Mechanism Of Suppression Research Articles

A STAG2-PAXIP1/PAGR1 axis suppresses lung tumorigenesis.

The cohesin complex is a critical regulator of gene expression. STAG2 is the most frequently mutated cohesin subunit across several cancer types and is a key tumor suppressor in lung cancer. Here, we coupled somatic CRISPR-Cas9 genome editing and tumor barcoding with an autochthonous oncogenic KRAS-driven lung cancer model and showed that STAG2 is uniquely tumor-suppressive among all core and auxiliary cohesin components. The heterodimeric complex components PAXIP1 and PAGR1 have highly correlated effects with STAG2 in human lung cancer cell lines, are tumor suppressors in vivo, and are epistatic to STAG2 in oncogenic KRAS-driven lung tumorigenesis in vivo. STAG2 inactivation elicits changes in gene expression, chromatin accessibility, and 3D genome conformation that impact the cancer cell state. Gene expression and chromatin accessibility similarities between STAG2- and PAXIP1-deficient neoplastic cells further relate STAG2-cohesin to PAXIP1/PAGR1. These findings reveal a STAG2-PAXIP1/PAGR1 tumor-suppressive axis and uncover novel PAXIP1-dependent and PAXIP1-independent STAG2-cohesin-mediated mechanisms of lung tumor suppression.

Electron traps in (Y0.97Zr0.03)2O3 transparent ceramics and its suppression by heavy Eu3+ doping

AbstractIn this paper, Eu3+:(Y0.97Zr0.03)2O3 transparent ceramics with different doping concentrations of Eu3+ were prepared by vacuum sintering. This series of transparent ceramic samples exhibits strong red emission when excited by an electron beam at the keV level. However, color changes observed in the samples after high‐energy electron irradiation. This is due to the capture of electrons by traps related to oxygen vacancies within the Y2O3 lattice. Specifically, under electron beam irradiation, the capture of the electrons by oxygen vacancy‐related defects in the Y2O3 lattice occurs, leading to radiation damage. The color change can be suppressed to some extent by the incorporation of Zr4+ into the Y2O3 lattice, which can effectively suppress the generation of oxygen vacancies. Interestingly, samples with heavy doping of Eu3+ exhibit stronger resistance to electron irradiation damage. Based on the detailed characterizations, including optical transmittance, cathodoluminescence, photoluminescence, thermoluminescence and luminescence decay time, it is found that under heavy doping conditions, Eu3+, which has a stronger cationic character than Y3+ can more effectively suppress the generation of electron traps induced by the oxygen vacancies and the interstitial oxygen in the Y2O3 lattice, thereby enhancing radiation resistance. This research can advance the understanding of defect suppression mechanisms and benefit the application of Y2O3‐based functional transparent ceramics in high‐energy electron and β‐ray irradiation environment.

Influence of cross-trial distractor volatility on statistical learning of spatial distractor suppression

ABSTRACT Learning to suppress location(s) where a distractor frequently occurs can improve search efficiency, known as distractor-location probability-cueing. However, the impact of the volatility of distractor occurrence – how often distractor-present and – absent events switch – remains poorly understood. To investigate this, we contrasted two volatility regimens in an additional-singleton search paradigm: a low-volatility environment in which distractor-present trials tended to occur in streaks, and a high-volatility environment with more frequent alternations. The distractor appeared 13 times more often at a designated frequent location than any rare locations. We replicated the probability-cueing effect, which was consistent across both volatilty conditions. Interestingly, the target-location effect – slower responses to a target at the frequent distractor location – was robust in the high-volatility condition, but non-significant in the low-volatility condition. We propose a suppression-thresholding account: the activation threshold of the saliency-triggered suppression mechanism is dynamically adjusted based on the volatility and local frequency of distractor occurrence.

Immunohaemostasis and the significance of immune reactions in the regulation of blood coagulation.

This study was conducted to determine the specific features of the mutual influence of the immune and haemostatic systems in immunohaemostasis, the role of immune reactions in the regulationof blood coagulation, and the efficacy of modern methods of treating thrombosis andbleeding. The study analysed relevant scientific sources on immunology and haematology and identified the specific features of the blood clotting process and the role of immune reactions in it. The study found that the immune system influences the haematological system through the interaction of blood clotting factors, platelets, plasminogen, endothelial cells with immune cells. Thehaemostatic system influences the immune system through mechanisms to maintain immune tolerance and immune memory and the properties of clotting factors to activate the stimulation and migration of immune cells to the site of infection. Immune reactions regulate blood coagulation by activating platelets, regulating blood coagulation factors, affecting fibrinolysis, and immune tolerance. The process of platelet activation involves immune cells, immune complexes, and microbial components.The regulation of blood coagulation factors is influenced by the ability of immune cells to produce activators and inhibitors of these factors and to stimulate or slow down fibrinolysis. The immune system's maintenance of immune tolerance to blood components is regulated by mechanisms of immune response suppression, partial immune ignoring of certain blood elements, inhibition of activation of certain immune cells, apoptosis, and selection of immature T-lymphocytes. Treatment methods for patients at risk of thrombosis and bleeding include anticoagulation, antiplatelet, dual antiplatelet therapy, thrombectomy, endovascular methods, medical prophylaxis of bleeding, and coagulation monitoring. The findings of this study suggest the significance of immune responses in the regulation of blood coagulation processes, and therefore they can be used in the development of immunotherapy methods for the treatment of thrombosis and bleeding.

Kazuyo Moro: Building relationships is essential for gaining both speed and opportunities in research.

Professor Kazuyo Moro holds dual appointments as a team leader for the Laboratory for Innate Immune Systems at RIKEN IMS as well as Osaka University Graduate School of Medicine. Her lab conducts multifaceted research on type 2 innate lymphoid cells (ILC2), from ILC2 differentiation, activation, suppression, and transcriptional control mechanisms, as well as basic research and drug discovery. The research from Prof. Moro lab aims to build new models and therapies for related immune diseases such as allergies, fibrosis, and metabolic diseases.

Effectiveness of composite fume suppression and deodorizing agents in improving performance and reducing emissions of rubber modified asphalt

The incorporation of crumb rubber (CR) modifiers significantly enhances the road performance of asphalt binders. However, the harmful emissions generated during their production and construction processes have a considerable negative impact on the environment. This study introduced composite fume suppression and deodorizing agents (CSDAs), formulating four distinct fume suppression and deodorizing rubber modified asphalts (SDRMAs). Microscale testing methods were employed to analyze the micro-morphology, physicochemical properties, and thermal stability of SDRMA. Fume tests were conducted to evaluate the fume suppression performance of CSDA, and the emission behavior and suppression mechanisms were investigated using mass balance methods and electrochemical sensors. Additionally, the high and low-temperature rheological properties and storage stability of SDRMA were comprehensively analyzed using tools such as the dynamic shear rheometer (DSR) and bending beam rheometer (BBR). The results indicated that CSDA effectively suppressed the harmful emissions of rubber modified asphalt (RMA). Compared to regular RMA, the four types of SDRMAs demonstrated a reduction in average fume emissions, particulate matter mass, and H2S gas concentration by 40.1%, 21.6%, and 47.0%, respectively. Furthermore, the addition of CSDA improved the high-temperature performance and storage stability of the modified asphalt, effectively reducing the environmental hazards and energy consumption during the production and storage of RMA, thereby facilitating the eco-friendly application and energy-saving emission reduction of RMA.

Effect of betahistine on pro-inflammatory cytokine expression in autoimmune inner ear disease and Meniere's disease patients.

Betahistine is a partial H1 receptor agonist and a potent H3 receptor antagonist commonly used for the treatment of MD and peripheral vertigo. The aim of this study was to investigate the impact of betahistine on the salt induced cytokine expression profiles of AIED and MD patients. Peripheral blood mononuclear cells (PBMCs) were obtained from 24 patients with autoimmune inner ear disease (AIED) or Meniere's disease (MD) during an acute exacerbation of hearing loss. These PBMCs were cultured with 80 mM NaCl or a combination of 80 mM NaCl and betahistine and IL-1β and IL-6 expression were measured by real time PCR and ELISA. In most patients, IL-1β expression in response to NaCl exceeded the unstimulated condition and this expression was abrogated by the addition of betahistine, which was statistically significant at p = .004. mRNA expression of IL-1β was not reduced when samples were treated with both salt and betahistine compared to samples treated with salt alone, inferring the mechanism of betahistine-mediated IL-1β suppression is post-translational. Similarly, IL-6 cellular release was augmented with salt exposure and reduced with co-culture of betahistine. Unlike IL-1 however, betahistine appeared to reduce IL-6 mRNA expression. We observe that betahistine abrogates salt-induced IL-1β expression, suggesting an additional treatment option for AIED and MD patients with inflammatory mediated disease. Level 4.

Multiomics reveals tumor microenvironment remodeling in locally advanced gastric and gastroesophageal junction cancer following neoadjuvant immunotherapy and chemotherapy

BackgroundPerioperative chemotherapy is the standard of care for patients with locally advanced gastric and gastroesophageal junction cancer. Recent evidence demonstrated the addition of programmed cell death protein 1 (PD-1) inhibitors...

Effects of ERK1/2 Inhibitors on the Growth of Acute Leukemia Cells.

Extracellular signal-regulated kinases (ERK)1/2 are important regulatory proteins that control cell proliferation and survival, playing a significant role in cancer progression, metastasis, and chemoresistance. This study investigated the effects of ERK1/2 inhibitors on the in vitro growth of acute leukemia cell lines. Three ERK1/2 inhibitors were used: SCH772984, temuterkib (LY3214996), and ulixertinib (BVD-523). Four acute myeloid leukemia cell lines (OCI/AML3, HL-60, THP-1, and U-937) and two T-lymphoblastic leukemia cell lines (Jurakt and KOPT-K1) were treated with these inhibitors. Cell growth was assessed using a colorimetric assay, and cell-cycle progression and apoptosis were analyzed using flow cytometry. The expression of intracellular signaling proteins was evaluated via immunoblotting. The effects of small interfering RNA (siRNA)-mediated ERK1/2 knockdown were also evaluated. The inhibitors suppressed the growth of three leukemia cell lines (OCI/AML3, HL-60, and THP-1) harboring neuroblastoma rat sarcoma virus (NRAS) mutations. Growth suppression occurred through G0/G1 arrest in all three cell lines and through apoptosis in OCI/AML3 cells. Immunoblotting demonstrated that these inhibitors suppressed the expression of MYC proto-oncogene, bHLH transcription factor (MYC), in the three cell lines. The additional molecular mechanisms of growth suppression varied depending on the specific inhibitor and cell line. The inhibitors had milder suppressive effects on normal lymphocytes compared to the leukemia cell lines. ERK1/2 inhibitors may serve as novel molecular-targeted drugs for treating leukemia with NRAS mutations.

A preclinical and phase I clinical study of ex vivo-expanded amyloid beta-specific human regulatory T cells in Alzheimer’s disease

IntroductionDespite advancements in adoptive regulatory T cell (Treg) therapy, its application in Alzheimer’s disease (AD) remains constrained by challenges in ex vivo Treg selection and expansion with antigen specificity. Our previous findings demonstrated the bystander suppressive immunomodulatory mechanism of ex vivo expanded amyloid β-specific mouse Tregs in AD models, prompting inquiry into the efficacy of ex vivo expanded human Tregs in AD. MethodsWe developed an effective ex vivo expansion method for manufacturing amyloid β-specific human Tregs (Aβ-hTreg) and evaluated their safety and efficacy in 3xTg mouse models of AD and a phase 1 clinical trial with six AD patients. The phenotype of Aβ-hTreg was analyzed using single-cell transcriptomics. The clinical trial involved intravenous administration of Aβ-hTreg, with three patients receiving a low dose and three receiving a high dose. Exploratory assessments of effectiveness, including cognitive tasks and functional evaluations, were conducted ninety days post-treatment. ResultsBehavioral spatial learning and memory impairment, neuroinflammatory and amyloid pathology were dramatically ameliorated by single intrathecal administration of ex vivo expanded Aβ−hTreg to 3xTg AD mice. Single cell transcriptomics analysis revealed alterations in five key genes within a cluster of Tregs under antigen-specific manufacturing conditions. In the clinical trial with six AD patients, dose-limiting toxicity was experienced by none of the participants within five days of receiving GMP-grade Aβ-hTreg (VT301), indicating its good tolerability. Although exploratory assessments of effectiveness did not reach statistically significant values among the groups, these findings offer valuable insights for AD treatment and management, guiding the planning of the next phase of clinical trials. DiscussionThis study suggests that hTregs may modulate Alzheimer's disease pathology by suppressing neuroinflammation, while VT301 shows promise as a safe treatment option. However, further research is necessary to confirm its clinical efficacy and optimize treatment strategies. Trial registrationTitle: A Study of Possibility of Using Regulatory T Cells (VT301) for Treatment of Alzheimer's Disease, ClinicalTrials.gov NCT05016427, Study approval date: Ministry of Food and Drug Safety of the Republic of Korea (MFDS) - August 31st, 2020, Institutional Review Board (IRB) of Seoul National University Hospital, Republic of Korea - September 29th, 2020, The date of first patient enrollment: December 7th, 2020. https://clinicaltrials.gov/study/NCT05016427

Numerical study of the effects of surface nitrogen-containing on soot formation process in ammonia/ethylene counterflow diffusion flames

In this paper, a modified soot kinetic model was developed to explore the potential inhibitory effects of nitrogen-containing functional groups on the soot surface growth process. In the modified soot kinetic model, the formation process of cyano functional groups on the soot surface was simulated through the reaction of hydrogen cyanide (HCN) and the surface open sites, and the surface cyano functional groups were assumed to no longer participate in the subsequent hydrogen-abstraction-acetylene-addition (HACA) reaction. The prediction performance of soot volume fraction (SVF) and average particle size (D63) in ammonia doping ethylene counterflow diffusion flames was compared between the traditional soot kinetic model and the modified kinetic soot model. The results show that both models reflected the suppression effects of ammonia doping on soot formation observed in the experiments. However, compared to the traditional soot kinetic model, the modified soot kinetic model exhibited better performances in predicting SVF and D63 with prediction deviations reduced by 52.7 % and 2.3 nm, respectively. The simulation results showed the formation of surface cyano functional groups led to a nitrogen content of up to 0.84 % in the soot, which is consistent with previous experimental measurements. In-depth analysis shows that the formation of cyano functional groups on the soot surface decreased the proportion of hydrogen sites and further diminished the number of open sites, resulting in reductions in the rates of HACA surface growth and the soot mass growth by up to 22 % and 29 %, respectively. It is proposed that the nitrogen-containing functional groups on the surface of soot in ammonia-doped hydrocarbon flames inhibit the formation of soot, providing an alternative pathway to the well-known gas-phase suppression mechanism.

Molecular Mechanisms of Curdlan-Induced Suppression of NFATc1 Expression in Osteoclasts.

Osteoclasts derived from hematopoietic stem cells express immunoreceptors on their cell surface. Previously, we showed that the β-glucan curdlan suppressed osteoclastogenesis via binding to dectin-1, a pattern recognition receptor. Curdlan negatively regulates osteoclast differentiation and bone resorption capacity by suppressing the expression of nuclear factor of activated T cells 1 (NFATc1), a master factor for osteoclast differentiation, in a dectin-1-dependent manner; however, the mechanism involved in this process has not yet been fully elucidated. In this study, we aimed to elucidate the molecular mechanism involved in the suppression of RANKL-induced osteoclast differentiation by curdlan. Real-time RT-qPCR results showed that curdlan suppressed the expression of NFATc1 in cells of the osteoclast progenitor cell line RAW264.7 overexpressing dectin-1 (d-RAW cells), without altering the expression of negative regulators. Therefore, we examined the effect of curdlan on the NF-κB pathway, which is important for the induction of NFATc1 expression. Western blot analysis results showed that curdlan addition suppressed RANKL-induced NF-κB activation in the vector control line (c-RAW) cells with low expression of dectin-1, in d-RAW cells, and the parental RAW264.7 (RAW) cells. The results of tartrate-resistant alkaline phosphatase staining and real-time RT-qPCR showed that curdlan addition suppressed osteoclast differentiation in RAW cells, suggesting the presence of a dectin-1-independent modification system. Finally, we focused on the complement receptor 3 (CR3), which binds β-glucan, and revealed that blocking the binding of β-glucan to the CD11b molecule, a component of CR3, by neutralizing antibody, recovered the suppression of IκBα degradation by curdlan. These results suggest that the suppression of osteoclast differentiation by curdlan involves not only the dectin-1-dependent pathway but also the negative regulation of NFATc1 via modification of the NF-κB pathway via CR3 recognition. The results of this study may aid to establish treatment methods for metabolic bone diseases and inflammatory bone destruction and to clarify their pathogenesis.

Blocking WNT7A Enhances MHC-I Antigen Presentation and Enhances the Effectiveness of Immune Checkpoint Blockade Therapy.

The limited infiltration of CD8+ T cells in tumors hampers the effectiveness of T cell-based immunotherapy, yet the mechanisms that limit tumor infiltration by CD8+ T cells remain unclear. Through bulk RNA sequencing of human tumors, we identified a strong correlation between WNT7A expression and reduced CD8+ T-cell infiltration. Further investigation demonstrated that inhibiting WNT7A substantially enhanced MHC-I expression on tumor cells. Mechanistically, WNT7A inhibition inactivated Wnt/β-catenin signaling pathway and thus resulted in reduced physical interaction between β-catenin and p65 in the cytoplasm, which increased the nuclear translocation of p65 and activated the NF-κB pathway, ultimately promoting the transcription of genes encoding MHC-I molecules. We found that our lead compound, 1365-0109, disrupted the protein-protein interaction between WNT7A and its receptor FZD5, resulting in the upregulation of MHC-I expression. In murine tumor models, both genetic and pharmaceutical suppression of WNT7A led to increased MHC-I levels on tumor cells, and consequently enhanced the infiltration and functionality of CD8+ T cells, which bolstered antitumor immunity and improved the effectiveness of immune checkpoint blockade therapy. These findings have elucidated the intrinsic mechanisms of WNT7A-induced immune suppression, suggesting that therapeutic interventions targeting WNT7A hold promise for enhancing the efficacy of immunotherapy.

Photoacoustic polydopamine-indocyanine green (PDA-ICG) nanoprobe for detection of senescent cells

Cellular senescence is considered an important tumour suppression mechanism in response to damage and oncogenic stress in early lesions. However, when senescent cells are not immune-cleared and persist in the tumour microenvironment, they can drive a variety of tumour-promoting activities, including cancer initiation, progression, and metastasis. Additionally, there is compelling evidence demonstrating a direct connection between chemo(radio)therapy-induced senescence and the development of drug resistance and cancer recurrence. Therefore, detection of senescent cells in tissues holds great promise for predicting cancer occurrence earlier, assessing tumour progression, aiding patient stratification and prognosis, and informing about the efficacy of potential senotherapies. However, effective detection of senescent cells is limited by lack of biomarkers and readout strategies suitable for in vivo clinical imaging. To this end, a nanoprobe composed of biocompatible polydopamine (PDA) nanoparticle doped with FDA-approved indocyanine green (ICG) dye, namely PDA-ICG, was designed as a contrast agent for senescence detection using photoacoustic imaging (PAI). In an in vitro model of chemotherapy-induced senescence, PDA-ICG nanoprobe showed an elevated uptake in senescent cells relative to cancer cells. In addition to its improved photostability, 2.5-fold enhancement in photoacoustic signal relative to ICG was observed. Collectively, the results indicate that the PDA-ICG nanoprobe has the potential to be used as a contrast agent for senescence detection of chemotherapy-induced senescence using PAI.

Soot Particle Emissions: Formation and Suppression Mechanisms in Gas Turbines

This article reports on field tests devoted to the emissions of particles from gas turbines (GT) and more particularly to the formation of soot and its suppression by fuel additives. These field tests involved four heavy-duty gas turbines used as power generators and equipped with air atomization systems. These machines were running on natural gas, No. 2 distillate oil, heavy crude oil and heavy fuel oil, respectively. The GT running on natural gas produced no soot or ash and its upstream air filtration system in fact allowed lower concentrations of exhaust particles than those found in ambient air. Soot emitted when burning the three liquid fuels (No. 2 distillate; heavy crude oil; and heavy oil) was effectively reduced using fuel additives based on iron(III), cerium(III) and cerium(IV). Cerium was found to be very effective as a soot suppressant and gave rise to two surprising effects: cerium(III) performed better than cerium(IV) and a “memory effect” was observed in the presence of heat recovery boilers due to the deposition of active cerium species. All of the reported results, both regarding natural gas emissions and soot reduction, are original. A review of the soot formation mechanisms and a detailed interpretation of the test results are provided.

Toll-Like receptor 3-mediated interferon-β production is suppressed by oncostatin m and a broader epithelial-mesenchymal transition program

BackgroundPatients with Triple Negative Breast Cancer (TNBC) currently lack targeted therapies, and consequently face higher mortality rates when compared to patients with other breast cancer subtypes. The tumor microenvironment (TME) cytokine Oncostatin M (OSM) reprograms TNBC cells to a more stem-like/mesenchymal state, conferring aggressive cancer cell properties such as enhanced migration and invasion, increased tumor-initiating capacity, and intrinsic resistance to the current standards of care. In contrast to OSM, Interferon-β (IFN-β) promotes a more differentiated, epithelial cell phenotype in addition to its role as an activator of anti-tumor immunity. Importantly, OSM suppresses the production of IFN-β, although the mechanism of IFN-β suppression has not yet been elucidated.MethodsIFN-β production and downstream autocrine signaling were assessed via quantitative real-time PCR (qRT-PCR) and Western blotting in TNBC cells following exposure to OSM. RNA-sequencing (RNA-seq) was used to assess an IFN-β metagene signature, and to assess the expression of innate immune sensors, which are upstream activators of IFN-β. Cell migration was assessed using an in vitro chemotaxis assay. Additionally, TNBC cells were exposed to TGF-β1, Snail, and Zeb1, and IFN-β production and downstream autocrine signaling were assessed via RNA-seq, qRT-PCR, and Western blotting.ResultsHere, we identify the repression of Toll-like Receptor 3 (TLR3), an innate immune sensor, as the key molecular event linking OSM signaling and the repression of IFN-β transcription, production, and autocrine IFN signaling. Moreover, we demonstrate that additional epithelial-mesenchymal transition-inducing factors, such as TGF-β1, Snail, and Zeb1, similarly suppress TLR3-mediated IFN-β production and signaling.ConclusionsOur findings provide a novel insight into the regulation of TLR3 and IFN-β production in TNBC cells, which are known indicators of treatment responses to DNA-damaging therapies. Furthermore, strategies to stimulate TLR3 in order to increase IFN-β within the TME may be ineffective in stem-like/mesenchymal cells, as TLR3 is strongly repressed. Rather, we propose that therapies targeting OSM or OSM receptor would reverse the stem-like/mesenchymal program and restore TLR3-mediated IFN-β production within the TME, facilitating improved responses to current therapies.

Mechanism of melanoma suppression by Prosopis juliflora derived alkaloids: Apoptosis induction and signaling pathway inhibition

BackgroundTraditional medicines remain integral to healthcare worldwide especially in developing countries. Our prior studies highlighted the anti-melanoma potential of Prosopis juliflora leave methanolic extract (PJLME), leading us to further isolate and characterize bioactive compounds from PJLME and evaluate their efficacy against melanoma. In this context, we identified alkaloid fractions derived from PJLME (PJLME-AF) as key agents in PJLME's cytotoxic effect against melanoma cells. PurposeThe purpose of this research was to evaluate the anti-cancer effects and mechanisms of PJLME-AF on melanoma cell lines. MethodsChemical Profiling of PJLME-AF was conducted by using LC-ESI-MS/MS. Cell viability and anti-migratory effects of PJLME-AF were assessed through MTT, wound healing and transwell assays. Mechanistic study of PJLME-AF was explored using ROS generation assay, apoptosis assays (Annexin V) assay, western blot (apoptotic protein, EMT markers, stem cell markers and signalling pathways), qPCR. In-vitro spheroid assay was performed to explored the PJLME-AF cytotoxic effects on tumour spheroid forming ability of melanoma cells. Additionally, the anti-tumor efficacy of PJLME-AF was tested in an in-vivo C57BL/6 mouse model. ResultsPJLME-AF demonstrated potent anti-proliferative, anti-migratory and anti-invasive effects on melanoma cells. Mechanistic study indicates that PJLME-AF strongly induce ROS generation and subsequent apoptotic cell death in melanoma cells. Furthermore, PJLME-AF downregulated epithelial-to-mesenchymal transition (EMT) proteins, stem cell markers and Akt/Erk cell survival proteins providing insights into its molecular mechanisms. Notably, PJLME-AF inhibited spheroid formation and reduced PD-L1 expression. Finally, anti-tumor activity of PJLME-AF was further confirmed in a in-vivo mice model. Additionally, PJLME-AF combined with dacarbazine, exhibited enhanced cytotoxicity on melanoma compared to the drug alone. ConclusionPJLME-AF exhibit promising natural anti-cancer agents for metastatic melanoma treatment. This research contributes to the development of novel, safe, and cost-effective agents for metastatic melanoma treatment and as a potential candidate for further cancer research.

Bioinformatics analysis of the Microsporidia sp. MB genome: a malaria transmission-blocking symbiont of the Anopheles arabiensis mosquito

BackgroundThe use of microsporidia as a disease-transmission-blocking tool has garnered significant attention. Microsporidia sp. MB, known for its ability to block malaria development in mosquitoes, is an optimal candidate for supplementing malaria vector control methods. This symbiont, found in Anopheles mosquitoes, can be transmitted both vertically and horizontally with minimal effects on its mosquito host. Its genome, recently sequenced from An. arabiensis, comprises a compact 5.9 Mbp.ResultsHere, we analyze the Microsporidia sp. MB genome, highlighting its major genomic features, gene content, and protein function. The genome contains 2247 genes, predominantly encoding enzymes. Unlike other members of the Enterocytozoonida group, Microsporidia sp. MB has retained most of the genes in the glycolytic pathway. Genes involved in RNA interference (RNAi) were also identified, suggesting a mechanism for host immune suppression. Importantly, meiosis-related genes (MRG) were detected, indicating potential for sexual reproduction in this organism. Comparative analyses revealed similarities with its closest relative, Vittaforma corneae, despite key differences in host interactions.ConclusionThis study provides an in-depth analysis of the newly sequenced Microsporidia sp. MB genome, uncovering its unique adaptations for intracellular parasitism, including retention of essential metabolic pathways and RNAi machinery. The identification of MRGs suggests the possibility of sexual reproduction, offering insights into the symbiont’s evolutionary strategies. Establishing a reference genome for Microsporidia sp. MB sets the foundation for future studies on its role in malaria transmission dynamics and host-parasite interactions.

Thermodynamic characterization on the suppression process of water mist under the interaction effect between two buoyant non-premixed flames

Realistic fire disaster scenarios always refer to multiple fires burning at adjacent positions at the same time (MF), leading to a higher risk compared with a single fire (SF). That is, fire suppression in realistic fire disasters differs from existing fire suppression studies focusing on a single flame. It is worthy to extend the fire suppression study to multiple fires. This study investigates the thermodynamic characteristics of applying the water mist on the double flames through FDS (Fire Dynamic Simulator v. 6.9.1). The fire suppression mechanism is discussed from two aspects (the cooling effect and the dynamic effect). The cooling effect of the water mist on the double flames is revealed based on the onset time of cooling. The droplet distribution is considered the main factor in the cooling effect of the water mist on the double flames (DF). The dynamic effect dominates in the two effects of the water mist. It is found that the interaction effect between double flames significantly improves the difficulty of penetrating the combustion area. This study can provide numerical data support and theoretical reference for water mist fire suppression systems applied in realistic scenarios.

Obesity-Specific improvement of lung cancer outcomes and immunotherapy efficacy with metformin.

Pre-clinical cancer studies ascribe promising anticancer properties to metformin. Yet, clinical findings vary, casting uncertainty on its therapeutic value for non-small cell lung cancer (NSCLC) patients. We hypothesized that metformin could benefit obese and overweight patients with NSCLC. We retrospectively analyzed two clinical cohorts and employed complementary mouse models to test our hypothesis. One cohort included NSCLC patients with overweight BMI (≥25, n = 511) and non-overweight BMI (<25, n = 232) who underwent lobectomy, evaluating metformin's impact on clinical outcomes. Another cohort examined metformin's effect on progression-free survival (PFS) after immune checkpoint inhibitors (ICI) in overweight (n = 284) vs non-overweight (n = 184) NSCLC patients. Metformin's effects on tumor progression, antitumor immunity, and ICI response in obese and normal-weight mice were assessed with lung cancer models. Metformin is associated with increased recurrence-free survival in overweight patients (HR = 0.47 [95%CI = 0.24-0.94], p = .035) after lobectomy. It also corrected accelerated tumor growth in diet-induced obese mouse models in a lymphocyte-specific manner while reversing several mechanisms of immune suppression potentiated by obesity. PD-1 blockade coupled with metformin was more effective at limiting tumor burden in obese mice and correlated with PFS only in overweight patients on immunotherapy (HR = 0.60, [95%CI = 0.39-0.93], p = .024). Metformin may improve lung cancer-specific clinical outcomes in obese and overweight lung cancer patients and enhance immunotherapy efficacy in this growing population as well. This work identifies obesity as a potential predictive biomarker of metformin's anticancer and immunotherapy-enhancing properties in lung cancer while shedding light on the underlying immunological phenomena.