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1.
PLoS One ; 19(5): e0302561, 2024.
Article in English | MEDLINE | ID: mdl-38718054

ABSTRACT

This paper uses the difference-in-differences model to research how the "piercing the corporate veil" system marked by the 2005 Company Law amendment affects the level of corporate creditor protection. The research results show that private enterprises and local state-owned enterprises are sensitive and significant to this legal amendment. In contrast, local state-owned enterprises are more sensitive and have a stronger motivation to protect the interests of creditors. The motivation of companies with weaker profitability for creditor protection lasts not only for the year of law revision but also extends to the year of implementation. With the law's implementation, the growth effect of creditor protection for local state-owned enterprises has become more significant. Further analysis shows that the main findings of this article are more significant in companies with larger debt scales, companies with a higher year-on-year growth rate of operating income, companies with controlling shareholders, and companies with higher stock market capitalization. From an empirical research view, this paper explains the economic effect and mechanism of the whole corporate personality under the complete system and adds economic evidence for how the law acts on the capital market.


Subject(s)
Investments , Investments/legislation & jurisprudence , Investments/economics , Humans , Models, Economic , Private Sector/economics , Private Sector/legislation & jurisprudence , Industry/economics , Industry/legislation & jurisprudence , Commerce/legislation & jurisprudence , Commerce/economics
2.
J Hazard Mater ; 471: 134385, 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38678711

ABSTRACT

Nitric oxide (NO) is a signaling molecule with diverse roles in various organisms. However, its role in the opportunistic pathogen Aspergillus flavus remains unclear. This study investigates the potential of NO, mediated by metabolites from A. oryzae (AO), as an antifungal strategy against A. flavus. We demonstrated that AO metabolites effectively suppressed A. flavus asexual development, a critical stage in its lifecycle. Transcriptomic analysis revealed that AO metabolites induced NO synthesis genes, leading to increased intracellular NO levels. Reducing intracellular NO content rescued A. flavus spores from germination inhibition caused by AO metabolites. Furthermore, exogenous NO treatment and dysfunction of flavohemoglobin Fhb1, a key NO detoxification enzyme, significantly impaired A. flavus asexual development. RNA-sequencing and metabolomic analyses revealed significant metabolic disruptions within tricarboxylic acid (TCA) cycle upon AO treatment. NO treatment significantly reduced mitochondrial membrane potential (Δψm) and ATP generation. Additionally, aberrant metabolic flux within the TCA cycle was observed upon NO treatment. Further analysis revealed that NO induced S-nitrosylation of five key TCA cycle enzymes. Genetic analysis demonstrated that the S-nitrosylated Aconitase Acon and one subunit of succinate dehydrogenase Sdh2 played crucial roles in A. flavus development by regulating ATP production. This study highlights the potential of NO as a novel antifungal strategy to control A. flavus by compromising its mitochondrial function and energy metabolism.


Subject(s)
Aspergillus flavus , Citric Acid Cycle , Mitochondria , Nitric Oxide , Citric Acid Cycle/drug effects , Aspergillus flavus/metabolism , Aspergillus flavus/growth & development , Aspergillus flavus/drug effects , Nitric Oxide/metabolism , Mitochondria/drug effects , Mitochondria/metabolism , Antifungal Agents/pharmacology , Membrane Potential, Mitochondrial/drug effects , Spores, Fungal/drug effects , Spores, Fungal/growth & development , Fungal Proteins/metabolism , Fungal Proteins/genetics
3.
Chem Commun (Camb) ; 60(38): 5034-5037, 2024 May 07.
Article in English | MEDLINE | ID: mdl-38630292

ABSTRACT

Herein, we describe an effective strategy for synthesizing polythioethers with a well-defined structure through the cationic polymerization of thiirane with electron-withdrawing substituents. This strategy allows for precisely controlling the regio- and stereochemistry of the ring-opening polymerization of 2-phenylthiirane, thus allowing for producing poly(2-phenylthiirane) with high stereoregularity using enantiomeric pure thiirane.

4.
World J Diabetes ; 15(4): 793-796, 2024 Apr 15.
Article in English | MEDLINE | ID: mdl-38680700

ABSTRACT

This letter to the editor discusses the publication on gut microbiome supplementation as therapy for metabolic syndrome. Gut microbiome dysbiosis disrupts intestinal bacterial homeostasis and is related to chronic inflammation, insulin resistance, cardiovascular diseases, type 2 diabetes mellitus, and obesity. Previous research has found that increasing the abundance of beneficial microbiota in the gut modulates metabolic syndrome by reducing chronic inflammation and insulin resistance. Prebiotics, probiotics, synbiotics, and postbiotics are often used as supplements to increase the number of beneficial microbes and thus the production of short-chain fatty acids, which have positive effects on the gut microbiome and metabolic syndrome. In this review article, the author summarizes the available supplements to increase the abundance of beneficial gut microbiota and reduce the abundance of harmful microbiota in patients with metabolic disorders. Our group is also researching the role of the gut microbiota in chronic liver disease. This article will be of great help to our research. At the end of the letter, the mechanism of the gut microbiota in chronic liver disease is discussed.

5.
Front Med (Lausanne) ; 11: 1288423, 2024.
Article in English | MEDLINE | ID: mdl-38660417

ABSTRACT

Objective: To investigate the knowledge, attitude, and practice (KAP) of psoriasis patients toward the disease. Methods: A web-based cross-sectional study was conducted among psoriasis patients who were diagnosed at the outpatient of Shaanxi Provincial People's Hospital in March 2023. A self-designed questionnaire was administered for data collection and KAP assessment. Results: A total of 526 valid questionnaires were included, including 257 males (48.86%) psoriasis patients. Their mean KAP scores were 8.09 ± 3.60 (possible range: 0-12), 31.94 ± 4.61 (possible range: 10-50), and 51.92 ± 8.83 (possible range: 15-75), respectively. Pearson's correlation analysis showed a positive correlation between knowledge and attitude (r = 0.186, p < 0.001), a positive correlation between knowledge and practice (r = 0.313, p < 0.001), and a negative correlation between attitude and practice (r = -0.181, p < 0.001). Moreover, structural equation model showed that medication (ß = 2.74, 95% CI: 2.17, 3.32, p < 0.001) has significantly positive effect on knowledge. Education (ß = 0.56, 95% CI: 0.31, 0.81, p < 0.001) and duration of psoriasis (ß = 1.01, 95% CI: 0.54, 1.49, p < 0.001) have significantly positive effect on attitude. Knowledge (ß = 1.03, 95% CI: 0.80, 1.26, p < 0.001) and medication (ß = 4.59, 95% CI: 2.78, 6.40, p < 0.001) has significantly positive effect on practice, while attitude (ß = -0.41, 95% CI: -0.57, -0.26, p < 0.001) and duration of psoriasis (ß = -2.53, 95% CI: -3.49, -1.57, p < 0.001) exhibit significantly negative effect on practice. Conclusion: Psoriasis patients have good knowledge, positive attitude, and proactive practice toward the disease. Education, medication, duration of psoriasis might have effect on their KAP.

6.
World J Gastrointest Oncol ; 16(4): 1660-1667, 2024 Apr 15.
Article in English | MEDLINE | ID: mdl-38660640

ABSTRACT

BACKGROUND: Gastric cancer (GC) is a significant health problem worldwide, and early detection and accurate diagnosis are crucial for improving patient outcomes. Crawling-type gastric adenocarcinoma is a rare subtype of GC that has unique histopathological and clinical characteristics, and its diagnosis and management can be challenging. This pathological type of GC is also rare. CASE SUMMARY: Here, we report the case of a patient who underwent ordinary endoscopy, narrow-band imaging, and endoscopic ultrasonography intending to determine the extent of tumor invasion and upper abdominal enhanced computed tomography and whether there was tumor metastasis. Then, endoscopic submucosal dissection was performed. After pathological and immunohistochemical examination, the pathological diagnosis was crawling-type gastric adenocarcinoma. This is a very rare and special pathological type of tumor. This case highlights the importance of using advanced endoscopic techniques and pathological examination in diagnosing and managing gastric crawling-type adenocarcinoma. Moreover, the findings underscore the need for continued research and clinical experience in this rare subtype of GC to improve patient outcomes. CONCLUSION: The "crawling-type" GC is a rare and specific tumor pathology. It is difficult to identify and diagnose gliomas via endoscopy. The tumor is ill-defined, with a flat appearance and indistinct borders due to the lack of contrast against the background mucosa. Pathology revealed that the tumor cells were hand-like, so the patient has diagnosed with "crawling-type" gastric adenocarcinoma.

7.
Nat Commun ; 15(1): 3002, 2024 Apr 08.
Article in English | MEDLINE | ID: mdl-38589410

ABSTRACT

The development of closed-loop recycling polymers that exhibit excellent performance is of great significance. Sulfur-rich polymers possessing excellent optical, thermal, and mechanical properties are promising candidates for chemical recycling but lack efficient synthetic strategies for achieving diverse structures. Herein, we report a universal synthetic strategy for producing polytrithiocarbonates, a class of sulfur-rich polymers, via the polycondensation of dithiols and dimethyl trithiocarbonate. This strategy has excellent compatibility with a wide range of monomers, including aliphatic, heteroatomic, and aromatic dithiols enabling the synthesis of polytrithiocarbonates with diverse structures. The present synthesis strategy offers a versatile platform for the construction of thermoplastics, elastomers, and vitrimers. Notably, these polytrithiocarbonates can be easily depolymerized via solvolysis into the corresponding monomers, which can be repolymerized to virgin polymers without changing the material properties.

8.
World J Stem Cells ; 16(3): 287-304, 2024 Mar 26.
Article in English | MEDLINE | ID: mdl-38577232

ABSTRACT

BACKGROUND: The self-assembly of solid organs from stem cells has the potential to greatly expand the applicability of regenerative medicine. Stem cells can self-organise into microsized organ units, partially modelling tissue function and regeneration. Dental pulp organoids have been used to recapitulate the processes of tooth development and related diseases. However, the lack of vasculature limits the utility of dental pulp organoids. AIM: To improve survival and aid in recovery after stem cell transplantation, we demonstrated the three-dimensional (3D) self-assembly of adult stem cell-human dental pulp stem cells (hDPSCs) and endothelial cells (ECs) into a novel type of spheroid-shaped dental pulp organoid in vitro under hypoxia and conditioned medium (CM). METHODS: During culture, primary hDPSCs were induced to differentiate into ECs by exposing them to a hypoxic environment and CM. The hypoxic pretreated hDPSCs were then mixed with ECs at specific ratios and conditioned in a 3D environment to produce prevascularized dental pulp organoids. The biological characteristics of the organoids were analysed, and the regulatory pathways associated with angiogenesis were studied. RESULTS: The combination of these two agents resulted in prevascularized human dental pulp organoids (Vorganoids) that more closely resembled dental pulp tissue in terms of morphology and function. Single-cell RNA sequencing of dental pulp tissue and RNA sequencing of Vorganoids were integrated to analyse key regulatory pathways associated with angiogenesis. The biomarkers forkhead box protein O1 and fibroblast growth factor 2 were identified to be involved in the regulation of Vorganoids. CONCLUSION: In this innovative study, we effectively established an in vitro model of Vorganoids and used it to elucidate new mechanisms of angiogenesis during regeneration, facilitating the development of clinical treatment strategies.

9.
Am J Cancer Res ; 14(3): 1419-1432, 2024.
Article in English | MEDLINE | ID: mdl-38590411

ABSTRACT

The pathogenesis of glioma has remained unclear. In this study, it was found that high expression of the outer dense fibers of sperm tail 3B (ODF3B) in gliomas was positively correlated with the grade of glioma. The higher the grade, the worse the prognosis. ODF3B is closely related to the growth and apoptosis of glioma. In terms of mechanism, ODF3B was found to affect the proliferation and apoptosis of glioma through the JAK1 and JAK2/STAT3 pathways. ODF3B was also found to affect the growth and apoptosis of glioma in vivo. We conclude that ODF3B affects glioma proliferation and apoptosis via the JAK/STAT pathway and is a potential therapeutic target.

10.
J Am Chem Soc ; 146(12): 8500-8507, 2024 Mar 27.
Article in English | MEDLINE | ID: mdl-38483183

ABSTRACT

The selective transmembrane permeation of sodium ions achieved by biomimetic chemistry shows great potential to solve the problem of sodium ion transport blockade in diseases, but its implementation faces enormous difficulties. Herein, we design and synthesize a series of helically folded nanopores by employing a quinoline-oxadiazole structural sequence to finely replicate the pentahydrate structure of sodium ions. Surprisingly, these nanopores are capable of achieving sodium transmembrane permeation with ion selectivity at the level of natural sodium channels, as observed in rationally designed nanopores (M1-M5) with Na+/K+ ion selectivity ratio of up to 20.4. Moreover, slight structural variations in nanopore structures can switch ion transport modes between the channel and carrier. We found that, compared to the carrier mode, the channel mode not only transports ions faster but also has higher ion selectivity during transmembrane conduction, clearly illustrating that the trade-off phenomenon between ion selectivity and transport activity does not occur between the two transport modes of channel and carrier. At the same time, we also found that the spatial position and numbers of coordination sites are crucial for the sodium ion selectivity of the nanopores. Moreover, carrier M1 reported in this work is totally superior to the commercial Na+ carrier ETH2120, especially in terms of Na+/K+ ion selectivity, thus being a potentially practical Na+ carrier. Our study provides a new paradigm on the rational design of sodium-specific synthetic nanopores, which will open up the possibility for the application of artificial sodium-specific transmembrane permeation in biomedicine and disease treatment.

11.
Spectrochim Acta A Mol Biomol Spectrosc ; 313: 124147, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38490123

ABSTRACT

The accurate and effective detection of moisture in coal gravels is crucial. Conventional air oven-drying method suffers from prolonged processing times and their disruptive nature. This paper proposes a deep learning-based adaptive fusion method for multiple microwave spectra to non-destructively detect the moisture content of coal gravels. First, a purpose-built free-space measurement platform is employed to acquire microwave spectra of coal samples, encompassing the magnitude and phase spectra of reflection coefficients (S11) and transmission coefficients (S21). Subsequently, a Monte-Carlo cross-validation-based method is adopted to detect and eliminate outliers in the spectra. Furthermore, a novel feature extraction module is proposed, enhancing the traditional U-shaped network using residual learning (ResNet) and the convolutional block attention module (CBAM) to extract and reconstruct subtle spectral features. Inspired by the high-level data fusion, an adaptive spectra fusion method is then introduced that can autonomously balance the contributions between different spectra. The experimental results underscore the advantages of the proposed method, with narrow frequency intervals between 2.50-3.25 GHz, 3.75-4.00 GHz, and 4.75-5.00 GHz exhibiting superior detection accuracy compared to the entire frequency band, achieving R2 = 0.9034, MAE = 1.0254, RMSE = 1.2948 and RPIQ = 6.0630.

12.
Comput Biol Med ; 171: 108200, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38428099

ABSTRACT

BACKGROUND: The COVID-19 pandemic caused by SARS-CoV-2 has led to significant global morbidity and mortality, with potential neurological consequences, such as Parkinson's disease (PD). However, the underlying mechanisms remain elusive. METHODS: To address this critical question, we conducted an in-depth transcriptome analysis of dopaminergic (DA) neurons in both COVID-19 and PD patients. We identified common pathways and differentially expressed genes (DEGs), performed enrichment analysis, constructed protein‒protein interaction networks and gene regulatory networks, and employed machine learning methods to develop disease diagnosis and progression prediction models. To further substantiate our findings, we performed validation of hub genes using a single-cell sequencing dataset encompassing DA neurons from PD patients, as well as transcriptome sequencing of DA neurons from a mouse model of MPTP(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced PD. Furthermore, a drug-protein interaction network was also created. RESULTS: We gained detailed insights into biological functions and signaling pathways, including ion transport and synaptic signaling pathways. CD38 was identified as a potential key biomarker. Disease diagnosis and progression prediction models were specifically tailored for PD. Molecular docking simulations and molecular dynamics simulations were employed to predict potential therapeutic drugs, revealing that genistein holds significant promise for exerting dual therapeutic effects on both PD and COVID-19. CONCLUSIONS: Our study provides innovative strategies for advancing PD-related research and treatment in the context of the ongoing COVID-19 pandemic by elucidating the common pathogenesis between COVID-19 and PD in DA neurons.


Subject(s)
COVID-19 , Parkinson Disease , Animals , Mice , Humans , Parkinson Disease/genetics , Parkinson Disease/metabolism , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/pharmacology , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/therapeutic use , Molecular Docking Simulation , Pandemics , SARS-CoV-2 , Disease Models, Animal
13.
J Integr Med ; 22(2): 93-101, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38519278

ABSTRACT

Obesity is defined as abnormal or excessive fat accumulation that may impair health. Obesity is associated with numerous pathological changes including insulin resistance, fatty liver, hyperlipidemias, and other obesity-related diseases. These comorbidities comprise a significant public health threat. Existing anti-obesity drugs have been limited by side effects that include depression, suicidal thoughts, cardiovascular complications and stroke. Acupuncture treatment has been shown to be effective for treating obesity and obesity-related conditions, while avoiding side effects. However, the mechanisms of acupuncture in treating obesity-related diseases, especially its effect on neural circuits, are not well understood. A growing body of research has studied acupuncture's effects on the endocrine system and other mechanisms related to the regulation of neural circuits. In this article, recent research that was relevant to the use of acupuncture to treat obesity and obesity-related diseases through the neuroendocrine system, as well as some neural circuits involved, was summarized. Based on this, acupuncture's potential ability to regulate neural circuits and its mechanisms of action in the endocrine system were reviewed, leading to a deeper mechanistic understanding of acupuncture's effects and providing insight and direction for future research about obesity. Please cite this article as: Jiang LY, Tian J, Yang YN, Jia SH, Shu Q. Acupuncture for obesity and related diseases: insight for regulating neural circuit. J Integr Med. 2024; 22(2): 93-101.


Subject(s)
Acupuncture Therapy , Anti-Obesity Agents , Humans , Acupuncture Therapy/adverse effects , Obesity/therapy
14.
Sci Rep ; 14(1): 7494, 2024 03 29.
Article in English | MEDLINE | ID: mdl-38553518

ABSTRACT

Brain structural changes in Parkinson's disease (PD) are progressive throughout the disease course. Changes in surface morphology with disease progression remain unclear. This study aimed to assess the volumetric and shape changes of the subcortical nuclei during disease progression and explore their association with clinical symptoms. Thirty-four patients and 32 healthy controls were enrolled. The global volume and shape of the subcortical nuclei were compared between patients and controls at baseline. The volume and shape changes of the subcortical nuclei were also explored between baseline and 2 years of follow-up. Association analysis was performed between the volume of subcortical structures and clinical symptoms. In patients with PD, there were significantly atrophied areas in the left pallidum and left putamen, while in healthy controls, the right putamen was dilated compared to baseline. The local morphology of the left pallidum was correlated with Mini Mental State Examination scores. The left putamen shape variation was negatively correlated with changes in Unified Parkinson's Disease Rating Scale PART III scores. Local morphological atrophy of the putamen and pallidum is an important pathophysiological change in the development of PD, and is associated with motor symptoms and cognitive status in patients with PD.


Subject(s)
Parkinson Disease , Humans , Parkinson Disease/pathology , Magnetic Resonance Imaging , Brain/pathology , Putamen/pathology , Disease Progression , Atrophy/pathology
15.
Phytomedicine ; 127: 155440, 2024 May.
Article in English | MEDLINE | ID: mdl-38452691

ABSTRACT

BACKGROUND: The high metastasis and mortality rates of head and neck squamous cell carcinoma (HNSCC) urgently require new treatment targets and drugs. A steroidal component of ChanSu, telocinobufagin (TBG), was verified to have anti-cancer effects in various tumors, but its activity and mechanism in anti-HNSCC were still unknown. PURPOSE: This study tried to demonstrate the anti-tumor effect of TBG on HNSCC and verify its potential mechanism. METHODS: The effect of TBG on cell proliferation and metastasis were performed and the TBG changed genes were detected by RNA-seq analysis in HNSCC cells. The GSEA and PPI analysis were used to identify the pathways targeted for TBG-regulated genes. Meanwhile, the mechanism of TBG on anti-proliferative and anti-metastasis were investigated in vitro and in vivo. RESULTS: The in vitro and in vivo experiments confirmed that TBG has favorable anti-tumor effects by induced G2/M phase arrest and suppressed metastasis in HNSCC cells. Further RNA-seq analysis demonstrated the genes regulated by TBG were enriched at the G2/M checkpoint and PLK1 signaling pathway. Then, the bioinformatic analysis of clinical data found that high expressed PLK1 were closely associated with poor overall survival in HNSCC patients. Furthermore, PLK1 directly and indirectly modulated G2/M phase and metastasis (by regulated CTCF) in HNSCC cells, simultaneously. TBG significantly inhibited the protein levels of PLK1 in both phosphorylated and non-phosphorylated forms and then, in one way, inactivated PLK1 failed to activate G2/M phase-related proteins (including CDK1, CDC25c, and cyclin B1). In another way, be inhibited PLK1 unable promote the nuclear translocation of CTCF and thus suppressed HNSC cell metastasis. In contrast, the anti-proliferative and anti-metastasis effects of TBG on HNSCC cell were vanished when cells high-expressed PLK1. CONCLUSION: The present study verified that PLK1 mediated TBG induced anti-tumor effect by modulated G2/M phase and metastasis in HNSCC cells.


Subject(s)
Bufanolides , Head and Neck Neoplasms , Humans , Squamous Cell Carcinoma of Head and Neck/drug therapy , G2 Phase Cell Cycle Checkpoints , Head and Neck Neoplasms/drug therapy , Cell Line, Tumor
16.
Head Neck ; 2024 Mar 01.
Article in English | MEDLINE | ID: mdl-38429055

ABSTRACT

BACKGROUND: The long-term effect of intraoperative usage of carbon nanoparticles (CN) and parathyroid hormone (PTH) test strip using immune colloidal gold technique (ICGT) is unclear. This study aims to compare the effect of intraoperative usage of CN and ICGT test strips on PG function. METHODS: This randomized clinical study involved adult patients who underwent total thyroidectomy. They were randomly allocated into three groups (control, CN, and ICGT group). Clinical data were analyzed. RESULTS: Each group involved 98 patients. Serum calcium and PTH concentrations at 24 h postoperatively (PTH24h ) were higher in CN group. The parathyroid function recovered quicker in CN group. Use of CN increased in situ PG preservation and PTH24h . Mediation analysis indicated that 23.05% of the total effect of CN on PTH24h was attributed to PGRIS. CONCLUSION: CN holds promise to improve in situ PG preservation and protect PG vasculature, thereby reducing the incidence of early hypoparathyroidism. The value of ICGT test strips for PG protection is dubious.

17.
Materials (Basel) ; 17(5)2024 Mar 04.
Article in English | MEDLINE | ID: mdl-38473666

ABSTRACT

Cemented carbide used in the rotor of a mud pulser is subjected to the scouring action of solid particles and corrosive mud media for a long time, which causes abrasive wear and electrochemical corrosion. To improve the wear and corrosive resistance of cemented carbide, samples with different cobalt content (WC-5Co, WC-8Co, and WC-10Co) receive deep cryogenic treatment (DCT) at -196 °C for 2.5 h. An optical metalloscope (OM) and X-ray diffractometer (XRD) are used to observe the phase changes of cemented carbides, and the XRD is also used to observe the change in residual stress on the cemented carbide's surface. A scanning electron microscope (SEM) is used to characterize the wear and electrochemical corrosion surface microstructure of cemented carbides (untreated and DCT). The results show that the DCT promotes the precipitation of the η phase, and the diffraction peak of ε-Co tends to intensify. Compared with the untreated, the wear rates of WC-5Co, WC-8Co, and WC-10Co can be reduced by 14.71%, 37.25%, and 41.01% by DCT, respectively. The wear form of the cemented carbides is mainly the extrusion deformation of Co and WC shedding. The precipitation of the η phase and the increase in WC residual compressive stress by DCT are the main reasons for the improvement of wear resistance. The electrochemical corrosion characteristic is the dissolution of the Co phase. DCT causes the corrosion potential of cemented carbide to shift forward and the corrosion current density to decrease. The enhancement of the corrosion resistance of cemented carbide caused by DCT is due to the Co phase transition, η phase precipitation, and the increase in the compressive stress of cemented carbide.

18.
Clin Cancer Res ; 30(9): 1739-1749, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38456660

ABSTRACT

PURPOSE: MEK inhibitors (MEKi) lack monotherapy efficacy in most RAS-mutant cancers. BCL-xL is an anti-apoptotic protein identified by a synthetic lethal shRNA screen as a key suppressor of apoptotic response to MEKi. PATIENTS AND METHODS: We conducted a dose escalation study (NCT02079740) of the BCL-xL inhibitor navitoclax and MEKi trametinib in patients with RAS-mutant tumors with expansion cohorts for: pancreatic, gynecologic (GYN), non-small cell lung cancer (NSCLC), and other cancers harboring KRAS/NRAS mutations. Paired pretreatment and day 15 tumor biopsies and serial cell-free (cf)DNA were analyzed. RESULTS: A total of 91 patients initiated treatment, with 38 in dose escalation. Fifty-eight percent had ≥3 prior therapies. A total of 15 patients (17%) had colorectal cancer, 19 (11%) pancreatic, 15 (17%) NSCLC, and 32 (35%) GYN cancers. The recommended phase II dose (RP2D) was established as trametinib 2 mg daily days 1 to 14 and navitoclax 250 mg daily days 1 to 28 of each cycle. Most common adverse events included diarrhea, thrombocytopenia, increased AST/ALT, and acneiform rash. At RP2D, 8 of 49 (16%) evaluable patients achieved partial response (PR). Disease-specific differences in efficacy were noted. In patients with GYN at the RP2D, 7 of 21 (33%) achieved a PR and median duration of response 8.2 months. No PRs occurred in patients with colorectal cancer, NSCLC, or pancreatic cancer. MAPK pathway inhibition was observed in on-treatment tumor biopsies. Reductions in KRAS/NRAS mutation levels in cfDNA correlated with clinical benefit. CONCLUSIONS: Navitoclax in combination with trametinib was tolerable. Durable clinical responses were observed in patients with RAS-mutant GYN cancers, warranting further evaluation in this population.


Subject(s)
Aniline Compounds , Mutation , Neoplasms , Proto-Oncogene Proteins p21(ras) , Pyridones , Pyrimidinones , Sulfonamides , bcl-X Protein , Humans , Female , Pyridones/administration & dosage , Pyridones/adverse effects , Pyridones/therapeutic use , Male , Middle Aged , Aniline Compounds/administration & dosage , Aniline Compounds/adverse effects , Aniline Compounds/therapeutic use , Pyrimidinones/administration & dosage , Pyrimidinones/adverse effects , Aged , Proto-Oncogene Proteins p21(ras)/genetics , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/pathology , bcl-X Protein/antagonists & inhibitors , bcl-X Protein/genetics , Adult , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Aged, 80 and over , GTP Phosphohydrolases/genetics , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , Treatment Outcome
19.
Nat Ecol Evol ; 8(5): 947-959, 2024 May.
Article in English | MEDLINE | ID: mdl-38519631

ABSTRACT

Mosquito transmitted viruses are responsible for an increasing burden of human disease. Despite this, little is known about the diversity and ecology of viruses within individual mosquito hosts. Here, using a meta-transcriptomic approach, we determined the viromes of 2,438 individual mosquitoes (81 species), spanning ~4,000 km along latitudes and longitudes in China. From these data we identified 393 viral species associated with mosquitoes, including 7 (putative) species of arthropod-borne viruses (that is, arboviruses). We identified potential mosquito species and geographic hotspots of viral diversity and arbovirus occurrence, and demonstrated that the composition of individual mosquito viromes was strongly associated with host phylogeny. Our data revealed a large number of viruses shared among mosquito species or genera, enhancing our understanding of the host specificity of insect-associated viruses. We also detected multiple virus species that were widespread throughout the country, perhaps reflecting long-distance mosquito dispersal. Together, these results greatly expand the known mosquito virome, linked viral diversity at the scale of individual insects to that at a country-wide scale, and offered unique insights into the biogeography and diversity of viruses in insect vectors.


Subject(s)
Culicidae , Mosquito Vectors , Virome , Animals , Culicidae/virology , China , Mosquito Vectors/virology , Metagenomics , Arboviruses/genetics , Arboviruses/classification , Phylogeny , Biodiversity
20.
Angew Chem Int Ed Engl ; 63(18): e202401926, 2024 Apr 24.
Article in English | MEDLINE | ID: mdl-38415944

ABSTRACT

Block copolymers, comprising polyether and polyolefin segments, are an important and promising category of functional materials. However, the lack of efficient strategies for the construction of polyether-b-polyolefin block copolymers have hindered the development of these materials. Herein, we propose a simple and efficient method to obtain various block copolymers through the copolymerization of epoxides and acrylates via bimetallic synergistic catalysis. The copolymerization of epoxides and acrylates proceeds in a sequence-controlled manner, where the epoxides-involved homo- or copolymerization occurs first, followed by the homopolymerization of acrylates initiated by the alkoxide species from the propagating polymer chain, thus yielding copolymers with a block structure. Notably, the high monomer compatibility of this powerful strategy provides a platform for synthesizing various polyacrylate-based block copolymers comprising polyether, polycarbonate, polythiocarbonate, polyester, and polyurethane segments, respectively.

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