Analyzed Data Research Articles

Optical quality in vitro and in vivo of an extended depth-of-focus intraocular lens with isofocal design.

The aim of this study is to compare optical quality results obtained in laboratory analysis (in vitro) versus clinical data (in vivo). The optical quality of ISOPure intraocular lens was assessed both in vitro and in vivo using the modulation transfer function (MTF) for 3.0 and 4.5mm pupil diameters. In vitro measurements were obtained using deflectometer NIMO TRF1504, while in vivo measurements were taken with OPD-Scan III in a set of patients implanted with this lens. Ray tracing techniques were used to determine the MTF and area under MTF curve (MTFa) from the measured wavefront for the isolated lens and for the whole eye. The MTF of the isolated lens obtained under both in vitro and in vivo conditions showed comparable results for both pupil sizes. However, differences were found when comparing the MTF of the whole eye with the lens implanted versus the MTF measured in vitro for 4.5mm pupil size. Also, the MTFa defocus curve was compared with the defocus curve measured in vivo. The defocus curve from the in vivo study aligns closely with the MTFa of the in vitro model, with a useful defocus range of 0.40D. Thus, it is possible to anticipate the visual results of the implanted isofocal lens by using measurements on an optical bench and conducting optical simulations.

Party priorities in different pre-election New Zealand policy statements, 1984-2023

ABSTRACT Pre-election policy statements are important because they reveal information about parties’ policies and intended post-election priorities. Content analysis data from election manifestos, webpages, television broadcasts, and leaders’ speeches reveal clear left-right differences between the dominant Labour and National parties at elections between 1984 and 2023, with the exception of 1990. Between 1993 and 1999 and since 2011 broadcasts and speeches by National have been more right-wing on a left-right summary dimension than National’s manifestos and detailed webpages. The reverse was usually true for the right-wing Act Party, while New Zealand First’s position varied more in broadcasts and speeches than in its print programme. No real pattern for left-right topics was evident for the other parties. However, references to the environment, indigenous rights, and foreign policy were higher in long print documents than in television broadcasts and speeches. In contrast, political authority references were relatively low in print documents. When using equivalent documents, the Green and Māori parties, followed by Labour, were usually most supportive of environmental protection and socially progressive policies. The results confirm the importance of using similar documents, insofar as is possible, when making comparisons. In addition, shorter documents may be more useful for understanding parties’ main priorities.

Unified Aedes aegypti Protein Resource Database (UAAPRD): An Integrated High-Throughput In Silico Platform for Comprehensive Protein Structure Modeling and Functional Target Analysis to Enhance Vector Control Strategies.

A comprehensive examination of Aedes aegypti's proteome to detect key proteins that can be targeted with small molecules can disrupt blood feeding and disease transmission. However, research currently only focuses on finding repellent-like compounds, limiting studies on identifying unexplored proteins in its proteome. High-throughput analysis generates vast amounts of data, raising concerns about accessibility and usability. Establishing a dedicated database is a solution, centralizing information on identified proteins, functions, and modeled structures for easy access and research. This study focuses on scrutinizing key proteins in A. aegypti, modeling their structures using RaptorX standalone tool, identification of druggable binding sites using BiteNet, validating the models via Ramachandran plot studies and refining them via 50-ns molecular dynamic simulations using Schrodinger Maestro. By analyzing ~ 18k proteins in the proteome of A. aegypti in our previous studies, all proteins involved in the light and dark circadian rhythm of the mosquito, inclusive of proteins in blood feeding, metabolism, etc. were chosen for the current study. The outcome is UAAPRD, a unique repository housing information on hundreds of previously unmodeled and un-simulated mosquito proteins. This robust MYSQL database ( https://uaaprd.onrender.com/user ) houses data on 309 modeled & simulated proteins of A. aegypti. It allows users to obtain protein data, view evolutionary analysis data of the protein categories, visualize proteins of interest, and send request to screen against the pharmacophore models present in UAAPRD against ligand of interest. This study offers crucial insights for developing targeted studies, which will ultimately contribute to more effective vector control strategies.

Interim results of neoadjuvant immunotherapy with prolgolimab in patients with locally advanced MSI / dMMR colorectal cancer

Introduction: Colorectal cancer is one of the leading malignancies in Russia [1]. The standard approach for selected patients (pts) with locally advanced colon cancer is surgery with adjuvant chemotherapy. Several studies have shown that colorectal cancer (CRC) with presence of a disorder in the mismatch repair (dMMR) / microsatellite instability (MSI) is characterized with high sensitivity to the immune checkpoint inhibitors. Several studies have shown that MSI / dMMR CRC patients tend to be more responsive to immune checkpoint inhibitors such as pembrolizumab, nivolumab or ipilimumab. However, there was no information about the efficacy of prolgolimab, a PD-1 receptor blocking antibody. Prolgolimab was highly effective in melanoma treatment, while the toxicity was comparable to pembrolizumab and nivolumab. Methods: We initiated the phase II non-randomized open-label clinical trial. Inclusion criteria were: histologically verified, MSI / dMMR, clinical stage II–III CRC. According to study protocol, prolgolimab (1 mg / kg) is administered every two weeks, then surgery should be done after 6 months of immunotherapy (12 cycles). In case of surgical treatment refusal, the systemic treatment proceeds for 1 year. The co-primary endpoint was the complete response (pCR) rate. Secondary endpoints included tumor regression grade by Mandard (TRG), major pathologic response (MPR), overall response rate (ORR) disease free survival (DFS) and overall survival (OS). Here is a presentation of safety and pathologic response data — rates of pCR / MPR, objective response rate. Results: A total of 26 patients began treatment with prolgolimab from April, 2022 to February, 2024. Immune-related adverse effects of grade III–IV, were recorded in 1 (3,8 %) patient (autoimmune hepatitis grade IV); 4 (15,4 %) patients had adverse effects grade I–II: autoimmune thyroiditis, diarrhea, hypothyroidism. Two patients were refused to make a surgical treatment because of clinical CR and possible volume of surgery. Nine (34,6 %) patients underwent surgical treatment within 3 months after the immunotherapy completion: 7 patients had TRG 1 and pCR, 2 — TRG 2 and MPR after the treatment. ORR was 100 %, complete clinical response rate 40 %. The study is still ongoing, DFS and OS will be announced in further publications. Median follow-up time was 5 months. Conclusion: The first interim analysis data suggest a strong potential for neoadjuvant immunotherapy to become standard of care and allow further exploration of organ-sparing approaches in MMR / MSI CRC patients.

China's green energy growth: Economic policies, environmental economics, and strategies for resilience in the global economy

China has become a major global power due to its rapid economic growth, which is being driven by resource-intensive industries but at a considerable environmental cost. This study investigates the intricate relationships that exist between China's mining regulations, resource utilization, and environmentally friendly policies, as well as the overall impacts of these relationships on economic growth. The research uses a rigorous regression analysis approach and data from the Ministry of National Resources and the China Statistical Yearbook from 1986 to 2022. Integrating a Vector Error Correction Model (VECM) enables an investigation of the relationships among debt levels, GDP, and natural financing. Wald test estimates also reveal exact Corporate Social Responsibility (CSR) relationships. The results indicate that while China's economy has significantly benefited from mineral-intensive sectors, green measures are urgently needed to slow environmental deterioration. The focus should be redirected toward encouraging sustainable and ongoing development. These results highlight the critical role that green projects play in fostering economic growth. How China strikes a careful balance between its goals for ecological sustainability and economic growth is crucial for both China and the rest of the world in an era characterized by worries about climate change and resource shortages. The objective of this study is to analyze the complex relationship among China's mining regulations, resource utilization, and environmental policies. It will evaluate the effects of these factors on economic growth, with a particular focus on the necessity of adopting sustainable development practices in the face of environmental challenges and economic expansion. The study's goal is to examine the intricate relationships between China's resource use, environmental policies, and mining restrictions. It focuses on the importance of sustainable development methods in the face of environmental issues and economic growth. This research highlights the essential relationship between environmental stewardship and sustainable economic development, and policymakers, businesses, and environmental activists can all benefit from it.

Psychological Consequences of Experiencing Child Min Girls

Aim: The research aimed to study the psychological consequences of child marriage among girls through a phenomenological approach and semi-structured interviews. Methods: Twenty women from Gilan, Khoozestan, Sistan and Baloochistan, Khorasan and Yazd province who experienced child marriage and their current ages were less than 50 years old were selected through purposive sampling. Interviews and observations were conducted by traveling to each province. Colaizzi method was used in order to analysis data. Results: Results were included of 5 main themes and 15 sub themes in psychological consequences. Main themes are crashed ego, psychic traumas, negative emotions, immaturity and personal maturity. Conclusion: The results showed that negative psychological consequences of child marriage are much more than their positive ones.

Cytotoxic of Usnic Acid Isolated from Ramalina sp.

Ramalina sp. (Ramalinaceae) is a type of lichen known to contain many active secondary metabolite compounds that have the potential to be used as medicine or medicinal raw materials. One of the biological activities possessed by Ramalina sp. lichen is its anticancer activity. This research aims to isolate and identify active secondary metabolite compounds from the methanol extract of the Ramalina sp. lichen and to find out the cytotoxic activity of the isolated compound against MCF7 breast cancer cells. Compound 1 (usnic acid) was successfully isolated from fraction A. The isolation and purification process was carried out starting with a maceration process using acetone solvent, followed by silica gel column chromatography using a gradient solvent system consisting of n-hexane, n-hexane: EtOAc, EtOAc, EtOAc: MeOH, and MeOH with 5% increment of polarity to obtain 17 fractions (F-1 to F-17). From the 17 fractions obtained, fraction 3 (F-3) and fraction 4 (F-4) (eluted with n-hexane: EtOAc 30%), which had the same TLC profile, were combined and named as fraction A. Compound 1 (50 mg) is a yellow needle crystal that was formed in a bottle of fraction A, which was obtained after the process of combining fractions F-3 and F-4 and solvent evaporation process. The crystals were then separated and purified with CHCl3 and MeOH. Compound 1 was then characterized based on spectroscopic data. Various spectroscopic analysis data, including FTIR, 1D- and 2D-NMR, and LC-ESI-MS, show that Compound 1 is a dibenzofuran derivative compound with 18 carbons (3 from carbonyl groups (C=O) and 3 from methyl groups) and 2 hydroxyls (-OH). Cytotoxicity assay showed that at a low concentration of 18.75 ug/mL, Com-pound 1 caused a 67.06% decrease in MCF7 viability.

One new triterpene glycoside from Cyclocarya paliurus

One previously undescribed triterpene glycoside (1) and two known compounds were isolated from the leaves of Cyclocarya paliurus (2-3). Their structures were elucidated based on methods of spectroscopic analysis and NMR data comparison with those in the literature. Compound 1 showed a moderate inhibitory effect on melanogenesis with an IC50 value of 282.3 μM, with the positive drug arbutin showing an IC50 value of 168.5 μM.

Study of secondary charged particles produced in 12C-emulsion interactions at 4.5A GeV/c

This paper deals with the interactions of [Formula: see text]C-nucleus with the nuclear emulsion at 4.5[Formula: see text]A[Formula: see text]GeV/c, focused on distributions of multiplicity and the variation of the average multiplicities for secondary charged particles (black, gray, shower, and heavy particles) for the events released from these interactions. These averages have been calculated based on a model of modified cascade evaporation. A comparison has been made between the average multiplicities of the charged secondary particles produced from [Formula: see text]C and others from projectiles that interact with the nuclear emulsion at different energies, this comparison of [Formula: see text]C with other projectiles shows the fluctuations of the values of the average shower with gray for [Formula: see text]O and [Formula: see text]Si interactions occurring somewhat faster. The average number of shower, gray particles increases with the increasing mass number of the projectile Ap, except for black particles, which are nearly constant. The correlations of the average multiplicities for the different charged secondary particles are discussed. There is strong linear dependence in the correlations of average particles of shower, compound, and heavy on gray particles. The results of experimental and theoretical data were also verified with recent analysis data and new observations and were found to be consistent. Moreover, the results indicate that the residual target nucleus may have reached a temperature and constant excitation energy at a certain value for shower particles. The excess amount of energy at higher values of shower particles may be pumped into the system, and this energy may be expended during a transition of phase in the target nucleus system. The theoretical calculation results show good agreement with experimental data.

Understanding the Biomechanics of Musculoskeletal Injuries in High-Risk Environmental Conditions

The present study examines the biomechanics of musculoskeletal injuries in high-risk environmental conditions by thoroughly analyzing diverse data sources and employing various methodologies. This study utilizes motion analysis, force sensor measurements, computer simulations, and biomechanical testing to examine the various factors contributing to musculoskeletal injuries. The analysis of motion indicates that specific tests, namely varus test, impose considerably greater biomechanical stress, thereby emphasizing their susceptibility to causing injuries. The force sensor data reveals that pressure mapping system is responsible for exerting the highest force, raising concerns regarding its potential impact on the risk of injury. According to computer simulations, various injury risks are associated with different conditions, with load carriage exhibiting the highest risk. The analysis of joint stability during biomechanical testing reveals discrepancies in joint stability levels across different tasks. Outliers within the dataset highlight tasks that exhibit notable concerns regarding joint stability. Moreover, supplementary motion analysis data about various task variants, such as Sulcus sign and vasus stress test unveils distinct variations that lead to heightened levels of biomechanical stress. The discoveries mentioned above offer valuable perspectives on the biomechanical foundations of musculoskeletal injuries in environments with elevated risk levels. The aforementioned findings emphasize the necessity of implementing focused interventions, enhancing equipment design, and implementing heightened safety measures to reduce the risks of injury effectively. The present study establishes a fundamental basis for subsequent research endeavors and proposes approaches designed to safeguard the welfare of individuals operating in demanding contexts.

Factors influencing IMF assistance in the Sub-Saharan African region.

This study examines the determinants influencing the likelihood of Sub-Saharan African (SSA) countries seeking assistance from the International Monetary Fund (IMF). The IMF, as a global institution, aims to promote sustainable growth and prosperity among its member countries by supporting economic strategies that foster financial stability and collaboration in monetary affairs. Utilising panel-probit regression, this study analyses data from thirty-nine SSA countries spanning from 2000 to 2022, focusing on twelve factors: Current Account Balance (CAB), inflation, corruption, General Government Net Lending and Borrowing (GGNLB), General Government Gross Debt (GGGD), Gross Domestic Product Growth (GDPG), United Nations Security Council (UNSC) involvement, regime types (Closed Autocracy, Electoral Democracy, Electoral Autocracy, Liberal Democracy) and China Loan. The results indicate that corruption and GDP growth rate have the most significant influence on the likelihood of SSA countries seeking IMF assistance. Conversely, factors such as CAB, UNSC involvement, LD and inflation show inconsequential effects. Notable, countries like Sudan, Burundi, and Guinea consistently rank high in seeking IMF assistance over various time frames within the observed period. Sudan emerges with a probability of more than 44% in seeking IMF assistance, holding the highest ranking. Study emphasises the importance of understanding SSA region rankings and the variability of variables for policymakers, investors, and international organisations to effectively address economic challenges and provide financial assistance.

Decoding depression: a comprehensive multi-cohort exploration of blood DNA methylation using machine learning and deep learning approaches

The causes of depression are complex, and the current diagnosis methods rely solely on psychiatric evaluations with no incorporation of laboratory biomarkers in clinical practices. We investigated the stability of blood DNA methylation depression signatures in six different populations using six public and two domestic cohorts (n = 1942) conducting mega-analysis and meta-analysis of the individual studies. We evaluated 12 machine learning and deep learning strategies for depression classification both in cross-validation (CV) and in hold-out tests using merged data from 8 separate batches, constructing models with both biased and unbiased feature selection. We found 1987 CpG sites related to depression in both mega- and meta-analysis at the nominal level, and the associated genes were nominally related to axon guidance and immune pathways based on enrichment analysis and eQTM data. Random forest classifiers achieved the highest performance (AUC 0.73 and 0.76) in CV and hold-out tests respectively on the batch-level processed data. In contrast, the methylation showed low predictive power (all AUCs < 0.57) for all classifiers in CV and no predictive power in hold-out tests when used with harmonized data. All models achieved significantly better performance (>14% gain in AUCs) with pre-selected features (selection bias), with some of the models (joint autoencoder-classifier) reaching AUCs of up to 0.91 in the final testing regardless of data preparation. Different algorithmic feature selection approaches may outperform limma, however, random forest models perform well regardless of the strategy. The results provide an overview over potential future biomarkers for depression and highlight many important methodological aspects for DNA methylation-based depression profiling including the use of machine learning strategies.

The Violence of Peace: Post Good Friday Agreement Paramilitary Vigilantism in Northern Ireland

ABSTRACT This paper focuses on post Belfast/Good Friday Agreement paramilitary violence in Northern Ireland, specifically the vigilantism of paramilitary style attacks (PSAs) carried out by the loyalist and republican paramilitaries. This localised form of violence, formerly referred to as punishment attacks, has been the most persistent form of paramilitary violence in a post-conflict Northern Ireland. This paper critically analyses the broad criminological literature on the emergence of vigilantism, including consideration of factors impacting police confidence. The findings are applied to Northern Irish PSAs from 1998 to 2023. The author analyses data relating to Freedom of Information (FOI) requests to the Police Service of Northern Ireland. The results of these FOIs indicate that loyalist and republican paramilitaries combined have been responsible for 3,260 PSAs from 1998 to February 2023. Paramilitary republicans have been responsible for 1,196 attacks and loyalists responsible for 2,064. The article considers the post-Agreement evolution of this violence in terms of victims, injuries, geographical location, and police response. The most recent data indicate a downturn in PSAs. However, there are still significant challenges faced in the development of broader trust for the criminal justice system, within certain areas of Northern Ireland.

The Rivalry between Intramolecular Tetrel Bonds and Intermolecular Hydrogen Bonds in (O-Si) Chelates of N-Silylmethylamides and -ureas. A Theoretical Study.

The comparison of the results of theoretical calculations of (O-Si) chelates of N-silylmethylated amides and ureas with the axial chlorine or fluorine atom at silicon to the data of X-ray analysis of related compounds revealed the formation of covalent O-Si tetrel bonds (TB) or noncovalent O⋅⋅⋅Si tetrel bonds (NTB). The nature of the formed tetrel bond depends on the substituents at silicon and the polarity of the medium. The competition between the intramolecular TB and intermolecular hydrogen bonds (HB) with proton donors depends on the center of basicity involved in the formation of HB, which could be either oxygen or halogen. The hydrogen bonding can result in changing the nature of the tetrel bonds from covalent to noncovalent and vice versa by varying their lengths and energies. The O-Si bond energies estimated by QTAIM analysis of N-[(chlorodimethylsilyl)methyl]-N-methylacetamide and its H-complexes vary within the range of 7.2 and 12 kcal/mol in gas and solution, respectively, and correlate with the O-Si bond lengths.

Comparative Analysis of the Mitochondrial Genomes of Three Species of Yangiella (Hemiptera: Aradidae) and the Phylogenetic Implications of Aradidae

The mitochondrial genomes of three species of Yangiella were sequenced, annotated, and analyzed. The genome length of the three species of the genus is 15,070–15,202 bp, with a typical gene number, including a control region, 2 ribosomal RNA genes (rRNAs), 22 transfer RNA genes (tRNAs), and 13 protein-coding genes (PCGs). It was found that the mitochondrial genome of Yangiella had AT bias. Except for the lack of a DHU arm of the trnS1 gene, the other tRNAs had a typical cloverleaf structure, and the codon usage preferences of the three species exhibited high similarity. In addition, tRNA gene rearrangements were observed among the three subfamilies of Aradidae (Mezirinae, Calisiinae, Aradinae), and it was found that codon usage preferences appeared to be less affected by base mutation and more by natural selection. The Pi and Ka/Ks values indicated that cox1 was the most conserved gene in the mitochondrial genome of Aradidae, while atp8 and nad6 were rapidly evolved genes. Substitution saturation level analysis showed that the nucleic acid sequence of mitochondrial protein-coding genes in Aradidae did not reach saturation, suggesting the rationality of the phylogenetic analysis data. Bayesian and maximum likelihood methods were used to analyze the phylogeny of 16 species of Hemiptera insects, which supported the monophyly of Aneurinae, Carventinae, and Mezirinae, as well as the monophyly of Yangiella. Based on fossils and previous studies, the differentiation time was inferred, indicating that Yangiella diverged about 57 million years ago.

The State of Health of Electrical Connectors

For modern machines, factories and electric and autonomous vehicles, the importance of vreliable electrical connectors cannot be overstated. With an increasing number of connectors being used in machines, factories and vehicles, ensuring their reliability is crucial for comfort and safety alike. One of the key indicators of reliability is the lifetime of connectors. To evaluate the lifetime of electrical connectors, a testing method and a model for calculating their lifetime based on the test data were developed. The results from these tests were compared to failure analysis data from long-term field operations. The findings indicate that the laboratory tests can accurately reproduce the main failures observed in the field. However, such lifetime tests can be time- and labor-intensive. To address this challenge, a data-driven method is proposed that predicts the lifetime of electrical connectors using statistical analysis of electrical contact resistance data collected from short-term tests. The predictions from this method were compared to actual results obtained from long-term tests. A strong correlation was observed between the contact resistance development in short-term tests and the number of failures in later stages of testing. Thus, apart from predicting the lifetime of connectors, this method can also be applied for failure prognosis in real-time operations.

Neuroimaging meta regression for coordinate based meta analysis data with a spatial model.

Coordinate-based meta-analysis combines evidence from a collection of neuroimaging studies to estimate brain activation. In such analyses, a key practical challenge is to find a computationally efficient approach with good statistical interpretability to model the locations of activation foci. In this article, we propose a generative coordinate-based meta-regression (CBMR) framework to approximate a smooth activation intensity function and investigate the effect of study-level covariates (e.g. year of publication, sample size). We employ a spline parameterization to model the spatial structure of brain activation and consider four stochastic models for modeling the random variation in foci. To examine the validity of CBMR, we estimate brain activation on 20 meta-analytic datasets, conduct spatial homogeneity tests at the voxel level, and compare the results to those generated by existing kernel-based and model-based approaches. Keywords: generalized linear models; meta-analysis; spatial statistics; statistical modeling.

Synthesis, Characterization, DNA, Fluorescence, Molecular Docking, and Antimicrobial Evaluation of Novel Pd(II) Complex Containing O, S Donor Schiff Base Ligand and Azole Derivative

Pd(II) with the Schiff base ligand 2-Hydroxy-3-Methoxy Benzaldehyde-Thiosemicarbazone (HMBATSC) (L2) and 2-aminobenzothiazole (2-ABZ) (L1) was synthesized. The Schiff base ligand and the Palladium(II) complex were characterized by C.H.N.S, FT-IR, conductance studies, magnetic susceptibility, XRD, and TGA. From the elemental analysis and spectral data, the complex was proposed to have the formula [Pd(HMBATSC)(2-ABZ)H2O]. The interaction between the Pd(II) complex and DNA was examined through various methods, including UV–Vis spectroscopy, fluorescence techniques, and DNA viscosity titrations. The findings provided strong evidence that the interaction between the Pd(II) complex and DNA occurs through the intercalation mode. The analysis yielded the following values: a Stern–Volmer quenching constant (ksv) of 1.67 × 104 M−1, a quenching rate constant (kq) of 8.35 × 1011 M−1 s−1, a binding constant (kb) of 5.20 × 105 M−1, and a number of binding the sites (n) of 1.392. DFT studies suggest that the azole derivative may act as an electron donor through pyridine nitrogen, while the Schiff base ligand may act as an electron donor via oxygen and sulfur atoms. TDDFT calculations indicate that the intramolecular charge transfer from the Schiff base to Pd(II) is responsible for the complex’s fluorescence quenching. The powder X-ray diffraction data revealed that the complex is arranged in a monoclinic system. The resulting Pd(II) complex was investigated for its antimicrobial activity and demonstrated antibacterial efficiency. Interestingly, it showed potent activity against E. coli and E. niger that was found to be more powerful than that recorded for Neomycin.

Nab-paclitaxel plus S-1 versus nab-paclitaxel plus gemcitabine in patients with advanced pancreatic cancer: a multicenter, randomized, phase II study.

Encouraging antitumor activity of nab-paclitaxel plus S-1 (AS) has been shown in several small-scale studies. This study compared the efficacy and safety of AS versus standard-of-care nab-paclitaxel plus gemcitabine (AG) as a first-line treatment for advanced pancreatic cancer (PC). In this multicenter, randomized, phase II trial, eligible patients with unresectable, locally advanced, or metastatic PC were recruited and randomly assigned (1:1) to receive AS (nab-paclitaxel 125mg/m2 on days 1 and 8; S-1 twice daily on days 1 through 14) or AG (nab-paclitaxel 125mg/m2 on days 1 and 8; gemcitabine 1000mg/m2 on days 1 and 8) for 6 cycles. The primary endpoint was progression-free survival (PFS). Between July 16, 2019, and September 9, 2022, 62 patients (AS, n = 32; AG, n = 30) were treated and evaluated. With a median follow-up of 8.36 months at preplanned interim analysis (data cutoff, March 24, 2023), the median PFS (8.48 vs 4.47 months; hazard ratio [HR], 0.402; P = .002) and overall survival (OS; 13.73 vs 9.59 months; HR, 0.226; P < .001) in the AS group were significantly longer compared to the AG group. More patients had objective response in the AS group than AG group (37.50% vs 6.67%; P = .005). The most common grade 3-4 adverse events were neutropenia and leucopenia in both groups, and gamma glutamyl transferase increase was observed only in the AG group. The first-line AS regimen significantly extended both PFS and OS of Chinese patients with advanced PC when compared with the AG regimen, with a comparable safety profile. (ClinicalTrials.gov Identifier: NCT03636308).

Actn2 defects accelerates H9c2 hypertrophy via ERK phosphorylation under chronic stress.

In humans, ACTN2 mutations are identified as highly relevant to a range of cardiomyopathies such as DCM and HCM, while their association with sudden cardiac death has been observed in forensic cases. Although ACTN2 has been shown to regulate sarcomere Z-disc organization, a causal relationship between ACTN2 dysregulation and cardiomyopathies under chronic stress has not yet been investigated. In this work, we explored the relationship between Actn2 dysregulation and cardiomyopathies under dexamethasone treatment. Previous cases of ACTN2 mutations were collected and the conservative analysis was carried out by MEGA 11, the possible impact on the stability and function of ACTN2 affected by these mutations was predicted by Polyphen-2. ACTN2 was suppressed by siRNA in H9c2 cells under dexamethasone treatment to mimic the chronic stress in vitro. Then the cardiac hypertrophic molecular biomarkers were elevated, and the potential pathways were explored by transcriptome analysis. Actn2 suppression impaired calcium uptake and increased hypertrophy in H9c2 cells under dexamethasone treatment. Concomitantly, hypertrophic molecular biomarkers were also elevated in Actn2-suppressed cells. Further transcriptome analysis and Western blotting data suggested that Actn2 suppression led to the excessive activation of the MAPK pathway and ERK cascade. In vitro pharmaceutical intervention with ERK inhibitors could partially reverse the morphological changes and inhibit the excessive cardiac hypertrophic molecular biomarkers in H9c2 cells. Our study revealed a functional role of ACTN2 under chronic stress, loss of ACTN2 function accelerated H9c2 hypertrophy through ERK signaling. A commercial drug, Ibudilast, was identified to reverse cell hypertrophy in vitro.