Nucleic acid-based drugs for patients with solid tumours.

The treatment of patients with advanced-stage solid tumours typically involves a multimodality approach (including surgery, chemotherapy, radiotherapy, targeted therapy and/or immunotherapy), which is often ultimately ineffective. Nucleic acid-based drugs, either as monotherapies or in combination with standard-of-care therapies, are rapidly emerging as novel treatments capable of generating responses in otherwise refractory tumours. These therapies include those using viral vectors (also referred to as gene therapies), several of which have now been approved by regulatory agencies, and nanoparticles containing mRNAs and a range of other nucleotides. In this Review, we describe the development and clinical activity of viral and non-viral nucleic acid-based treatments, including their mechanisms of action, tolerability and available efficacy data from patients with solid tumours. We also describe the effects of the tumour microenvironment on drug delivery for both systemically administered and locally administered agents. Finally, we discuss important trends resulting from ongoing clinical trials and preclinical testing, and manufacturing and/or stability considerations that are expected to underpin the next generation of nucleic acid agents for patients with solid tumours.

Defining competencies in robotic thyroidectomy: development of a model assessing an expert operator's intraoperative performance skills and cognitive strategies.

Background: The changing medical education environment emphasizes the need for time efficiency, increasing the demand for competency-based medical education to improve trainees' learning strategies. This study was performed to determine the competencies required for successful performance of robotic thyroidectomy (RT) and to determine the consensus of experts for performance of RT. Methods: Data were collected through 12 semi-structured interviews with RT experts and 11 field observations. Cognitive task analysis was performed to determine the competencies required for experts to perform RT. A modified Delphi methodology was used to determine how 20 experts rated the importance of each item of RT performance on a Likert 7-point scale. The criteria for the Delphi consensus were set at a Cronbach's α≥0.80 with two survey rounds. Results: After 11 field observations and 12 semi-structured interviews, 89 items were identified within six modules. These items were grouped into sub-modules according to their theme. The modified Delphi survey, involving 21 experts, reached the consensus standard during the second round (Cronbach's α=0.954), enabling the identification of the 64 most important items within six modules related to RT performance: midline incision to isthmectomy (MID module; n=8), lateral dissection (LAT module; n=7), preservation of inferior parathyroid glands (INF module; n=16), preservation of recurrent laryngeal nerve and dissection of the ligament of Berry (BER module; n=21), dissection of the thyroid upper pole (SUP module; n=10), and specimen removal and closure (END module; n=2). Conclusions: This mixed-method study combining qualitative and quantitative methodology identified modules of core competencies required to perform RT. These modules can be used as a standard and objective guide to train surgeons to perform RT and evaluate outcomes.

Hollow-structured cobalt sulfide electrocatalyst for alkaline oxygen evolution reaction: Rational tuning of electronic structure using iron and fluorine dual-doping strategy.

Utilizing renewable electricity for water electrolysis offers a promising way for generating high-purity hydrogen gases while mitigating the emission of environmental pollutants. To realize the water electrolysis, it is necessary to develop highly active and precious metal-free electrocatalyst for oxygen evolution reaction (OER) which incurs significant overpotential due to its complicated four-electron transfer mechanism. Hence, we propose a facile preparation method for hollow-structured Fe and F dual-doped CoS2 nanosphere (Fe-CoS2-F) as an efficient OER electrocatalyst. The uniform hollow and porous structure of Fe-CoS2-F enlarge the specific surface area and increase the number of exposed active sites. Furthermore, the Fe and F dual-dopants synergistically contributed to the adjustment of electronic structure, thereby promoting the adsorption/desorption of oxygen-containing reaction intermediates on active sites during the alkaline OER procedure. As a result, the prepared Fe-CoS2-F exhibits outstanding OER activity, characterized by a low overpotential of 298 mV to achieve a current density of 10 mA cm-2 and a Tafel slope as small as 46.0 mV dec-1. Based on computational theoretical calculations, the introduction of the dual-dopants into CoS2 structure reduce the excessively strong adsorption energy of reaction intermediate in the rate determining step, leading to effectively promoted electrocatalytic cycle for OER in alkaline environment. This study presents an effective strategy for preparing noble metal-free OER electrocatalysts with promising potential for large-scale industrial water electrolysis.

Beef peptides mitigate skeletal muscle atrophy in C2C12 myotubes through protein degradation, protein synthesis, and the oxidative stress pathway.

This study aimed to investigate the potential of beef peptides (BPs) in mitigating muscle atrophy induced by dexamethasone (DEX) with underlying three mechanisms in vitro (protein degradation, protein synthesis, and the oxidative stress pathway). Finally, the anti-atrophic effect of BPs was enhanced through purification and isolation. BPs were generated using beef loin hydrolyzed with alcalase/ProteAX/trypsin, each at a concentration of 0.67%, followed by ultrafiltration through a 3 kDa cut-off. BPs (10-100 µg mL-1) dose-dependently counteracted the DEX-induced reductions in myotube diameters, differentiation, fusion, and maturation indices (p < 0.05). Additionally, BPs significantly reduced FoxO1 protein dephosphorylation, thereby suppressing muscle-specific E3 ubiquitin ligases such as muscle RING-finger containing protein-1 and muscle atrophy F-box protein in C2C12 myotubes at concentrations exceeding 25 µg mL-1 (p < 0.05). BPs also enhanced the phosphorylation of protein synthesis markers, including mTOR, 4E-BP1, and p70S6K1, in a dose-dependent manner (p < 0.05) and increased the mRNA expression of antioxidant enzymes. Fractionated peptides derived from BPs, through size exclusion and polarity-based fractionation, also demonstrated enhanced anti-atrophic effects compared to BPs. These peptides downregulated the mRNA expression of primary muscle atrophy markers while upregulated that of antioxidant enzymes. Specifically, peptides GAGAAGAPAGGA (MW 924.5) and AFRSSTKK (MW 826.4) were identified from fractionated peptides of BPs. These findings suggest that BPs, specifically the peptide fractions GAGAAGAPAGGA and AFRSSTKK, could be a potential strategy to mitigate glucocorticoid-induced skeletal muscle atrophy by reducing the E3 ubiquitin ligase activity.

Light-field flow cytometry for high-resolution, volumetric and multiparametric 3D single-cell analysis.

Imaging flow cytometry (IFC) combines flow cytometry and fluorescence microscopy to enable high-throughput, multiparametric single-cell analysis with rich spatial details. However, current IFC techniques remain limited in their ability to reveal subcellular information with a high 3D resolution, throughput, sensitivity, and instrumental simplicity. In this study, we introduce a light-field flow cytometer (LFC), an IFC system capable of high-content, single-shot, and multi-color acquisition of up to 5,750 cells per second with a near-diffraction-limited resolution of 400-600 nm in all three dimensions. The LFC system integrates optical, microfluidic, and computational strategies to facilitate the volumetric visualization of various 3D subcellular characteristics through convenient access to commonly used epi-fluorescence platforms. We demonstrate the effectiveness of LFC in assaying, analyzing, and enumerating intricate subcellular morphology, function, and heterogeneity using various phantoms and biological specimens. The advancement offered by the LFC system presents a promising methodological pathway for broad cell biological and translational discoveries, with the potential for widespread adoption in biomedical research.

Targeting the CSF-1/CSF-1R Axis: Exploring the Potential of CSF1R Inhibitors in Neurodegenerative Diseases.

We report herein the potential of colony-stimulating factor-1 receptor (CSF1R) inhibitors as therapeutic agents in neuroinflammatory diseases, with a focus on Alzheimer's disease (AD). Employing a carefully modified scaffold, N-(4-heterocycloalkyl-2-cycloalkylphenyl)-5-methylisoxazole-3-carboxamide, we identify highly selective and potent CSF1R inhibitors─7dri and 7dsi. Molecular docking studies shed light on the binding modes of these key compounds within the CSF1R binding site. Remarkably, kinome-wide selectivity assessment underscores the impressive specificity of 7dri for CSF-1R. Notably, 7dri emerges as a potent CSF-1R inhibitor with favorable cellular activity and minimal cytotoxicity among the synthesized compounds. Demonstrating efficacy in inhibiting CSF1R phosphorylation in microglial cells and successfully mitigating neuroinflammation in an in vivo LPS-induced model, 7dri establishes itself as a promising antineuroinflammatory agent.

Prediction of Cancer Incidence and Mortality in Korea, 2024.

PURPOSE: This study aimed to report the projected cancer incidence and mortality for the year 2024 to estimate Korea's current cancer burden. MATERIALS AND METHODS: Cancer incidence data from 1999 to 2021 were obtained from the Korea National Cancer Incidence Database, and cancer mortality data from 1993 to 2022 were acquired from Statistics Korea. Cancer incidence and mortality were projected by fitting a linear regression model to observed age-specific cancer rates against their respective years and multiplying the projected age-specific rates by the anticipated age-specific population for 2024. A joinpoint regression model was used to determine the year in which the linear trend changed significantly; we only used the data of the latest trend for prediction. RESULTS: In total, 292,221 new cancer cases and 83,770 cancer deaths are expected to occur in Korea in 2024. The most common cancer site is expected to be the thyroid, followed by the colon and rectum, lung, breast, and stomach. These five cancers are expected to represent 55.7% of the overall burden of cancer in Korea. The most common type of cancer leading to death is expected to be lung cancer, followed by liver, colorectal, pancreatic, and stomach cancers. CONCLUSION: The age-standardized incidence rates for female breast and prostate cancers are estimated to continue to increase. These up-to-date estimates of the cancer burden in Korea could be an important resource for planning and evaluating cancer-control programs.

Cationic cholesterol-dependent LNP delivery to lung stem cells, the liver, and heart.

Adding a cationic helper lipid to a lipid nanoparticle (LNP) can increase lung delivery and decrease liver delivery. However, it remains unclear whether charge-dependent tropism is universal or, alternatively, whether it depends on the component that is charged. Here, we report evidence that cationic cholesterol-dependent tropism can differ from cationic helper lipid-dependent tropism. By testing how 196 LNPs delivered mRNA to 22 cell types, we found that charged cholesterols led to a different lung:liver delivery ratio than charged helper lipids. We also found that combining cationic cholesterol with a cationic helper lipid led to mRNA delivery in the heart as well as several lung cell types, including stem cell-like populations. These data highlight the utility of exploring charge-dependent LNP tropism.

Understanding the role of biodiversity in the climate, food, water, energy, transport and health nexus in Europe.

Biodiversity underpins the functioning of ecosystems and the diverse benefits that nature provides to people, yet is being lost at an unprecedented rate. To halt or reverse biodiversity loss, it is critical to understand the complex interdependencies between biodiversity and key drivers and sectors to inform the development of holistic policies and actions. We conducted a literature review on the interlinkages between biodiversity and climate change, food, water, energy, transport and health ("the biodiversity nexus"). Evidence extracted from 194 peer-reviewed articles was analysed to assess how biodiversity is being influenced by and is influencing the other nexus elements. Out of the 354 interlinkages between biodiversity and the other nexus elements, 53 % were negative, 29 % were positive and 18 % contained both positive and negative influences. The majority of studies provide evidence of the negative influence of other nexus elements on biodiversity, highlighting the substantial damage being inflicted on nature from human activities. The main types of negative impacts were land or water use/change, land or water degradation, climate change, and direct species fatalities through collisions with infrastructure. Alternatively, evidence of biodiversity having a negative influence on the other nexus elements was limited to the effects of invasive alien species and vector-borne diseases. Furthermore, a range of studies provided evidence of how biodiversity and the other nexus elements can have positive influences on each other through practices that promote co-benefits. These included biodiversity-friendly management in relevant sectors, protection and restoration of ecosystems and species that provide essential ecosystem services, green and blue infrastructure including nature-based solutions, and sustainable and healthy diets that mitigate climate change. The review highlighted the complexity and context-dependency of interlinkages within the biodiversity nexus, but clearly demonstrates the importance of biodiversity in underpinning resilient ecosystems and human well-being in ensuring a sustainable future for people and the planet.

Cancer Statistics in Korea: Incidence, Mortality, Survival, and Prevalence in 2021.

PURPOSE: The current study provides national cancer statistics and their secular trends in Korea, including incidence, mortality, survival, and prevalence in 2021. MATERIALS AND METHODS: Incidence, survival, and prevalence rates of cancer were calculated using the Korea National Cancer Incidence Database, from 1999 to 2021, with survival follow-up until December 31, 2022. Deaths from cancer were assessed using causes-of-death data obtained from Statistics Korea. RESULTS: The number of new cancer diagnoses in 2021 increased by 27,002 cases (10.8%) compared to 2020. In 2021, newly diagnosed cancer cases and deaths from cancer were reported as 277,523 (age-standardized rate [ASR], 289.3 per 100,000) and 82,688 (ASR, 67.6 per 100,000), respectively. The overall cancer incidence rates increased by 3.3% annually from 1999 to 2012, and decreased by 5.3% from 2012 to 2015, thereafter, followed by non-significant changes. Cancer mortality rates have been decreasing since 2002, with more rapid decline in recent years (annual decrease of 2.8% from 2002 to 2013; 3.2% from 2013 to 2021). The 5-year relative survival between 2017 and 2021 was 72.1%, which contributed to prevalent cases reaching over 2.4 million in 2021. CONCLUSION: In 2021, the number of newly diagnosed cancer patients increased as healthcare utilization recovered from the coronavirus disease 2019-related declines of 2020. Revised cancer registration guidelines expanded the registration scope, particularly for stomach and colorectal cancer. Survival rates have improved over the years, leading to a growing population of cancer survivors, necessitating a comprehensive cancer control strategy. The long-term impact of the pandemic on cancer statistics requires future investigation.

Discovery of N-(5-amido-2-methylphenyl)-5-methylisoxazole-3-carboxamide as dual CSF-1R/c-Kit Inhibitors with improved stability and BBB permeability.

This study explores the potential of CSF-1R inhibitors as therapeutic agents for neurodegenerative diseases. CSF-1R, a receptor tyrosine kinase primarily expressed in macrophage lineages, plays a pivotal role in regulating various cellular processes. Recent research highlights the significance of CSF-1R inhibition in mitigating neuroinflammation, particularly in Alzheimer's disease, where microglial overactivation contributes to neurodegeneration. The research reveals a series of N-(5-amido-2-methylphenyl)-5-methylisoxazole-3-carboxamide CSF-1R inhibitors, where compounds 7d, 7e, and 9a exhibit outstanding inhibitory activities and selectivity, with IC50 values of 33, 31, and 64 nM, respectively. These most promising compounds in this series were profiled for cellular potency and subjected to in vitro pharmacokinetic profiling. These inhibitors exhibit minimal cytotoxicity, even at higher concentrations, and possess promising blood-brain barrier permeability, making them potential candidates for central nervous system diseases. The investigation into the in vitro ADME properties, including plasma and microsomal stability, reveals that these CSF-1R inhibitors maintain their structural integrity and plasma concentration. This resilience positions them for further development as therapeutic agents for neurodegenerative diseases.

Genome-wide association analyses using machine learning-based phenotyping reveal genetic architecture of occupational creativity and overlap with psychiatric disorders.

Creativity is known to be heritable and exhibits familial aggregation with psychiatric disorders; however, the complex nature of their relationship has not been well-established. In the present study, we demonstrate that using an expanded and validated machine learning (ML)-based phenotyping of occupational creativity (OC) can allow us to further understand the trait of creativity, which was previously difficult to define and study. We conducted the largest genome-wide association study (GWAS) on OC with 241,736 participants from the UK Biobank and identified 25 lead variants that have not yet been reported and three candidate causal genes that were previously associated with educational attainment and psychiatric disorders. We found extensive genetic overlap between OC and psychiatric disorders with mixed effect direction through various post-GWAS analyses, including the bivariate causal mixture model. In addition, we discovered a strongly genetic correlation between our original GWAS and the GWAS adjusted for education years (rg = 0.95). Our GWAS analysis via ML-based phenotyping contributes to the understanding of the genetic architecture of creativity, which may inform genetic discovery and genetic prediction in human cognition and psychiatric disorders.

Concordance of esophageal and tracheal temperatures in patients using breathing circuit with heated wire humidifier: A prospective observational study.

RESULTS: After excluding 4 patients with an anesthesia duration of < 2 hours, data from 34 patients (1163 sets of tracheal and esophageal temperatures) were analyzed. Concordance correlation coefficient was 0.78. The overall mean bias (95% limits of agreement) between the tracheal and esophageal temperatures was -0.16°C (-0.65°C to 0.34°C). The percentage of temperature differences within ±â€…0.25°C was 73.5% ± 32.3, with a median of 89.4% [0,100]. The linear mixed-effects model revealed that the estimated intercept was 0.17°C with a 95% confidence interval (CI) of 0.13°C to 0.22°C. The duration of anesthesia and the number of temperature measurements were associated with higher concordance between the tracheal and esophageal temperatures in univariate analysis.

Enhancing polyethylene degradation: a novel bioprocess approach using Acinetobacter nosocomialis pseudo-resting cells.

Despite the discovery of several bacteria capable of interacting with polymers, the activity of the natural bacterial isolates is limited. Furthermore, there is a lack of knowledge regarding the development of bioprocesses for polyethylene (PE) degradation. Here, we report a bioprocess using pseudo-resting cells for efficient degradation of PE. The bacterial strain Acinetobacter nosocomialis was isolated from PE-containing landfills and characterized using low-density PE (LDPE) surface oxidation when incubated with LDPE. We optimized culture conditions to generate catalytic pseudo-resting cells of A. nosocomialis that are capable of degrading LDPE films in a bioreactor. After 28 days of bioreactor operation using pseudo-resting cells of A. nosocomialis, we observed the formation of holes on the PE film (39 holes per 217 cm2, a maximum diameter of 1440 µm). This study highlights the potential of bacteria as biocatalysts for the development of PE degradation processes. KEY POINTS: • New bioprocess has been proposed to degrade polyethylene (PE). • Process with pseudo-resting cells results in the formation of holes in PE film. • We demonstrated PE degradation using A. nosocomialis as a biocatalyst.

Internal Resistor Effect of Multilayer-Structured Synaptic Device for Low-Power Operation.

A synaptic device with a multilayer structure is proposed to reduce the operating power of neuromorphic computing systems while maintaining a high-density integration. A simple metal-insulator-metal (MIM)-structured multilayer synaptic device is developed using an 8-inch wafer-based and complementary metal-oxide-semiconductor (CMOS) fabrication process. The three types of MIM-structured synaptic devices are compared to assess their effects on reducing the operating power. The obtained results exhibited low-power operation owing to the inserted layers acting as an internal resistor. The modulated operational conductance level and simple MIM structure demonstrate the feasibility of implementing both low-power operation and high-density integration in multilayer synaptic devices.

Uncertainty in surrogate decision-making about end-of-life care for people with dementia: An integrative review.

AIM: To describe uncertainty in surrogate decision-making regarding end-of-life care for people with dementia using Mishel's reconceptualized uncertainty in illness theory. DESIGN: Integrative literature review using Whittemore and Knafl's approach. DATA SOURCES: PubMed, CINAHL, EMBASE, Scopus and Web of Science were searched using terms such as uncertainty/unpredictability, decision-making/advance care planning/end-of-life care planning, surrogate/family/caregiver/proxy and dementia. The search was initially conducted on 28 September 2021 and updated on 31 July 2023. REVIEW METHODS: Through systematic screening, 20 research articles were included in the analysis. Content related to uncertainty in surrogate decision-making regarding end-of-life care was extracted and analysed, focusing on the reconceptualized uncertainty in illness theory. RESULTS: First, surrogate uncertainty exists in various areas of surrogate decision-making regarding end-of-life care. Second, antecedents of surrogate uncertainty include numerous intrinsic and extrinsic factors. Third, surrogates exhibited some negative psychological responses to uncertainty but continually processed and structured their uncertainty through certain approaches, leading them to grow as decision-makers. Finally, research-based evidence on surrogates' processing of uncertainty and shifts to new life perspectives remains limited. CONCLUSION: Surrogates' uncertainty in decision-making regarding end-of-life care for people with dementia is well characterized using the reconceptualized uncertainty in illness theory. Healthcare providers should help surrogates manage their uncertainty in surrogate decision-making more constructively throughout the dementia trajectory. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: The findings highlight the importance of assessing how surrogates process uncertainty and gauging how to help them process uncertainty and transition to new life perspectives. IMPACT: This review contributes to healthcare professionals' understanding of surrogates' uncertainty in end-of-life care planning for people with dementia, especially what they are uncertain about, what influences their uncertainty and how they process it. REPORTING METHOD: This study adheres to the PRISMA reporting guidelines. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Multimodal Golden DNA Superstructures (GDSs) for Highly Efficient Photothermal Immunotherapy.

DNA-templated metallization has emerged as an efficient strategy for creating nanoscale-metal DNA hybrid structures with a desirable conformation and function. Despite the potential of DNA-metal hybrids, their use as combinatory therapeutic agents has rarely been examined. Herein, we present a simple approach for fabricating a multipurpose DNA superstructure that serves as an efficient photoimmunotherapy agent. Specifically, we adsorb and locally concentrate Au ions onto DNA superstructures through induced local reduction, resulting in the formation of Au nanoclusters. The mechanical and optical properties of these metallic nanoclusters can be rationally controlled by their conformations and metal ions. The resulting golden DNA superstructures (GDSs) exhibit significant photothermal effects that induce cancer cell apoptosis. When sequence-specific immunostimulatory effects of DNA are combined, GDSs provide a synergistic effect to eradicate cancer and inhibit metastasis, demonstrating potential as a combinatory therapeutic agent for tumor treatment. Altogether, the DNA superstructure-templated metal casting system offers promising materials for future biomedical applications.

Dielectrophoretic force-induced wrinkling of graphene oxide: Enhancing electrical conductivity and expanding biosensing applications.

Graphene oxide (GO) has many advantages, making it suitable for various applications. However, it has low electrical conductivity, restricting its applicability to electrochemical biosensors. This study used dielectrophoretic (DEP) force to control the movement and deformation of GO nanosheets to achieve high electrical conductivity without the chemical reduction of oxygen functional groups. Subjecting the DEP force to GO nanosheets induced physical deformation leading to the formation of wrinkled structures. A computational simulation was performed to set an appropriate electrical condition for operating a positive DEP force effect of at least 1019 v2/m3, and the interdigitated microelectrode structure was selected. The resulting wrinkled GO exhibited significantly improved electrical conductivity, reaching 21.721 µS while preserving the essential oxygen functional groups. Furthermore, a biosensor was fabricated using wrinkled GO deposited via DEP force. The biosensor demonstrated superior sensitivity, exhibiting a 9.6-fold enhancement compared with reduced GO (rGO) biosensors, as demonstrated through biological experiments targeting inducible nitric oxide synthase. This study highlights the potential of using DEP force to enhance electrical conductivity in GO-based biosensing applications, opening new avenues for high-performance diagnostics.