Limited Effect Research Articles

Super multiple primary lung cancers harbor high-frequency BRAF and low-frequency EGFR mutations in the MAPK pathway

The incidence of multiple primary lung cancer (MPLC) is increasing, with some of our surgical patients exhibiting numerous lesions. We defined lung cancer with five or more primary lesions as super MPLCs. Elucidating the genomic characteristics of this special MPLC subtype can help reduce disease burden and understand tumor evolution. In our cohort of synchronous super early-stage MPLCs (PUMCH-ssesMPLC), whole-exome sequencing on 130 resected malignant specimens from 18 patients provided comprehensive super-MPLC genomic landscapes. Mutations are enriched in PI3k-Akt and MAPK pathways. Their BRAF mutation frequency (31.5%) is significantly higher than MPLC with fewer lesions and early-stage single-lesion cancer, while EGFR mutations are significantly fewer (13.8%). As lesion counts increase, BRAF mutations gradually become dominant. Also, invasive lesions more tend to have classic super-MPLC mutation patterns. High-frequency BRAF mutations, especially Class II, and low-frequency EGFR mutations could be a reason for the limited effectiveness of targeted therapy in super-MPLC patients.

Dual-functionalized architecture enables stable and tumor cell-specific SiO2NPs in complex biological fluids.

Most commercial anticancer nanomedicines are administered intravenously. This route is fast and precise as the drug enters directly into the systemic circulation, without undergoing absorption processes. When nanoparticles come into direct contact with the blood, however, they interact with physiological components that can induce colloidal destabilization and/or changes in their original biochemical identity, compromising their ability to selectively accumulate at target sites. In this way, these systems usually lack active targeting, offering limited therapeutic effectiveness. In the literature, there is a paucity of in-depth studies in complex environments to evaluate nanoparticle stability, protein corona formation, hemolytic activity, and targeting capabilities. To address this issue, fluorescent silica nanoparticles (SiO2NPs) are here functionalized with zwitterionic (kinetic stabilizer) and folate groups (targeting agent) to provide selective interaction with tumor cell lines in biological media. The stability of these dually functionalized SiO2NPs is preserved in unprocessed human plasma while yielding a decrease in the number of adsorbed proteins. Experiments in murine blood further proved that these nanoparticles are not hemolytic. Remarkably, the functionalized SiO2NPs are more internalized by tumor cells than their healthy counterparts. Investigations of this nature play a crucial role in garnering results with greater reliability, allowing the development of nanoparticle-based pharmaceutical drugs that exhibit heightened efficacy and reduced toxicity for medical purposes.

Functional and therapeutic significant of heat-shock protein 90 (HSP90) in reproductive cancers.

Reproductive cancers, such as ovarian, cervical, and endometrial carcinomas, have a poor prognosis in metastatic stages. Researchers are continuously seeking improved and safer methods to target cancer-related oncoproteins, addressing the limitations of current treatments, including their limited effectiveness, drug resistance, and off-target effects. Recent advancements in understanding the molecular mechanisms involved in the progress of reproductive cancers have provided valuable insights into potential targeted therapies. By engaging with oncoproteins and co-chaperones, heat-shock protein 90 (HSP90) regulates signaling networks and fixes protein folding errors in cancer cells. The potential of HSP90 inhibition as cancer-targeted treatments is underscored by the continuous discovery and testing of novel HSP90-targeted molecules for their antitumor properties in preclinical and clinical settings. Therefore, this study aims to shed light on the mechanism and recent research breakthroughs of HSP90, as well as provide an in-depth review of their therapeutic potential in reproductive cancers.

Development of phyto-compound-based nanoformulation for skin regeneration and its in vitro evaluation

Skin regeneration is a process that regenerates damaged or aged skin cells, resulting in a healthier and younger appearance. The demand for nano dosage forms containing phyto-compounds in the cosmetics industry is increasing daily to control or prevent this process. Phyto-compounds with cell regenerative properties often show limited effectiveness in conventional use due to their low hydrophilicity and molecular weight, as well as their low absorption from the skin. Glycyrrhizic acid (GA), a phyto-compound obtained from licorice root, has many pharmacological properties, including skin regeneration properties. The aim of this study is to develop a highly stable GA-containing nanoemulsion (GA-NE) formulation for topical application, determine its anti-collagenase activity, and evaluate its safety and effectiveness by in vitro cell culture methods. In this context, GA-NEs were synthesized with sixteen production procedures using independent variables (oil, water percentage, surfactant, and homogenization time). The average droplet size, polydispersity index (PdI), and zeta potential (ZP) of the synthesized GA-NEs were determined by dynamic light scattering (DLS) analysis. The heating-cooling cycle (H-C) test result showed that the F4P3 formulation was the most stable formulation. Therefore, 90-day physicochemical stability tests were performed with the F4P3 formulation. In vitro release results revealed that GA was released from NEs at a rate of 93.15 ± 0.61 % within 24 h. An ex vivo permeation and penetration study was performed, and the permeation and penetration profile of F4P3 was determined. In vitro cell culture studies showed that the F4P3 formulation had higher cell viability and regeneration than GA in the HaCaT cell line. Anti-collagenase activity results also revealed a better activity of the F4P3 formulation compared to GA. Consequently, characterization, efficacy, and safety studies showed that the F4P3 formulation could be an innovative cell regeneration product candidate suitable for topical use with high stability.

6851 Rapidly Increasing Use of Anti-Obesity Medications among Veterans in the Veterans Health Administration (VA)

Abstract Disclosure: V. Vimalananda: None. S. Qian: None. R. Bolton: None. A. Hung: None. V. Smith: None. M. Maciejewski: None. Introduction: Obesity is a prevalent and costly chronic disease that compromises quality of life; increases risks of cardiometabolic disease, osteoarthritis, and several cancers; and accounts for 28% of U.S. health care costs. Anti-obesity medications (AOMs) may fill the treatment gap given the low uptake of bariatric surgery and limited effectiveness of behavioral interventions, and are guideline-recommended as part of a comprehensive obesity treatment plan. The landscape for obesity treatment has changed with introduction of the highly effective and in-demand glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual GLP-1 + GIP receptor agonists (GIP/GLP-1 RAs). Given limited knowledge of use patterns, we describe use of AOMs among patients receiving care in the Veterans Health Administration (VA), which is the largest integrated health system in the United States. Methods: In a retrospective cohort study of VA patients from 7/1/2021-6/30/2023, we examined data from the VHA Corporate Data Warehouse separately for patients on AOMs without and with diagnosed diabetes, since the newer AOMs can be used at lower doses for the diabetes indication. Results: There were 31,106 patients without diabetes and at least one AOM prescription in the two year study period, who were 60% male and 62% White. AOM prescriptions from Year 1 to Year 2 among this group increased 215%. Overall, prescriptions were: semaglutide 34%, liraglutide 18%, orlistat 18%, phentermine/topiramate 14%, bupropion/naltrexone 12%, phentermine 4% and tirzepatide 0.03%. Prescribers were physicians 60%, LIPs 25%, and pharmacists 13%. There were 188,017 patients with diagnosed diabetes and at least one AOM prescription, and they were 92% male and 67% white. AOM prescriptions from Year 1 to Year 2 among this group increased 14% and were primarily (87%) for semaglutide. Prescribers were physicians 63%, licensed independent practitioners (LIPs) 23%, and pharmacists 10%. Conclusions AOM use is increasing in VA across all AOM classes, particularly among patients without diabetes, indicating growing interest in medical treatment of obesity. As AOM use spreads, real-world evidence on weight loss and clinical outcomes is needed among patients like those in VA who tend to be older and less healthy than the highly selected patients included in randomized clinical trials. Data is especially needed to guide practice among patients with obesity and without diabetes, given the dramatic increase in use among that group over the past 2 years. Presentation: 6/1/2024

Robust and automatic beamstop shadow outlier rejection: combining crystallographic statistics with modern clustering under a semi-supervised learning strategy.

During the automatic processing of crystallographic diffraction experiments, beamstop shadows are often unaccounted for or only partially masked. As a result of this, outlier reflection intensities are integrated, which is a known issue. Traditional statistical diagnostics have only limited effectiveness in identifying these outliers, here termed Not-Excluded-unMasked-Outliers (NEMOs). The diagnostic tool AUSPEX allows visual inspection of NEMOs, where they form atypical pattern: clusters at the low-resolution end of the AUSPEX plots of intensities or amplitudes versus resolution. To automate NEMO detection, a new algorithm was developed by combining data statistics with a density-based clustering method. This approach demonstrates a promising performance in detecting NEMOs in merged data sets without disrupting existing data-reduction pipelines. Re-refinement results indicate that excluding the identified NEMOs can effectively enhance the quality of subsequent structure-determination steps. This method offers a prospective automated means to assess the efficacy of abeamstop mask, as well as highlighting the potential of modern pattern-recognition techniques for automating outlier exclusion during data processing, facilitating future adaptation to evolving experimental strategies.

Strategies for the treatment of hormone receptor-positive HER2-low breast cancer based on clinical practice: a round table discussion.

Human epidermal growth factor receptor 2 (HER2)-low breast cancer is a newly identified targetable subset of breast tumors, and its clinical characteristics and treatment strategies are controversial. The emergence of novel anti-HER2 antibody-drug conjugate (ADC) has brought promising approaches for HER2-low breast cancer treatment. Several clinical trials have validated the efficacy and safety of trastuzumab deruxtecan (T-Dxd) in HER2-low breast cancer at different treatment settings. The treatment timing, candidate identification, long-term management, and overcoming drug resistance are crucial questions to improve breast cancer patient survival. Here we present a clinical case of hormone receptor-positive (HR+) HER2-low breast cancer patient who experienced neoadjuvant chemotherapy, surgery, adjuvant, and first-line endocrine therapy with limited effectiveness. After the treatment failure of CDK4/6 inhibitors, the utilization of T-Dxd brought a long-term disease response and tolerable low toxicities. In this round table discussion, we summarized opinions and recommendations from breast cancer surgeons and oncologists on treatment strategies for this patient. The discussion mainly focused on the precise diagnosis of HER2-low breast cancer, treatment design at different disease status, regimens selection according to drug response, strategies consideration for overcoming drug resistance and the management of adverse events in long-term survival. These opinions would provide critical insights to improve HER2-low breast cancer treatment and offer valuable suggestions for clinical practice.

Effect of critical limit of saline water irrigation in suitable rice (Oryza sativa L.) varieties

Effect of critical limit of saline water irrigation in suitable rice (Oryza sativa L.) varieties

Overexpression of ATF4 Inhibits Ferroptosis to Alleviate Anxiety Disorders by Activating the TGF-β Signaling Pathway.

Anxiety disorders seriously impair patients' mental health and quality of life, with limited effectiveness of current treatments. Dysregulation of activating transcription factor 4 (ATF4) is involved in various mental diseases, but the research on its potential roles in alleviating anxiety disorders remains limited. ATF4 was screened out by bioinformatic analysis and its expression was verified in vivo. Mice were treated with 21 d of chronic restraint stress to establish the anxiety mice model. The anxiolytic effect of ATF4 was assessed by a battery of behavior tests and evaluation of hippocampal tissue damage after overexpressing ATF4. Ferroptosis-related indicators were detected by enzyme-linked immunosorbent assay and Western blotting. Then the transforming growth factor beta (TGF-β) signaling pathway was predicted as the downstream regulatory pathway of ATF4 by bioinformatic methods. Western blotting was conducted to detect the protein expression level of TGF-β1, small mothers against decapentaplegic 3 (Smad3), and phospho-Smad3 (p-Smad3). ATF4 was screened out as a ferroptosis-related anxiolytic gene after bioinformatics analysis and was down-regulated in the anxiety mice model. Mice with ATF4 overexpression spent more time in the open arms in the elevated plus-maze test, appeared more frequently in the central area in the open-field test, and decreased the immobility time in the forced swimming and tail suspension tests. Hippocampal tissue damage was alleviated, ferroptosis was suppressed, and the levels of TGF-β1 and p-Smad3/Smad3 were increased by AFT4 overexpression. ATF4 overexpression can repress ferroptosis to improve anxiety disorders by activating the TGF-β signaling pathway.

N-Acetyl-L-Cysteine (NAC) Blunts Axitinib-Related Adverse Effects in Preclinical Models of Glioblastoma.

Axitinib is a tyrosine kinase inhibitor characterized by a strong affinity for Vascular Endothelial Growth Factor Receptors (VEGFRs). It was approved in 2012 by Food and Drug Administration and European Medicines Agency as a second line treatment for advanced renal cell carcinoma and is currently under evaluation in clinical trial for the treatment of other cancers. Glioblastoma IDH-wild type (GBM) is a highly malignant brain tumor characterized by diffusely infiltrative growth pattern and by a prominent neo-angiogenesis. In GBM, axitinib has demonstrated a limited effectiveness as a monotherapy, while it was recently shown to significantly improve its efficacy in combination treatments. In preclinical models, axitinib has been reported to trigger cellular senescence both in tumor as well as in normal cells, through a mechanism involving intracellular reactive oxygen species (ROS) accumulation and activation of Ataxia Telangiectasia Mutated kinase (ATM). Limiting axitinib-dependent ROS increase by antioxidants prevents senescence specifically in normal cells, without affecting tumor cells. We used brain tumor xenografts obtained by engrafting Glioma Stem Cells (GSCs) into the brain of immunocompromised mice, to investigate the hypothesis that the antioxidant molecule N-Acetyl-L-Cysteine (NAC) might be used to reduce senescence-associated adverse effects of axitinib treatment without altering its anti-tumor activity. We demonstrate that the use of the antioxidant molecule N-Acetyl-Cysteine (NAC) in combination with axitinib stabilizes tumor microvessels in GBM tumor orthotopic xenografts, eventually resulting in vessel normalization, and protects liver vasculature from axitinib-dependent toxicity. Overall, we found that NAC co-treatment allows vessel normalization in brain tumor vessels and exerts a protective effect on liver vasculature, therefore minimizing axitinib-dependent toxicity.

ASSESSING FEDERAL ROAD SAFETY CORPS (FRSC) IMPACT ON EASING TRAFFIC CONGESTION ALONG THE ILESA-BENIN HIGHWAY AT AKURE, ONDO STATE, NIGERIA: EDUCATION, ENFORCEMENT, AND PATROL EFFICIENCY

This study evaluates the efficacy of the Federal Road Safety Corps (FRSC) in mitigating traffic congestion along the Ilesa-Benin Highway in Akure, Ondo State, Nigeria. It scrutinizes the efficiency of FRSC's education, patrol, and enforcement strategies to discern their impact on traffic congestion levels. The data were collected from primary sources via questionnaires and activity-based trip surveys, supplemented by secondary sources including satellite imagery and literature. The results revealed high internal consistency in the respondents' perceptions and no evidence of multicollinearity in the dataset. It also indicates the significant contributions of education and enforcement in reducing traffic congestion, contrary to the limited effectiveness of patrols. Among the recommendations include prioritizing improvements in education and enforcement efforts through enhanced training programs and community collaborations as well as re-evaluating and potentially restructuring patrol activities. These insights offer valuable guidance for policymakers and stakeholders in devising strategies to alleviate traffic congestion and enhance road safety on critical highway routes like the Ilesa-Benin Highway.

Medical practice in classical Greece : The neurological and psychiatric case reports of the Hippocratic Corpus

Which theoretical and practical competences do the neurological and psychiatric case histories of the Hippocratic Corpus convey? The 431 Hippocratic case histories have been studied for reports and communication on the diagnostics, treatment and prognosis of single persons and groups of patients suffering from neurological and psychiatric diseases. In the 7books of the Hippocratic Epidemics, atotal of 128 patients with neurological and psychiatric symptoms are described. Epidemic fever and its variants were the leading predisposing conditions and the main symptoms were delirium, coma, insomnia, headache, speech disorders and convulsions. Anumber of patients with phrenitis and opisthotonos are also reported. The majority of the sick persons were male, were teenagers or adults and 47of them are mentioned by name. The patient's information about the course is often just as informative as the doctor's observations. Treatment was limited to physical and dietary measures. The Hippocratic physician diagnosed and attempted to treat alarge number of neurological and psychiatric diseases. The often almost continuous observations of the patients led to astonishingly precise predictions of the course and the prospects of recovery. Numerous symptoms described in the case studies, including carphologia and opisthotonus, have entered the neurological vocabulary. The retrospective etiological analysis of the reports leads to the almost explicit identification of neurosyphilis and encephalitis lethargica. The therapeutic measures described by the author were, as the changeable course of the diseases shows, only of limited effectiveness despite a very differentiated application over time, both against the underlying diseases and the neurological and psychiatric complications.

Nanoparticle Formulations for the Improvement of Symptomatic Treatments of Neurodegenerative Disorders

Neuronanomedicine merges nanotechnology and neuroscience in the pursuit of engineering therapeutic interventions for neurological disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). While no nanoparticle‐based drug delivery systems (NDDSs) are yet approved for use for targeting the central nervous system, this review critically analyses the development of NDDSs for the improvement of currently approved therapeutics for the symptomatic treatment of AD and PD. It showcases how NDDSs can help therapeutic payloads overcome existing limitations, such as insufficient drug accumulation in the brain and limited effectiveness, by enhancing their pharmacokinetics, bioavailability, brain penetration and accumulation, and overall therapeutic efficacy through drug encapsulation, manipulation of nanoparticle properties, and nanoparticle surface functionalisation. However, we also draw attention to widespread issues in the field that impede progress, including the poor selection of in vitro models and the inadequate design of pre‐clinical in vivo studies. We further advocate for greater standardisation of study design and reporting requirements in the future, which would likely enhance outcomes and expedite the translation of neuronanomedicines.

In Vitro Digestion of Vacuum-Impregnated Yam Bean Snacks: Pediococcus acidilactici Viability and Mango Seed Polyphenol Bioaccessibility.

This study investigates the in vitro digestion of vacuum-impregnated yam bean snacks enriched with Pediococcus acidilactici and mango seed polyphenols, focusing on bacterial survival and polyphenol bioaccessibility. The snacks were prepared by vacuum impregnation (VI) with solutions containing either mango seed extract, P. acidilactici, or a combination of both, followed by dehydration. The antimicrobial activity of the treatments was assessed against pathogens, revealing limited effectiveness, likely due to insufficient concentrations of mango seed extract and the intrinsic resistance of the bacteria. VI of mango seed extract improved the total soluble phenols (TSP) content up to 400% and maintained the initial probiotic concentration (106 cell/mL). In vitro digestion was performed to simulate gastrointestinal conditions, measuring the stability of TSP and the survival of P. acidilactici. The results indicated that the viability of P. acidilactici fluctuated throughout the digestion process (106 to 104 log UFC/g), the polyphenols showed varying degrees of bioaccessibility (11 to 30%), and the TSP content in the intestinal fraction ranged from 1.95 to 6.54 mg GAE/g. The study highlights the potential of VI for incorporating functional components into plant-based snacks, though further optimization is necessary to enhance the stability of P. acidilactici and the effectiveness of the bioactive ingredients.

SRPK Inhibitors Reduce the Phosphorylation and Translocation of SR Protein Splicing Factors, thereby Correcting BIN1, MCL-1 and BCL2 Splicing Errors and Enabling Apoptosis of Cholangiocarcinoma Cells.

Cholangiocarcinoma (CCA) is a malignancy of the bile duct epithelium that is commonly found in the Thai population. CCA has poor prognosis and a low survival rate due to the lack of early diagnosis methods and the limited effectiveness of current treatments. A number of oncogenic spliced-transcripts resulting from mRNA splicing errors have been reported in CCA, and aberrant mRNA splicing is suspected to be a key driver of this cancer type. The hyperphosphorylation of serine/arginine rich-splicing factors (SRSFs) by serine/arginine protein kinases (SRPKs) causes them to translocate to the nucleus where they facilitate gene splicing errors that generate cancer-related mRNA/protein isoforms. The correlation between SRPK expression and the survival of CCA patients was analyzed using data from The Cancer Genome Atlas (TCGA) dataset. The effect of SRPK inhibitors (SRPIN340 and SPHINX31) on two CCA cell lines (KKU-213A and TFK-1) was also investigated. The induction of cell death was studied by Calcein-AM/PI staining, AnnexinV/7AAD staining, immunofluorescence (IF), and Western blotting (WB). The phosphorylation and nuclear translocation of SRSFs was tracked by WB and IF, and the repair of splicing errors was examined by Reverse Transcription-Polymerase Chain Reaction (RT-PCR). High levels of SRPK1 and SRPK2 transcripts, and in particular SRPK1, correlated with shorter survival in CCA patients. SRPIN340 and SPHINX31 increased the number of dead and apoptotic cells in a dose-dependent manner. CCA also showed diffuse expression of cytoplasmic cytochrome C and upregulation of cleaved caspase-3. Moreover, SRSFs showed low levels of phosphorylation, resulting in the accumulation of cytoplasmic SRSF1. To link these phenotypes with aberrant gene splicing, the apoptosis-associated genes Bridging Integrator 1 (BIN1), Myeloid cell leukemia factor 1 (MCL-1) and B-cell lymphoma 2 (BCL2) were selected for further investigation. Treatment with SRPIN340 and SPHINX31 decreased anti-apoptotic BIN1+12A and increased pro-apoptotic MCL-1S and BCL-xS. The SRPK inhibitors SRPIN340 and SPHINX31 can suppress the phosphorylation of SRSFs and their nuclear translocation, thereby producing BIN1, MCL-1 and BCL2 isoforms that favor apoptosis and facilitate CCA cell death.

Biological Potential and Essential Oil Profile of Two Wild Apiaceae Species from Algeria (Daucus carota L. and Foeniculum vulgare Mill.): Larvicidal and Antibacterial Effects.

Infectious diseases, including vector-borne and antibiotic-resistant infections, present significant global health challenges, necessitating the exploration of natural alternatives for disease control. In this study, we investigated the essential oil (EO) profile as well as larvicidal and antibacterial properties of two wild Apiaceae species used in Algeria: Daucus carota L. (DCEO) and Foeniculum vulgare Mill. (FVEO). EO was extracted from the aerial parts by steam distillation and analyzed using Gas Chromatography Mass Spectrometry (GC/MS). Major constituents identified in DCEO were geranyl acetate (50.07%) and elemicin (10.77%), while FVEO contained estragole (24.93%), fenchone (20.20%), and α-phellandrene (17.96%). Both EOs were highly effective towards Culex pipiens larvae, with low LC50 values of 30.6 ± 1.06 ppm for DCEO and 34.7 ± 1.06 ppm for FVEO, indicating their potential as bioinsecticides due to their bioactivity and bioavailability. Additionally, the two Eos demonstrated moderate antibacterial efficacy against gram-positive bacteria, Staphylococcus aureus ATCC 25923 and Staphylococcus aureus MRSA ATCC 43300, respectively, with DCEO showing MIC values of 10 and 20 mg/mL, respectively, and FVEO exhibiting MIC values > 20 mg/mL. However, both EOs showed limited effectiveness against gram-negative bacteria, Escherichia coli ATCC 25922 and Klebsiella pneumonia ATCC 700603. These results highlight the potential applications of DCEO and FVEO as natural bioinsecticides and antibacterial agents, offering promising avenues for further research and development in pest control and food preservation.

Evaluating the performance of egami, kobayashi and sano scores in predicting IVIG resistance in infant kawasaki disease

BackgroundThis study aimed to evaluate the effectiveness of Egami, Kobayashi and Sano scores in predicting intravenous immunoglobulin (IVIG) resistance in infant Kawasaki disease (KD), considering its unique clinical presentation.MethodsWe retrospectively analysed 143 infants aged < 12 months and diagnosed with KD at a single centre from 2019 to 2023. Patients were divided into IVIG-resistant and IVIG-responsive groups. Demographic, clinical and laboratory data were compared between the groups. The diagnostic performance of Egami, Kobayashi and Sano scores in predicting IVIG resistance was evaluated using sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and area under the receiver operating characteristic curve (AUC). Additionally, we developed a new scoring system based on significant predictors identified in our cohort.ResultsAmong 143 infants, 45 (31.5%) showed IVIG resistance. The IVIG-resistant group had a significantly higher rate of coronary artery lesions (15.6% vs. 5.1%, p = 0.036). Incomplete KD was observed in 61.5% of cases. Egami, Kobayashi and Sano scores exhibited low sensitivity (35.6%, 55.6% and 20%, respectively) and moderate specificity (77.6%, 63.3% and 95.9%, respectively) in predicting IVIG resistance. The AUC ranged from 0.583 to 0.674, indicating poor to fair discriminative ability. Our newly developed scoring system, based on total bilirubin and albumin levels, showed similar performance (AUC 0.633) to existing scores.ConclusionsExisting Japanese risk scoring systems and our newly developed score showed limited effectiveness in predicting IVIG resistance in infant KD. The high proportion of incomplete presentation and IVIG resistance in infants highlights the need for age-specific risk assessment and management. Further research is necessary to develop more sophisticated, dedicated prediction model for IVIG resistance in infants with KD.

Fatty acid synthase inhibitor cerulenin hinders liver cancer stem cell properties through FASN/APP axis as novel therapeutic strategies

Hepatocellular carcinoma (HCC) poses significant treatment challenges due to high postoperative recurrence rates and the limited effectiveness of targeted medications. Researchers have identified the unique metabolic profiles of cancer stem cells (CSCs) as the primary drivers of cancer recurrence, metastasis, and drug resistance. Therefore, to address the therapeutic conundrum, this study focused on rewinding metabolic reprogramming of CSCs as a novel therapeutic strategy. HCC CSCs exhibited elevated fatty acid (FA) metabolism compared with parental cells. To specifically target FA metabolism in CSCs, we utilized cerulenin, a fatty acid synthase (FASN) inhibitor. Surprisingly, cerulenin can diminish CSC-like characteristics, including stemness gene expression, spherogenicity, tumorigenicity, and metastatic potential. In addition, sorafenib, a multikinase inhibitor used as targeted therapy for advanced HCC, was employed in combination with cerulenin, demonstrating a great synergistic effect, particularly in CSCs. Importantly, our RNA sequencing analysis disclosed that the amyloid protein precursor (APP) is a crucial downstream effector of FASN in regulating CSC properties. We found that APP plays a crucial role in CSCs’ characteristics that can be inhibited by cerulenin. By focusing on FA metabolism, this study identified the FASN/APP axis as a viable target to develop a more potent therapy strategy for advanced HCC.

Glucose Oxidase-Immobilized Dually-Crosslinked Nanogels for Rapid-Responsive Insulin Delivery.

Despite the potential benefits of close-looped insulin delivery systems in regulating glycemic homeostasis and effectively alleviating diabetes, they still encounter challenges such as limited effectiveness in preventing low glycemic episodes due to sluggish glucose response, and issues with the instability of enzymes and carriers. In this study, dually-crosslinked and glucose oxidase (GOx)-immobilized insulin nanogels (DC-NGs@Ins) are developed for rapid-responsive and sustained hypoglycemic therapy. The DC-NGs@Ins with the phenylborate ester linker enabled the insulin release in a close-looped fashion, and moreover, immobilized GOx-generated hydrogen peroxide (H2O2) by consuming the glucose, which can further bind to phenylborate ester for enhancing glucose response and accelerating the insulin release. The dually-crosslinked structure (phenylboronic ester and UV-crosslinking) effectively minimized the initial burst release of insulin, thus preventing the potential risk of hypoglycemia. More interestingly, GOx immobilized in the nanogels mitigated GOx leakage and enhanced its multiple utilization compared to free GOx. In vivo study demonstrated that DC-NGs@Ins effectively maintained glycemic levels (BGLs) below 200mgdL-1 for at least 8h compared to singly-crosslinked nanogels (SC-NGs@Ins). Therefore, this intelligent insulin delivery system shows potential applications in diabetes treatment.

Histone demethylase enzymes KDM5A and KDM5B modulate immune response by suppressing transcription of endogenous retroviral elements.

The histone demethylases KDM5A and KDM5B are transcriptional repressors that play an important role in cancer and immune response, making them attractive drug targets. Unfortunately, small molecule inhibitors, including CPI-455, that block KDM5A and KDM5B enzymatic activity, have shown only limited effectiveness at suppressing cancer cell viability as single agents in vitro. In this study we undertook a multi-omics approach to map transcriptional and chromatin changes in KDM5A and KDM5B deficient cells compared to those treated with CPI-455. The datasets revealed that KDM5A and KDM5B modulate the expression of KRAB-ZNF genes and that loss of either gene was associated with increased expression of ERV genes and upregulation of immune response markers. Surprisingly, pharmacological inhibition of these enzymes did not phenocopy genetic ablation. In contrast, acute degradation of KDM5A using a dTAG system caused an increase in ERV expression, providing evidence that this immune modulation is independent of demethylase activity. Together with the limited success of small molecule inhibitors, our data provide strong rationale for the development of KDM5A and KDM5B degraders to modulate tumor immune responses.