimal cut-off value. The Kaplan-Meier method was used to plot the survival curves of the high and low NLR groups. Risk factors for the 90-day death in elderly patients with severe sepsis combined with DM were analyzed by a multivariate cox regression model. RESULTS: There were no significant differences in gender, age, history of hypertension and hyperlipidemia, intensive care unit (ICU) stay, duration of mechanical ventilation, and oxygenation index between the survival group and death group (p > 0.05). However, acute physiological and chronic health evaluation II (APACHE II) scores, and sepsis-related organ failure assessment (SOFA) scores were significantly lower in the survival group compared with the death group (p < 0.05). In the survival group, neutrophils counts and NLR were much lower than those in the death group, while lymphocytes counts were much higher (p < 0.05). ROC curves showed that the optimal cut-off value for NLR to predict 90-day mortality in elderly patients with severe sepsis combined with DM was 3.482. Patients were divided into high NLR and low NLR groups based on whether NLR was ≥ 3.482. In terms of the log-rank test results, patients in the low NLR group had a significantly higher 90-day survival rate than those in the high NLR group (Logrank χ2 = 8.635, p = 0.003). The multivariate cox regression model showed that the length of ICU stay longer than 15 days and NLR ≥ 3.482 were independent risk factors for 90-day prognosis in elderly patients with severe sepsis combined with DM. CONCLUSION: NLR ≥ 3.482 can be used to predict whether poor prognosis occurs in the short term after illness in elderly patients with severe sepsis combined with DM, and has good assessment value.

Early cartilage lesion and 5-year incident joint surgery in knee osteoarthritis patients: a retrospective cohort study.

OBJECTIVE: to investigate the association between cartilage lesion-related features observed in knee osteoarthritis (OA) patients' first MRI examination and incident knee surgery within 5 years. Additionally, to assess the predictive value of these features for the incident knee surgery. METHODS: We identified patients diagnosed with knee OA and treated at our institution between January 2015 and January 2018, and retrieved their baseline clinical data and first MRI examination films from the information system. Next, we proceeded to determine joint space narrowing grade, cartilage lesion size grade, cartilage full-thickness loss grade and cartilage lesion sum score for the medial and lateral compartments, respectively. Generalized linear regression models examined the association of these features with 5-year incident knee surgery. Positive and negative predictive values (PPVs and NPVs) were determined referring to 5-year incident knee surgery. RESULTS: Totally, 878 participants (knees) were found eligible to form the study population. Within the 5 years, surgery was performed on 61 knees. None of the cartilage-related features had been found significantly associated with incident surgery. The results were similar for medial and lateral compartments. The PPVs were low for all the features. CONCLUSIONS: Among symptomatic clinically diagnosed OA knees, cartilage lesions observed in the first MRI examinations were not found to be associated with the occurrence of joint surgery within a 5-year period. All these cartilage-related features appear to have no additional value in predicting 5-year incident joint surgery.