Trigonometric Bundling Disulfide Unit Starship Synergizes More Effectively to Promote Cellular Uptake.

A small molecule disulfide unit technology platform based on dynamic thiol exchange chemistry at the cell membrane has the potential for drug delivery. However, the alteration of the CSSC dihedral angle of the disulfide unit caused by diverse substituents directly affects the effectiveness of this technology platform as well as its own chemical stability. The highly stable open-loop relaxed type disulfide unit plays a limited role in drug delivery due to its low dihedral angle. Here, we have built a novel disulfide unit starship based on the 3,4,5-trihydroxyphenyl skeleton through trigonometric bundling. The intracellular delivery results showed that the trigonometric bundling of the disulfide unit starship effectively promoted cellular uptake without any toxicity, which is far more than 100 times more active than that of equipment with a single disulfide unit in particular. Then, the significant reduction in cell uptake capacity (73-93%) using thiol erasers proves that the trigonometric bundling of the disulfide starship is an endocytosis-independent internalization mechanism via a dynamic covalent disulfide exchange mediated by thiols on the cell surface. Furthermore, analysis of the molecular dynamics simulations demonstrated that trigonometric bundling of the disulfide starship can significantly change the membrane curvature while pushing lipid molecules in multiple directions, resulting in a significant distortion in the membrane structure and excellent membrane permeation performance. In conclusion, the starship system we built fully compensates for the inefficiency deficiencies induced by poor dihedral angles.

Programmed alternating current optimization of Cu-catalyzed C-H bond transformations.

Direct current (DC) electrosynthesis, which has undergone optimization over the past century, plays a pivotal role in a variety of industrial processes. Alternating current (AC) electrosynthesis, characterized by polarity reversal and periodic fluctuations, may be advantageous for multiple chemical reactions, but apparatus, principles, and application scenarios remain underdeveloped. In this work, we introduce a protocol for programmed AC (pAC) electrosynthesis that systematically adjusts currents, frequencies, and duty ratios. The application of representative pAC waveforms facilitates copper-catalyzed carbon-hydrogen bond cleavage in cross-coupling and difunctionalization reactions that exhibit suboptimal performance under DC and chemical oxidation conditions. Moreover, observing catalyst dynamic variation under diverse waveform applications provides mechanistic insight.

From Sea to Science: Coral Aquaculture for Sustainable Anticancer Drug Development.

Marine natural products offer immense potential for drug development, but the limited supply of marine organisms poses a significant challenge. Establishing aquaculture presents a sustainable solution for this challenge by facilitating the mass production of active ingredients while reducing our reliance on wild populations and harm to local environments. To fully utilize aquaculture as a source of biologically active products, a cell-free system was established to target molecular components with protein-modulating activity, including topoisomerase II, HDAC, and tubulin polymerization, using extracts from aquaculture corals. Subsequent in vitro studies were performed, including MTT assays, flow cytometry, confocal microscopy, and Western blotting, along with in vivo xenograft models, to verify the efficacy of the active extracts and further elucidate their cytotoxic mechanisms. Regulatory proteins were clarified using NGS and gene modification techniques. Molecular docking and SwissADME assays were performed to evaluate the drug-likeness and pharmacokinetic and medicinal chemistry-related properties of the small molecules. The extract from Lobophytum crassum (LCE) demonstrated potent broad-spectrum activity, exhibiting significant inhibition of tubulin polymerization, and showed low IC50 values against prostate cancer cells. Flow cytometry and Western blotting assays revealed that LCE induced apoptosis, as evidenced by the increased expression of apoptotic protein-cleaved caspase-3 and the populations of early and late apoptotic cells. In the xenograft tumor experiments, LCE significantly suppressed tumor growth and reduced the tumor volume (PC3: 43.9%; Du145: 49.2%) and weight (PC3: 48.8%; Du145: 7.8%). Additionally, LCE inhibited prostate cancer cell migration, and invasion upregulated the epithelial marker E-cadherin and suppressed EMT-related proteins. Furthermore, LCE effectively attenuated TGF-ß-induced EMT in PC3 and Du145 cells. Bioactivity-guided fractionation and SwissADME validation confirmed that LCE's main component, 13-acetoxysarcocrassolide (13-AC), holds greater potential for the development of anticancer drugs.

Frontoparietal and salience network synchronizations during nonsymbolic magnitude processing predict brain age and mathematical performance in youth.

The development and refinement of functional brain circuits crucial to human cognition is a continuous process that spans from childhood to adulthood. Research increasingly focuses on mapping these evolving configurations, with the aim to identify markers for functional impairments and atypical development. Among human cognitive systems, nonsymbolic magnitude representations serve as a foundational building block for future success in mathematical learning and achievement for individuals. Using task-based frontoparietal (FPN) and salience network (SN) features during nonsymbolic magnitude processing alongside machine learning algorithms, we developed a framework to construct brain age prediction models for participants aged 7-30. Our study revealed differential developmental profiles in the synchronization within and between FPN and SN networks. Specifically, we observed a linear increase in FPN connectivity, concomitant with a decline in SN connectivity across the age span. A nonlinear U-shaped trajectory in the connectivity between the FPN and SN was discerned, revealing reduced FPN-SN synchronization among adolescents compared to both pediatric and adult cohorts. Leveraging the Gradient Boosting machine learning algorithm and nested fivefold stratified cross-validation with independent training datasets, we demonstrated that functional connectivity measures of the FPN and SN nodes predict chronological age, with a correlation coefficient of .727 and a mean absolute error of 2.944 between actual and predicted ages. Notably, connectivity within the FPN emerged as the most contributing feature for age prediction. Critically, a more matured brain age estimate is associated with better arithmetic performance. Our findings shed light on the intricate developmental changes occurring in the neural networks supporting magnitude representations. We emphasize brain age estimation as a potent tool for understanding cognitive development and its relationship to mathematical abilities across the critical developmental period of youth. PRACTITIONER POINTS: This study investigated the prolonged changes in the brain's architecture across childhood, adolescence, and adulthood, with a focus on task-state frontoparietal and salience networks. Distinct developmental pathways were identified: frontoparietal synchronization strengthens consistently throughout development, while salience network connectivity diminishes with age. Furthermore, adolescents show a unique dip in connectivity between these networks. Leveraging advanced machine learning methods, we accurately predicted individuals' ages based on these brain circuits, with a more mature estimated brain age correlating with better math skills.

Interface-driven structural evolution on diltiazem as novel uPAR inhibitors: from in silico design to in vitro evaluation.

The urokinase-type plasminogen activator receptor (uPAR) emerges as a key target for anti-metastasis owing to its pivotal role in facilitating the invasive and migratory processes of cancer cells. Recently, we identified the uPAR-targeting anti-metastatic ability of diltiazem (22), a commonly used antihypertensive agent. Fine-tuning the chemical structures of known hits represents a vital branch of drug development. To develop novel anti-metastatic drugs, we performed an interface-driven structural evolution strategy on 22. The uPAR-targeting and anti-cancer abilities of this antihypertensive drug wereidentified by us recently. Based on in silico strategy, including extensive molecular dynamics (MD) simulations, hierarchical binding free energy predictions, and ADMET profilings, we designed, synthesized, and identified three new diltiazem derivatives (221-8, 221-57, and 221-68) as uPAR inhibitors. Indeed, all of these three derivatives exhibited uPAR-depending inhibitory activity against PC-3 cell line invasion at micromolar level. Particularly, derivatives 221-68 and 221-8 showed enhanced uPAR-dependent inhibitory activity against the tumor cell invasion compared to the original compound. Microsecond timesclae MD simulations demonstrated the optimized moiety of 221-68 and 221-8 forming more comprehensive interactions with the uPAR, highlighting the reasonability of our strategy. This work introduces three novel uPAR inhibitors, which not only pave the way for the development of effective anti-metastatic therapeutics, but also emphasize the efficacy and robustness of an in silico-based lead compound optimization strategy in drug design.

Regulating the vacancies of nitrogen-doped carbon nanohorns for high-performance electromagnetic wave absorption.

Single-walled carbon nanohorns (SWCNHs), which are sealed on one side with a conical cap and can self-aggregate, are aggregates with spherical morphology ranging from 30 to 100 nm and include dahlia, bud, and seed structures. These SWCNHs are suitable for electromagnetic wave absorption (EMWA) due to their conductivity loss. However, conductivity loss, which is part of three primary loss mechanisms, leads to SWCNHs suffering from impedance mismatching and a narrow effective absorption bandwidth (EAB). In this work, the content of vacancy-type defects in "dahlia-like" nitrogen-doped single-walled carbon nanohorns (NSWCNHs) is regulated by dielectric barrier discharge (DBD) plasma with argon to adjust their polarization and impedance matching. The high-energy argon ions from the plasma impact the bonds between the carbon atoms and adsorbed oxygen, leading to the sputtering of oxygen atoms from the surface and resulting in an increase in surface disorder and defect content. Vacancy-type defects improved polarization loss and optimized impedance matching, leading to the satisfactory EMWA performance of NSWCNHs. The NSWCNHs exhibit an outstanding minimum reflection loss (RLmin) of -57.94 dB when subjected to argon DBD treatment for 5 minutes, achieving this remarkable result at a thickness of 1.9 mm. Additionally, the effective absorption bandwidth (EAB) can cover 4.78 GHz after a treatment period of 1 minute. These results suggest that NSWCNHs have great potential as high-efficiency EMWA materials and demonstrate a new approach for designing high-performance EMWA absorbers.

Formation and Fluorescent Mechanism of Multiple Color Emissive Carbon Dots from o-Phenylenediamine.

Carbon dots (CDs) have received considerable attention in many application areas owing to their unique optical properties and potential applications; however, the fluorescent mechanism is an obstacle to their applications. Herein, three-color emissive CDs are prepared from single o-phenylenediamine (oPD) by regulating the ratio of ethanol and dimethylformamide (DMF). Fluorescent mechanism of these CDs is proposed as molecular state fluorescence. Reaction intermediates are identified using liquid chromatrography-mass spectroscopy (LC-MS) and 1H nuclear magnetic resonance (NMR) spectra. 1H-Benzo[d]imidazole (BI), 2,3-diaminophenazine (DAP), and 5,14-dihydroquinoxalino[2,3-b] phenazine (DHQP) are proposed to be the fluorophores of blue, green, and red emissive CDs by comparing their optical properties. As per the LC-MS and 1H-NMR analysis, DHQP with red emission tends to form from DAP and oPD in pure ethanol. By adding DMF, BI formation is enhanced and DHQP formation is suppressed. The prepared CDs exhibit green emission with DAP. When the DMF amount is >50%, BI formation is considerably promoted, resulting in DAP formation being suppressed. BI with blue emission then turns into the fluorophore of CDs. This result provides us an improved understanding of the fluorescent mechanism of oPD-based CDs, which guides us in designing the structure and optical properties of CDs.

Ten-year epidemiology and risk factors of cytomegalovirus infection in hematopoietic stem cell transplantation patients in Taiwan.

BACKGROUND: Cytomegalovirus (CMV) can cause infection and critical diseases in hematopoietic stem cell transplantation (HSCT) recipients. This study aimed to explore the cumulative incidence and risk factors for CMV infection and disease among HSCT recipients in Taiwan. METHODS: This retrospective cohort study using the Taiwan Blood and Marrow Transplantation Registry (TBMTR) included HSCT recipients between 2009 and 2018 in Taiwan. The primary outcome was cumulative incidence of CMV infection or disease at day 100 after HSCT. Secondary outcomes included day 180 cumulative incidence of CMV infection or disease, infection sites, risk factors for CMV infection or disease, survival analysis, and overall survival after CMV infection and disease. RESULTS: There were 4394 HSCT recipients included in the study (2044 auto-HSCT and 2350 allo-HSCT). The cumulative incidence of CMV infection and disease was significantly higher in allo-HSCT than in auto-HSCT patients at day 100 (53.7% vs. 6.0%, P < 0.0001 and 6.1% vs. 0.9%, P < 0.0001). Use of ATG (HR 1.819, p < 0.0001), recipient CMV serostatus positive (HR 2.631, p < 0.0001) and acute GVHD grades ≥ II (HR 1.563, p < 0.0001) were risk factors for CMV infection, while matched donor (HR 0.856, p = 0.0180) and myeloablative conditioning (MAC) (HR 0.674, p < 0.0001) were protective factors. CONCLUSION: The study revealed a significant disparity in terms of the incidence, risk factors, and clinical outcomes of CMV infection and disease between auto and allo-HSCT patients. These findings underscore the importance of considering these factors in the management of HSCT recipients to improve outcomes related to CMV infections.

Mechanistic Investigation into Single-Electron Oxidative Addition of Single-Atom Cu(I)-N4 Site: Revealing the Cu(I)-Cu(II)-Cu(I) Catalytic Cycle in Photochemical Hydrophosphinylation.

Understanding the valency and structural variations of metal centers during reactions is important for mechanistic studies of single-atom catalysis, which could be beneficial for optimizing reactions and designing new protocols. Herein, we precisely developed a single-atom Cu(I)-N4 site catalyst via a photoinduced ligand exchange (PILE) strategy. The low-valent and electron-rich copper species could catalyze hydrophosphinylation via a novel single-electron oxidative addition (OA) pathway under light irradiation, which could considerably decrease the energy barrier compared with the well-known hydrogen atom transfer (HAT) and single electron transfer (SET) processes. The Cu(I)-Cu(II)-Cu(I) catalytic cycle, via single-electron oxidative addition and photoreduction, has been proven by multiple in situ or operando techniques. This catalytic system demonstrates high efficiency and requires room temperature conditions and no additives, which improves the turnover frequency (TOF) to 1507 h-1. In particular, this unique mechanism has broken through the substrate limitation and shows a broad scope for different electronic effects of alkenes and alkynes.

Prognostic mutation signature would serve as a potential prognostic predictor in patients with diffuse large B-cell lymphoma.

The present study aimed to elucidate the prognostic mutation signature (PMS) associated with long-term survival in a diffuse large B-cell lymphoma (DLBCL) cohort. All data including derivation and validation cohorts were retrospectively retrieved from The Cancer Genome Atlas (TCGA) database and whole-exome sequencing (WES) data. The Lasso Cox regression analysis was used to construct the PMS based on WES data, and the PMS was determined using the area under the receiver operating curve (AUC). The predictive performance of eligible PMS was analyzed by time-dependent receiver operating curve (ROC) analyses. After the initial evaluation, a PMS composed of 94 PFS-related genes was constructed. Notably, this constructed PMS accurately predicted the 12-, 36-, and 60-month PFS, with AUC values of 0.982, 0.983, and 0.987, respectively. A higher level of PMS was closely linked to a significantly worse PFS, regardless of the molecular subtype. Further evaluation by forest plot revealed incorporation of international prognostic index or tumor mutational burden into PMS increased the prediction capability for PFS. The drug-gene interaction and pathway exploration revealed the PFS-related genes were associated with DNA damage, TP53, apoptosis, and immune cell functions. In conclusion, this study utilizing a high throughput genetic approach demonstrated that the PMS could serve as a prognostic predictor in DLBCL patients. Furthermore, the identification of the key signaling pathways for disease progression also provides information for further investigation to gain more insight into novel drug-resistant mechanisms.

The effects of restraint stress on ceramide metabolism disorders in the rat liver: the role of CerS6 in hepatocyte injury.

BACKGROUND: Stress is implicated in various pathological conditions leading to liver injury. Existing evidence suggests that excessive stress can induce mitochondrial damage in hepatocytes, yet the underlying mechanism remains unclear. Ceramide synthase 6 (CerS6)-derived C16:0 ceramide is recognised as a lipotoxic substance capable of causing mitochondrial damage. However, the role of CerS6 in stress has received insufficient attention. This study aimed to explore the involvement of CerS6 in stress-induced hepatic damage and its associated mechanisms. METHODS: The rat restraint stress model and a corticosterone (CORT)-induced hepatocyte stress model were employed for in vivo and in vitro experimental analyses, respectively. Changes in mitochondrial damage and ceramide metabolism in hepatocytes induced by stress were evaluated. The impact of CORT on mitochondrial damage and ceramide metabolism in hepatocytes was assessed following CerS6 knockdown. Mitochondria were isolated using a commercial kit, and ceramides in liver tissue and hepatocytes were detected by LC-MS/MS. RESULTS: In comparison to the control group, rats subjected to one week of restraint exhibited elevated serum CORT levels. The liver displayed significant signs of mitochondrial damage, accompanied by increased CerS6 and mitochondrial C16:0 ceramide, along with activation of the AMPK/p38 MAPK pathway. In vitro studies demonstrated that CORT treatment of hepatocytes resulted in mitochondrial damage, concomitant with elevated CerS6 and mitochondrial C16:0 ceramide. Furthermore, CORT induced sequential phosphorylation of AMPK and p38 MAPK proteins, and inhibition of the p38 MAPK pathway using SB203580 mitigated the CORT-induced elevation in CerS6 protein. Knocking down CerS6 in hepatocytes inhibited both the increase in C16:0 ceramide and the release of mitochondrial cytochrome c induced by CORT. CONCLUSIONS: CerS6-associated C16:0 ceramide plays a mediating role in stress-induced mitochondrial damage in hepatocytes. The molecular mechanism is linked to CORT-induced activation of the AMPK/p38 MAPK pathway, leading to upregulated CerS6.

The effects of awe on interpersonal forgiveness: the mediating role of small-self.

Awe could increase prosocial behavior, but little is known about its effects on interpersonal forgiveness. This study aims to explore the potential impact of awe on interpersonal forgiveness and the underlying mechanism of this process, using a combination of questionnaires, economic game and computational modeling. In Study 1, we utilized Trait Awe Scale (TAS) and Forgiveness Trait Scale (FTS) to examine the association between trait awe and trait forgiveness. In Study 2, we employed pre-screened video to induce awe, happy and neutral emotions, then evaluated the effects of induced awe on small-self and interpersonal forgiveness in hypothetical interpersonal offensive situations (Study 2a) and two economic interaction situations (Study 2b). Results from Study 1 indicate that there is a positive correlation between trait awe and trait forgiveness. Study 2 reveal that awe can enhance interpersonal forgiveness in both interpersonal conflict situations and economic interaction situations, and this effect is mediated by the sense of small-self elicited by awe. Overall, these findings contribute to our understanding of the potential impact of awe on interpersonal forgiveness and provide valuable insights into the mechanisms through which awe may influence forgiveness. Further research in this area could help to elucidate the potential applications of awe-based interventions in promoting forgiveness and positive social interactions.

Norepinephrine-Activated p38 MAPK Pathway Mediates Stress-Induced Cytotoxic Edema of Basolateral Amygdala Astrocytes.

The amygdala is a core region in the limbic system that is highly sensitive to stress. Astrocytes are key players in stress disorders such as anxiety and depression. However, the effects of stress on the morphology and function of amygdala astrocytes and its potential mechanisms remain largely unknown. Hence, we performed in vivo and in vitro experiments using a restraint stress (RS) rat model and stress-induced astrocyte culture, respectively. Our data show that norepinephrine (NE) content increased, cytotoxic edema occurred, and aquaporin-4 (AQP4) expression was up-regulated in the basolateral amygdala (BLA) obtained from RS rats. Additionally, the p38 mitogen-activated protein kinase (MAPK) pathway was also observed to be significantly activated in the BLA of rats subjected to RS. The administration of NE to in vitro astrocytes increased the AQP4 level and induced cell edema. Furthermore, p38 MAPK signaling was activated. The NE inhibitor alpha-methyl-p-tyrosine (AMPT) alleviated cytotoxic edema in astrocytes, inhibited AQP4 expression, and inactivated the p38 MAPK pathway in RS rats. Meanwhile, in the in vitro experiment, the p38 MAPK signaling inhibitor SB203580 reversed NE-induced cytotoxic edema and down-regulated the expression of AQP4 in astrocytes. Briefly, NE-induced activation of the p38 MAPK pathway mediated cytotoxic edema in BLA astrocytes from RS rats. Thus, our data provide novel evidence that NE-induced p38 MAPK pathway activation may be one of the mechanisms leading to cytotoxic edema in BLA under stress conditions, which also could enable the development of an effective therapeutic strategy against cytotoxic edema in BLA under stress and provide new ideas for the treatment of neuropsychiatric diseases.

Bispecific Nanobody-Aptamer Conjugates for Enhanced Cancer Therapy in Solid Tumors.

Bispecific antibodies possess exceptional potential as therapeutic agents due to their capacity to bind to two different antigens simultaneously. However, challenges pertain to unsatisfactory stability, manufacturing complexity, and limited tumor penetration hinder their broad applicability. In this study, a versatile technology is presented for the rapid generation of bispecific nanobody-aptamer conjugates with efficient tumor penetration. The approach utilizes microbial transglutaminase (MTGase) and click chemistry to achieve site-specific conjugation of nanobodies and aptamers, which are termed nanotamers. The nanotamers recognize and bind to two types of molecular targets expressed on cancer cells. As a prototype, a bispecific nanotamer is developed that binds both clusters of differentiation 47 (CD47) and mesenchymal epithelial transition receptor (Met) expressed on the tumor cell membrane. This CD47-Met nanotamer demonstrates high affinity and specificity toward tumor cells expressing both targets, exhibits improved receptor functional inhibition through a strong steric hindrance effect. Moreover, its capacity for deep tumor penetration greatly enhances the impact of conventional chemotherapy on antitumor efficacy. The as-developed nanotamer synthesis approach shows promise to customize bispecific molecular probes targeting different cancer types and different therapeutic goals.

In silico screening of natural products as uPAR inhibitors via multiple structure-based docking and molecular dynamics simulations.

Cancer remains one of the most pressing challenges to global healthcare, exerting a significant impact on patient life expectancy. Cancer metastasis is a critical determinant of the lethality and treatment resistance of cancer. The urokinase-type plasminogen activator receptor (uPAR) shows great potential as a target for anticancer and antimetastatic therapies. In this work, we aimed to identify potential uPAR inhibitors by structural dynamics-based virtual screenings against a natural product library on four representative apo-uPAR structural models recently derived from long-timescale molecular dynamics (MD) simulations. Fifteen potential inhibitors (NP1-NP15) were initially identified through molecular docking, consensus scoring, and visual inspection. Subsequently, we employed MD-based molecular mechanics-generalized Born surface area (MM-GBSA) calculations to evaluate their binding affinities to uPAR. Structural dynamics analyses further indicated that all of the top 6 compounds exhibited stable binding to uPAR and interacted with the critical residues in the binding interface between uPAR and its endogenous ligand uPA, suggesting their potential as uPAR inhibitors by interrupting the uPAR-uPA interaction. We finally predicted the ADMET properties of these compounds. The natural products NP5, NP12, and NP14 with better binding affinities to uPAR than the uPAR inhibitors previously discovered by us were proven to be potentially orally active in humans. This work offers potential uPAR inhibitors that may contribute to the development of novel effective anticancer and antimetastatic therapeutics.Communicated by Ramaswamy H. Sarma.

The Prognosis Performance of a Neutrophil- and Lymphocyte-Associated Gene Mutation Score in a Head and Neck Cancer Cohort.

The treatment of head and neck squamous cell carcinomas (HNSCCs) is multimodal, and chemoradiotherapy (CRT) is a critical component. However, the availability of predictive or prognostic markers in patients with HNSCC is limited. Inflammation is a well-documented factor in cancer, and several parameters have been studied, with the neutrophil-to-lymphocyte ratio (NLR) being the most promising. The NLR is the most extensively researched clinical biomarker in various solid tumors, including HNSCC. In our study, we collected clinical and next-generation sequencing (NGS) data with targeted sequencing information from 107 patients with HNSCC who underwent CRT. The difference in the NLR between the good response group and the poor response group was significant, with more patients having a high NLR in the poor response group. We also examined the genetic alterations linked to the NLR and found a total of 41 associated genes across eight common pathways searched from the KEGG database. The overall mutation rate was low, and there was no significant mutation difference between the low- and high-NLR groups. Using a multivariate binomial generalized linear model, we identified three candidate genes (MAP2K2, MAP2K4, and ABL1) that showed significant results and were used to create a gene mutation score (GMS). Using the NLR-GMS category, we noticed that the high-NLR-GMS group had significantly shorter relapse-free survival compared to the intermediate- or low-NLR-GMS groups.

Heterogeneity of Phase II Enzyme Ligands on Controlling the Progression of Human Gastric Cancer Organoids as Stem Cell Therapy Model.

Gastric cancer (GC) organoids are frequently used to examine cell proliferation and death as well as cancer development. Invasion/migration assay, xenotransplantation, and reactive oxygen species (ROS) production were used to examine the effects of antioxidant drugs, including perillaldehyde (PEA), cinnamaldehyde (CA), and sulforaphane (SFN), on GC. PEA and CA repressed the proliferation of human GC organoids, whereas SFN enhanced it. Caspase 3 activities were also repressed on treatment with PEA and CA. Furthermore, the tumor formation and invasive activities were repressed on treatment with PEA and CA, whereas they were enhanced on treatment with SFN. These results in three-dimensional (3D)-GC organoids showed the different cancer development of phase II enzyme ligands in 2D-GC cells. ROS production and the expression of TP53, nuclear factor erythroid 2-related factor (NRF2), and Jun dimerization protein 2 were also downregulated on treatment with PEA and CA, but not SFN. NRF2 knockdown reversed the effects of these antioxidant drugs on the invasive activities of the 3D-GC organoids. Moreover, ROS production was also inhibited by treatment with PEA and CA, but not SFN. Thus, NRF2 plays a key role in the differential effects of these antioxidant drugs on cancer progression in 3D-GC organoids. PEA and CA can potentially be new antitumorigenic therapeutics for GC.

Serological Responses and Predictive Factors of Booster COVID-19 Vaccines in Patients with Hematologic Malignancies.

Patients with hematologic malignancies are reported to have a more severe course of coronavirus disease 2019 (COVID-19) and be less responsive to vaccination. In this prospective study, we aimed to evaluate the serological responses to booster COVID-19 vaccines of Taiwanese patients with hematologic malignancies and identify potential predictive markers for effective neutralizing immunity. This study enrolled 68 patients with hematologic malignancies and 68 age- and gender-matched healthy control subjects who received three doses of vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from 1 January 2022 to 31 October 2022. The SARS-CoV-2 immunoglobulin G (IgG) spike antibody level was measured with the Abbott assay. The effective neutralization capacity was defined as an anti-spike IgG level of ≥4160 AU/mL. Among the 68 patients with hematologic malignancies, 89.7% achieved seroconversion after booster doses. Seven patients with actively treated lymphoma remained seronegative and had the lowest humoral responses among patients with different types of hematologic malignancies. Despite comparable antibody titers between patients and healthy individuals, rates of effective neutralization (66.2% vs. 86.8%, respectively; p = 0.005) were significantly reduced in patients with hematologic malignancies. In a multivariate analysis, the independent predictors for effective neutralization were a lack of B-cell-targeted agents within six months of vaccination (odds ratio, 15.2; 95% confidence interval, 2.7-84.2; p = 0.002) and higher immunoglobulin levels (odds ratio, 4.4; 95% confidence interval, 1.3-14.7; p = 0.017). In conclusion, the majority of patients with hematologic malignancies achieved seroconversion after booster vaccination. Patients with ongoing B-cell depletion and hypogammaglobinemia were identified as having negative predictive markers for effective neutralization.

High G9a Expression in DLBCL and Its Inhibition by Niclosamide to Induce Autophagy as a Therapeutic Approach.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a malignant lymphoid tumor disease that is characterized by heterogeneity, but current treatment does not benefit all patients, which highlights the need to identify oncogenic genes and appropriate drugs. G9a is a histone methyltransferase that catalyzes histone H3 lysine 9 (H3K9) methylation to regulate gene function and expression in various cancers. METHODS: TCGA and GTEx data were analyzed using the GEPIA2 platform. Cell viability under drug treatment was assessed using Alamar Blue reagent; the interaction between G9a and niclosamide was assessed using molecular docking analysis; mRNA and protein expression were quantified in DLBCL cell lines. Finally, G9a expression was quantified in 39 DLBCL patient samples. RESULTS: The TCGA database analysis revealed higher G9a mRNA expression in DLBCL compared to normal tissues. Niclosamide inhibited DLBCL cell line proliferation in a time- and dose-dependent manner, reducing G9a expression and increasing p62, BECN1, and LC3 gene expression by autophagy pathway regulation. There was a correlation between G9a expression in DLBCL samples and clinical data, showing that advanced cancer stages exhibited a higher proportion of G9a-expressing cells. CONCLUSION: G9a overexpression is associated with tumor progression in DLBCL. Niclosamide effectively inhibits DLBCL growth by reducing G9a expression via the cellular autophagy pathway; therefore, G9a is a potential molecular target for the development of therapeutic strategies for DLBCL.

Clinical Trial on the Safety and Tolerability of Personalized Cancer Vaccines Using Human Platelet Lysate-Induced Antigen-Presenting Cells.

Research and development of personalized cancer vaccines as precision medicine are ongoing. We predicted human leukocyte antigen (HLA)-compatible cancer antigen candidate peptides based on patient-specific cancer genomic profiles and performed a Phase I clinical trial for the safety and tolerability of cancer vaccines with human platelet lysate-induced antigen-presenting cells (HPL-APCs) from peripheral monocytes. Among the five enrolled patients, two patients completed six doses per course (2-3 × 107 cells per dose), and an interim analysis was performed based on the immune response. An immune response was detected by enzyme-linked immunosorbent spot (ELISpot) assays to HLA-A*33:03-matched KRASWT, HLA-DRB1*09:01-compliant KRASWT or G12D, or HLA-A*31:01-matched SMAD4WT, and HLA-DRB1*04:01-matched SMAD4G365D peptides in two completed cases, respectively. Moreover, SMAD4WT-specific CD8+ effector memory T cells were amplified. However, an attenuation of the acquired immune response was observed 6 months after one course of cancer vaccination as the disease progressed. This study confirmed the safety and tolerability of HPL-APCs in advanced and recurrent cancers refractory to standard therapy and is the first clinical report to demonstrate the immunoinducibility of personalized cancer vaccines using HPL-APCs. Phase II clinical trials to determine immune responses with optimized adjuvant drugs and continued administration are expected to demonstrate efficacy.