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1.
EMBO J ; 43(20): 4522-4541, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39174852

RESUMO

Tumor cell heterogeneity defines therapy responsiveness in neuroblastoma (NB), a cancer derived from neural crest cells. NB consists of two primary subtypes: adrenergic and mesenchymal. Adrenergic traits predominate in NB tumors, while mesenchymal features becomes enriched post-chemotherapy or after relapse. The interconversion between these subtypes contributes to NB lineage plasticity, but the underlying mechanisms driving this phenotypic switching remain unclear. Here, we demonstrate that SWI/SNF chromatin remodeling complex ATPases are essential in establishing an mesenchymal gene-permissive chromatin state in adrenergic-type NB, facilitating lineage plasticity. Targeting SWI/SNF ATPases with SMARCA2/4 dual degraders effectively inhibits NB cell proliferation, invasion, and notably, cellular plasticity, thereby preventing chemotherapy resistance. Mechanistically, depletion of SWI/SNF ATPases compacts cis-regulatory elements, diminishes enhancer activity, and displaces core transcription factors (MYCN, HAND2, PHOX2B, and GATA3) from DNA, thereby suppressing transcriptional programs associated with plasticity. These findings underscore the pivotal role of SWI/SNF ATPases in driving intrinsic plasticity and therapy resistance in neuroblastoma, highlighting an epigenetic target for combinational treatments in this cancer.


Assuntos
Plasticidade Celular , Neuroblastoma , Fatores de Transcrição , Neuroblastoma/genética , Neuroblastoma/patologia , Neuroblastoma/metabolismo , Humanos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , DNA Helicases/metabolismo , DNA Helicases/genética , Montagem e Desmontagem da Cromatina , Proteínas Cromossômicas não Histona/metabolismo , Proteínas Cromossômicas não Histona/genética , Resistencia a Medicamentos Antineoplásicos/genética , Animais , Proteínas Nucleares
2.
PLoS Biol ; 22(3): e3002240, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38547242

RESUMO

MYCN activates canonical MYC targets involved in ribosome biogenesis, protein synthesis, and represses neuronal differentiation genes to drive oncogenesis in neuroblastoma (NB). How MYCN orchestrates global gene expression remains incompletely understood. Our study finds that MYCN binds promoters to up-regulate canonical MYC targets but binds to both enhancers and promoters to repress differentiation genes. MYCN binding also increases H3K4me3 and H3K27ac on canonical MYC target promoters and decreases H3K27ac on neuronal differentiation gene enhancers and promoters. WDR5 facilitates MYCN promoter binding to activate canonical MYC target genes, whereas MYCN recruits G9a to enhancers to repress neuronal differentiation genes. Targeting both MYCN's active and repressive transcriptional activities using both WDR5 and G9a inhibitors synergistically suppresses NB growth. We demonstrate that MYCN cooperates with WDR5 and G9a to orchestrate global gene transcription. The targeting of both these cofactors is a novel therapeutic strategy to indirectly target the oncogenic activity of MYCN.


Assuntos
Transformação Celular Neoplásica , Proteínas Nucleares , Humanos , Proteínas Nucleares/metabolismo , Proteína Proto-Oncogênica N-Myc/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Histona Metiltransferases/genética , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Carcinogênese/genética , Regulação Neoplásica da Expressão Gênica , Transcrição Gênica , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
3.
J Biol Chem ; 300(9): 107728, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39214298

RESUMO

Leber's Hereditary Optic Neuropathy (LHON) is a rare, maternally inherited eye disease, predominantly due to the degeneration of retinal ganglion cells (RGCs). It is associated with a mitochondrial DNA (mtDNA) point mutation. Our previous study identified that the m.15927G > A homoplasmic mutation damaged the highly conserved base pairing (28C-42G) in anticodon stem of tRNAThr, caused deficient t6A modification and significantly decreased efficiency in aminoacylation and steady-state levels of tRNAThr, and led to mitochondrial dysfunction. Meanwhile, mechanisms underlying mtDNA mutations regulate intracellular signaling related to mitochondrial and cellular integrity are less explored. Here, we manifested that defective nucleotide modification induced by the m.15927G > A mutation interfered with the expression of nuclear genes involved in cytoplasmic proteins essential for oxidative phosphorylation system (OXPHOS), thereby impacting the assemble and integrity of OXPHOS complexes. As a result of these mitochondrial dysfunctions, there was an imbalance in mitochondrial dynamics, particularly distinguished by an increased occurrence of mitochondrial fission. Excessive fission compromised the autophagy process, including the initiation phase, formation, and maturation of autophagosomes. Both Parkin-mediated mitophagy and receptor-dependent mitophagy were significantly impaired in cybrids haboring the m.15927G > A mutation. These changes facilitated intrinsic apoptosis, as indicated by increased cytochrome c release and elevated levels of apoptosis-associated proteins (e.g., BAK, BAX, cleaved caspase 9, cleaved caspase 3, and cleaved PARP) in the mutant cybrids. This study demonstrates that the m.15927G > A mutation contributes to LHON by dysregulating OXPHOS biogenesis, aberrant quality control, increased autophagy, inhibited mitophagy, and abnormal apoptosis.


Assuntos
Mitocôndrias , Mitofagia , Atrofia Óptica Hereditária de Leber , Atrofia Óptica Hereditária de Leber/metabolismo , Atrofia Óptica Hereditária de Leber/genética , Atrofia Óptica Hereditária de Leber/patologia , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/genética , Mitocôndrias/patologia , Homeostase , Processamento Pós-Transcricional do RNA , DNA Mitocondrial/metabolismo , DNA Mitocondrial/genética , Fosforilação Oxidativa , RNA de Transferência de Treonina/metabolismo , RNA de Transferência de Treonina/genética , Dinâmica Mitocondrial , Apoptose , Mutação Puntual , Autofagia , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética
4.
FASEB J ; 38(9): e23654, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38717442

RESUMO

Heart failure and cardiac remodeling are both characterized by mitochondrial dysfunction. Healthy mitochondria are required for adequate contractile activity and appropriate regulation of cell survival. In the mammalian heart, enhancement of the mitochondrial unfolded protein response (UPRmt) is cardioprotective under pressure overload conditions. We explored the UPRmt and the underlying regulatory mechanism in terms of hypertension-induced cardiac remodeling and the cardioprotective effect of metformin. Male spontaneously hypertensive rats and angiotensin II-treated neonatal rat cardiomyocytes were used to induce cardiac hypertrophy. The results showed that hypertension induced the formation of aberrant mitochondria, characterized by a reduced mtDNA/nDNA ratio and swelling, as well as lower levels of mitochondrial complexes I to V and inhibition of the expression of one protein subunit of each of complexes I to IV. Such changes eventually enlarged cardiomyocytes and increased cardiac fibrosis. Metformin treatment increased the mtDNA/nDNA ratio and regulated the UPRmt, as indicated by increased expression of activating transcription factor 5, Lon protease 1, and heat shock protein 60, and decreased expression of C/EBP homologous protein. Thus, metformin improved mitochondrial ultrastructure and function in spontaneously hypertensive rats. In vitro analyses revealed that metformin reduced the high levels of angiotensin II-induced mitochondrial reactive oxygen species in such animals and stimulated nuclear translocation of heat shock factor 1 (HSF1). Moreover, HSF1 small-interfering RNA reduced the metformin-mediated improvements in mitochondrial morphology and the UPRmt by suppressing hypertrophic signals and cardiomyocyte apoptosis. These results suggest that HSF1/UPRmt signaling contributes to the beneficial effects of metformin. Metformin-mediated targeting of mitochondrial protein homeostasis and modulation of HSF1 levels have potential therapeutic implications in terms of cardiac remodeling.


Assuntos
Fatores de Transcrição de Choque Térmico , Metformina , Miócitos Cardíacos , Resposta a Proteínas não Dobradas , Animais , Masculino , Ratos , Angiotensina II/farmacologia , Cardiomegalia/metabolismo , Cardiomegalia/tratamento farmacológico , Cardiomegalia/patologia , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Fatores de Transcrição de Choque Térmico/efeitos dos fármacos , Fatores de Transcrição de Choque Térmico/metabolismo , Hipertensão/metabolismo , Hipertensão/tratamento farmacológico , Metformina/farmacologia , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
5.
Chem Soc Rev ; 53(8): 3687-3713, 2024 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-38411997

RESUMO

The cornerstones of the advancement of flexible optoelectronics are the design, preparation, and utilization of novel materials with favorable mechanical and advanced optoelectronic properties. Molecular crystalline materials have emerged as a class of underexplored yet promising materials due to the reduced grain boundaries and defects anticipated to provide enhanced photoelectric characteristics. An inherent drawback that has precluded wider implementation of molecular crystals thus far, however, has been their brittleness, which renders them incapable of ensuring mechanical compliance required for even simple elastic or plastic deformation of the device. It is perplexing that despite a plethora of reports that have in the meantime become available underpinning the flexibility of molecular crystals, the "discovery" of elastically or plastically deformable crystals remains limited to cases of serendipitous and laborious trial-and-error approaches, a situation that calls for a systematic and thorough assessment of these properties and their correlation with the structure. This review provides a comprehensive and concise overview of the current understanding of the origins of crystal flexibility, the working mechanisms of deformations such as plastic and elastic bending behaviors, and insights into the examples of flexible molecular crystals, specifically concerning photoelectronic changes that occur in deformed crystals. We hope this summary will provide a reference for future experimental and computational efforts with flexible molecular crystals aimed towards improving their mechanical behavior and optoelectronic properties, ultimately intending to advance the flexible optoelectronic technology.

6.
Mol Microbiol ; 120(5): 684-701, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37718557

RESUMO

Syphilis is a persistent sexually transmitted disease caused by infiltration of the elusive pathogen Treponema pallidum. Despite the prevalence of human polymorphonuclear neutrophils (hPMNs) within cutaneous lesions, which are characteristic of incipient syphilis, their role in T. pallidum infection remains unclear. Tp92 is the only T. pallidum helical outer membrane protein that exhibits structural features similar to those of outer membrane proteins in other gram-negative bacteria. However, the functional mechanism of this protein in immune cells remains unclear. Neutrophils are short-lived cells that undergo innate apoptosis in response to external stimuli that typically influence this process. In this study, we determined that Tp92 impedes the activation of procaspase-3 via the ERK MAPK, PI3K/Akt, and NF-κB signaling pathways, consequently suppressing caspase-3 activity within hPMNs, and thereby preventing hPMNs apoptosis. Furthermore, Tp92 could also modulate hPMNs apoptosis by enhancing the expression of the anti-apoptotic protein Mcl-1, stimulating IL-8 secretion, and preserving the mitochondrial membrane potential. These findings provide valuable insights into the molecular mechanisms underlying T. pallidum infection and suggest potential therapeutic targets for syphilis treatment.


Assuntos
NF-kappa B , Sífilis , Humanos , NF-kappa B/metabolismo , Treponema pallidum/genética , Treponema pallidum/metabolismo , Sífilis/metabolismo , Sífilis/microbiologia , Sífilis/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas de Membrana/metabolismo , Neutrófilos , Apoptose
7.
Anal Chem ; 96(28): 11463-11471, 2024 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-38962829

RESUMO

In this work, we reported a cholesterol oxidase (Chox)-loaded platinum (Pt) nanozyme with the collaborative cascade nanoreactor for the construction of nanozyme-enzyme-linked immunosorbent assay (N-ELSA) models to realize high-throughput rapid evaluation of cancer markers. Considering the high specific surface area and manipulable surface sites, ZIF-8 was used as a substrate for natural enzyme and nanozyme loading. The constructed ZIF-8-Pt nanozyme platform exhibited efficient enzyme-like catalytic efficiency with a standard corrected activity of 60.59 U mg-1, which was 12 times higher than that of the ZIF-8 precursor, and highly efficient photothermal conversion efficiency (∼35.49%). In N-ELISA testing, developed multienzyme photothermal probes were immobilized in microplates based on antigen-antibody-specific reactions. Cholesterol was reacted in a cascade to reactive oxygen radicals, which attacked 3,3',5,5'-tetramethylbenzidine, causing it to oxidize and color change, thus exhibiting highly enhanced efficient photothermal properties. Systematic temperature evaluations were performed by a hand-held microelectromechanical system thermal imager under the excitation of an 808 nm surface light source to determine the cancer antigen 15-3 (CA15-3) profiles in the samples. Encouragingly, the temperature signal from the microwells increased with increasing CA15-3, with a linear range of 2 mU mL-1 to 100 U mL-1, considering it to be the sensor with the widest working range for visualization and portability available. This work provides new horizons for the development of efficient multienzyme portable colorimetric-photothermal platforms to help advance the community-based process of early cancer detection.


Assuntos
Colesterol Oxidase , Platina , Humanos , Platina/química , Colesterol Oxidase/química , Colesterol Oxidase/metabolismo , Ensaio de Imunoadsorção Enzimática , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/análise , Benzidinas/química , Colesterol/química , Colesterol/metabolismo , Colesterol/análise , Ensaios de Triagem em Larga Escala , Zeolitas/química
8.
Mol Phylogenet Evol ; : 108223, 2024 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-39481463

RESUMO

The genus Sylvirana includes 12 species widely distributed in South China and Southeast Asia. The phylogenetic relationships and species diversity for Sylvirana and allied genera remain unresolved and controversial due to insufficient data and incomplete taxon sampling. Using a combined dataset of mitochondrial genes (16S and COI) and 101 nuclear genes obtained through the amplicon sequence capture approach, we generated the most comprehensive phylogenetic analysis for the genus Sylvirana to date, inferring diversity, phylogenetic relationships, and historical biogeography with unprecedented levels of taxon and geographic sampling. Our results conservatively reveal six undescribed species, mostly distributed in peninsular Indochina. Phylogenetic analyses strongly support the non-monophyly of Sylvirana with respect to Pterorana. Additionally, phylogenetic results place Sylvirana guentheri and Pelophylax lateralis into genus Humerana, supporting the inclusion of Hylarana latouchii, Papurana milleti, and Hylarana attigua within Pterorana + Sylvirana. The long-disputed species of Hylarana bannanica (previously Sylvirana) cluster with genus Papurana. Because the results of multiple non-monophyletic genera create taxonomic confusion, we suggest relegating all genera to subgenus rank of Hylarana. Sylvirana is a junior synonym of the Pterorana. Biogeographically, we trace the origin of Pterorana to Southeast Asia during the early Miocene, with subsequent dispersal thereafter. Our study shows that climatic changes may have profoundly influenced the diversification of Pterorana during the Miocene.

9.
Chemistry ; 30(42): e202400741, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-38745544

RESUMO

To address key concerns on solid-state pyrene-based luminescent materials, we propose a novel and efficient mechanical bond strategy. This strategy results in a transformation from ACQ to AIE effect and a remarkable enhancement of pyrene emission in the solid state. Moreover, an unusual purification of emission is also achieved. Through computational calculation and experimental characterisation, finally determined by X-ray diffraction analysis, we prove that the excellent emissions result from mechanical bond induced refinement of molecular arrangements, including reduced π-π stacking, well-ordered packing and enhanced structural stability. This work demonstrates the potential of mechanical bond in the field of organic luminescent molecules, providing a new avenue for developing high-performance organic luminescent materials.

10.
Soft Matter ; 2024 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-39495480

RESUMO

Revealing the mechanism of directed transport of active matter is critical for advancing our fundamental understanding of non-equilibrium physics. Asymmetric microstructures are commonly used to rectify random movement of active particles. However, it remains unclear as to how to achieve unidirectional movement of active particles in long narrow channels. Here, we study the dynamics of active particles in a device which is divided into two chambers by V-shaped barriers and connected by a narrow channel. We find three distinct movement modes of active particles within this symmetric channel, including stochastic movement, self-sustained oscillation, and long-lived unidirectional flows. We demonstrate that the three movement modes are determined by the competition between the ratchet effect induced by the V-shaped barriers and the particle transport mediated by the long-narrow channel. Finally, we show that the unidirectional particle flow can serve as an "energy battery" to continuously supply energy for the directed transport of other objects. Our findings offer valuable insights into a unique approach for realizing unidirectional movement of active matter and open new avenues for application in microfluidics and material transport.

11.
J Org Chem ; 89(2): 986-993, 2024 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-38196087

RESUMO

Two new energetic coordination compounds with 1D helical chain structures have been synthesized. First, the polyamine precursor 4,5-diamino-2-((4-amino-1,2,5-oxadiazole-3-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-imino chloride salt (TATAF-Cl) is obtained by incorporating 4-(chloromethyl)-1,2,5-oxadiazol-3-amine with 4H-1,2,4-triazole-3,4,5-triamine. Using a simple hydrothermal method, two energetic complexes, Ag(TATAF)(ClO4)2 (ECP-1) and Ag(TATAF)(NO3)2·H2O (ECP-2), with a helical 1D MOF structure of furazan and triazole were synthesized. Compounds ECP-1 and ECP-2 have relatively high nitrogen and oxygen content (N + O%: 52.04%, 61.04%), excellent crystal density (2.229 g cm-3, 2.116 g cm-3 at 298 K) and high heat of detonation (1.18 kcal g-1, 1.06 kcal g-1), good detonation performance (P: 35.34 GPa, 29.52 GPa; Dv: 8412 m s-1, 7794 m s-1), and moderate sensitivity (IS: 8 J, 13 J; FS: 72 N, 64 N). Structurally, the Ag+ of the two ECPs is coordinated with two energetic cations, two perchlorates, or one nitrate via tetragonal coordination to form a single helical structure that is interspersed up and down in two directions.

12.
Inorg Chem ; 63(34): 16056-16069, 2024 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-39129474

RESUMO

The olivine-based gallate CaYGaO4 (CYG) with unique cationic ordering, rich lattice sites, and self-photoluminescence (PL) is suitable for application as a host of phosphor. However, research in this area is still in its early stages, especially in high-quality full-spectrum white lighting. Herein, novel CYG: Bi3+/Eu3+ with a controllable PL property is designed based on energy transfer and superposition of emissions from blue self-PL, blue PL of Bi3+, and red-PL of Eu3+. Intriguingly, PL intensity and quantum efficiency could be enhanced via codoping Li+/Zn2+ separately/simultaneously because of their two intentional functions as both charge balancer and flux. Unlike self- and Eu3+ PL, Bi3+ PL is quite sensitive to the lattice environment owing to its exposed 6s2 electronic configuration and is tuned via codoping Sr2+ to regulate the nephelauxetic effect and crystal field splitting concurrently around Bi3+. Meanwhile, for further regulating the PL of Bi3+ and obtaining "warm" white light, La3+ is codoped into the phosphor via crystallographic site engineering to control the substitution trends of Bi3+ at distinct lattice sites. Finally, as a proof-of-concept, a full-spectrum phosphor-converted white-light-emitting diode device under nUV pumping with remarkable color rendering index (Ra), high luminous efficiency, and chemical/thermal stability is achieved by utilizing the individual CYG:Bi/Eu/Li/Zn/Sr/La phosphor via a remote "capping" packaging method.

13.
Inorg Chem ; 63(19): 8958-8969, 2024 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-38687123

RESUMO

Atomically precise Ag4Ni2 nanoclusters with 2,4-dimethylbenzenethiol as the ligands were synthesized and characterized as a cocatalyst of SiC for the selective hydrogenation of nitroarenes to arylamine in the presence of NaBH4. The obtained Ag4Ni2/SiC samples exhibited extraordinary catalytic activity, and a self-accelerated catalytic process was observed with the reduction of nitrophenol to aminophenol as the model reaction. Experimental comparison between the Ag4Ni2/SiC samples before and after the catalysis showed that the transformation of Ag4Ni2 clusters to polydisperse Ag particles as well as amorphous NiOx on the surface of SiC in the catalysis was the key to their high activity. AIMD calculations revealed that the transformation of Ag4Ni2 was driven by the presence of multiple hydrides on the cluster, which induced the detachment of the thiol ligand of the nanoclusters.

14.
Support Care Cancer ; 32(8): 529, 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-39028382

RESUMO

BACKGROUND: Testicular cancer usually occurs in young adult men between the ages of 20 and 40 years, which largely coincides with the age of men's reproductive intentions. However, a serious side effect of testicular cancer therapy could reduce the fertility of patients. PURPOSE: To explore the experience of fertility concerns in patients with testicular cancer. METHODS: A phenomenological research was conducted on 12 patients with testicular cancer. Data collection was from May 2023 to August 2023, and Colaizzi analysis method was used to analyze the data. RESULTS: Four themes were found: (1) multiple worries and negative emotions, (2) fertility decision-making faces many challenges, (3) self-coping strategies for facing fertility concerns, (4) unmet supportive care needs. CONCLUSION: Medical staff should pay attention to the fertility needs of patients with testicular cancer and provide relevant interventions and support to reduce their fertility concerns.


Assuntos
Pesquisa Qualitativa , Neoplasias Testiculares , Humanos , Masculino , Neoplasias Testiculares/psicologia , Neoplasias Testiculares/terapia , Adulto , Adaptação Psicológica , Adulto Jovem , Tomada de Decisões , Preservação da Fertilidade/métodos , Preservação da Fertilidade/psicologia , Fertilidade
15.
BMC Pregnancy Childbirth ; 24(1): 268, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38605288

RESUMO

BACKGROUND: Although acetaminophen is widely used in women during pregnancy, its safety has not been clearly stated. The study aimed to investigate the association between acetaminophen use and adverse pregnancy outcomes in pregnant women in China. METHODS: We conducted a retrospective cohort study by collecting data on pregnant women who delivered in the Beijing Obstetrics and Gynecology Hospital from January 2018 to September 2023. An acetaminophen use group and a control group were formed based on prenatal exposure to acetaminophen. The pregnancy outcomes that we focused on were stillbirth, miscarriage, preterm birth, APGAR score, birth weight, and congenital disabilities. Pregnant women exposed to acetaminophen were matched to unexposed in a 1:1 ratio with propensity score matching, using the greedy matching macro. SPSS software was used for statistical analysis. Multivariable logistics regression was used to assess the association between acetaminophen use during pregnancy and adverse pregnancy outcomes. RESULTS: A total of 41,440 pregnant women were included, of whom 501 were exposed to acetaminophen during pregnancy, and 40,939 were not exposed. After the propensity score matching, the acetaminophen use and control groups consisted of 501 pregnant women each. The primary analysis showed that acetaminophen exposure during pregnancy was associated with an increased risk of stillbirth (adjusted OR (aOR) = 2.29, 95% CI, 1.19-4.43), APGAR score < 7 at 1 min (aOR = 3.28, 95% CI, 1.73-6.21), APGAR score < 7 at 5 min (aOR = 3.54, 95% CI, 1.74-7.20), APGAR score < 7 at 10 min (aOR = 3.18, 95% CI, 1.58-6.41), and high birth weight (HBW) (aOR = 1.75, 95% CI, 1.05-2.92). Drug exposure during the first and second trimesters increased the odds of stillbirth, miscarriage, APGAR < 7, and the occurrence of at least one adverse pregnancy outcome. In addition, the frequency of drug use more than two times was associated with a higher risk of preterm birth and APGAR score < 7. CONCLUSIONS: Exposure to acetaminophen during pregnancy was significantly associated with the occurrence of adverse pregnancy outcomes, particularly exposure in the first and second trimesters and frequency of use more than twice. It is suggested that acetaminophen should be prescribed with caution in pregnant women.


Assuntos
Aborto Espontâneo , Complicações na Gravidez , Nascimento Prematuro , Gravidez , Recém-Nascido , Feminino , Humanos , Gestantes , Natimorto/epidemiologia , Peso ao Nascer , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/etiologia , Acetaminofen/efeitos adversos , Estudos Retrospectivos , Aborto Espontâneo/induzido quimicamente , Aborto Espontâneo/epidemiologia , Pontuação de Propensão , Complicações na Gravidez/epidemiologia , Resultado da Gravidez/epidemiologia
16.
Int J Clin Pharmacol Ther ; 62(10): 479-485, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39157917

RESUMO

OBJECTIVE: To evaluate the bioequivalence of two different afatinib dimaleate formulations in healthy Chinese subjects under fasting conditions and to assess their pharmacokinetic and safety profiles. MATERIALS AND METHODS: This randomized, open-label, 2-period, crossover, bioequivalence study included 32 healthy Chinese subjects. The subjects were assigned to receive a single 40-mg dose of generic or brand-named afatinib dimaleate tablet. Blood samples were collected pre-dose and up to 120 hours after dosing. Healthy subjects orally took the trial preparation (T) (afatinib maleate tablets developed by Jiangxi Shanxiang Pharmaceutical Co., Ltd., Gan Zhou, China) and the reference preparation (R) (afatinib maleate tablets developed by Boehringer Ingelheim Pharma GmbH & Co., Ingelheim, Germany) under fasting conditions in the appropriate period according to the randomization. We measured the blood concentrations, calculated the pharmacokinetic parameters of the two preparations in the human body, and evaluated whether formulations were bioequivalent. Safety of the preparations in healthy subjects was monitored during the whole trial. Safety assessment was conducted by vital signs, physical examination, laboratory examination, and 12-lead electrocardiogram during the study, i.e., from the time the subject received the test drug to the end of the last visit. RESULTS: Under fasting conditions, the 90% confidence intervals (CIs) of the geometric mean ratios of the test/reference for afatinib dimaleate were 93.34 - 103.92% for AUC0-t, 90.26 - 105.52% for Cmax, and 93.49 - 104.05% for AUC0-∞. CONCLUSION: The 90% CI for the geometric mean ratios (test/reference) of Cmax, AUC0-t, and AUC0-∞ were within the range of 80.00 - 125.00%, indicating that the test formulation was equivalent to the reference formulation in healthy Chinese subjects under fasting conditions. Both products were similar in terms of safety.


Assuntos
Afatinib , Estudos Cross-Over , Jejum , Voluntários Saudáveis , Comprimidos , Equivalência Terapêutica , Humanos , Masculino , Adulto , Adulto Jovem , Feminino , Afatinib/farmacocinética , Afatinib/administração & dosagem , Afatinib/efeitos adversos , Área Sob a Curva , Administração Oral , Medicamentos Genéricos/farmacocinética , Medicamentos Genéricos/administração & dosagem , Medicamentos Genéricos/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/sangue
17.
BMC Geriatr ; 24(1): 550, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38918727

RESUMO

BACKGROUND: Potentially inappropriate medications (PIMs) are common among older adults with cancer, but their association with overall survival (OS) among non-small cell lung cancer (NSCLC) patients remains unclear. This study aimed to investigate the association between the use of PIMs and OS in patients with NSCLC. METHODS: In this cohort study, we included patients ≥ 65 years with newly diagnosed NSCLC from January 2014 to December 2020. Potentially inappropriate medication (PIM) is defined by the Beers criteria of 2019 at baseline and within six months following the initiation of systemic therapy. Multivariable Cox regression model was built to assess the association between PIMs and overall survival (OS). RESULTS: We finally included 338 patients with a median follow-up for OS of 1777 days. The prevalence of patients receiving at least one PIM was 39.9% (135/338) and 61.2% (71/116) at baseline and after systemic therapy, respectively. The most important factor associated with PIM use was the number of prescribed medications (P < 0.001). Baseline PIM use and PIM after systemic therapy were significantly associated with inferior OS (476 days vs. 844 days, P = 0.044; and 633 days vs. 1600 days, P = 0.007; respectively). In multivariable analysis, both baseline PIM use and PIM after systemic therapy were independent predictors of poor prognosis (adjusted HR, 1.33; 95% CI, 1.01-1.75; P = 0.041; and adjusted HR, 1.86; 95% CI, 1.11-3.14; P = 0.020; respectively). CONCLUSIONS: PIMs are prevalent among older patients with NSCLC and are independent predictors of NSCLC prognosis. There is an urgent need for clinicians to conduct medication reconciliation and appropriate deprescribing for this population, especially for patients with multiple PIMs.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Lista de Medicamentos Potencialmente Inapropriados , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Masculino , Feminino , Idoso , Neoplasias Pulmonares/tratamento farmacológico , Prognóstico , Idoso de 80 Anos ou mais , Estudos de Coortes , Estudos Retrospectivos , Prescrição Inadequada/tendências
18.
J Eur Acad Dermatol Venereol ; 38(8): 1478-1490, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38376088

RESUMO

Treponema pallidum is the causative factor of syphilis, a sexually transmitted disease (STD) characterized by perivascular infiltration of inflammatory cells, vascular leakage, swelling and proliferation of endothelial cells (ECs). The endothelium lining blood and lymphatic vessels is a key barrier separating body fluids from host tissues and is a major target of T. pallidum. In this review, we focus on how T. pallidum establish intimate interactions with ECs, triggering endothelial dysfunction such as endothelial inflammation, abnormal repairment and damage of ECs. In addition, we summarize that migration and invasion of T. pallidum across vascular ECs may occur through two pathways. These two mechanisms of transendothelial migration are paracellular and cholesterol-dependent, respectively. Herein, clarifying the relationship between T. pallidum and endothelial dysfunction is of great significance to provide novel strategies for diagnosis and prevention of syphilis, and has a great potential prospect of clinical application.


Assuntos
Endotélio Vascular , Sífilis , Treponema pallidum , Humanos , Sífilis/microbiologia , Endotélio Vascular/fisiopatologia , Endotélio Vascular/patologia , Células Endoteliais/patologia , Células Endoteliais/microbiologia
19.
Sensors (Basel) ; 24(5)2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38474909

RESUMO

Simultaneous Localization and Mapping (SLAM), as one of the core technologies in intelligent robotics, has gained substantial attention in recent years. Addressing the limitations of SLAM systems in dynamic environments, this research proposes a system specifically designed for plant factory transportation environments, named GY-SLAM. GY-SLAM incorporates a lightweight target detection network, GY, based on YOLOv5, which utilizes GhostNet as the backbone network. This integration is further enhanced with CoordConv coordinate convolution, CARAFE up-sampling operators, and the SE attention mechanism, leading to simultaneous improvements in detection accuracy and model complexity reduction. While mAP@0.5 increased by 0.514% to 95.364, the model simultaneously reduced the number of parameters by 43.976%, computational cost by 46.488%, and model size by 41.752%. Additionally, the system constructs pure static octree maps and grid maps. Tests conducted on the TUM dataset and a proprietary dataset demonstrate that GY-SLAM significantly outperforms ORB-SLAM3 in dynamic scenarios in terms of system localization accuracy and robustness. It shows a remarkable 92.59% improvement in RMSE for Absolute Trajectory Error (ATE), along with a 93.11% improvement in RMSE for the translational drift of Relative Pose Error (RPE) and a 92.89% improvement in RMSE for the rotational drift of RPE. Compared to YOLOv5s, the GY model brings a 41.5944% improvement in detection speed and a 17.7975% increase in SLAM operation speed to the system, indicating strong competitiveness and real-time capabilities. These results validate the effectiveness of GY-SLAM in dynamic environments and provide substantial support for the automation of logistics tasks by robots in specific contexts.

20.
Sensors (Basel) ; 24(4)2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38400507

RESUMO

There has been a significant shift in research focus in recent years toward laser-induced graphene (LIG), which is a high-performance material with immense potential for use in energy storage, ultrahydrophobic water applications, and electronic devices. In particular, LIG has demonstrated considerable potential in the field of high-precision human motion posture capture using flexible sensing materials. In this study, we investigated the surface morphology evolution and performance of LIG formed by varying the laser energy accumulation times. Further, to capture human motion posture, we evaluated the performance of highly accurate flexible wearable sensors based on LIG. The experimental results showed that the sensors prepared using LIG exhibited exceptional flexibility and mechanical performance when the laser energy accumulation was optimized three times. They exhibited remarkable attributes, such as high sensitivity (~41.4), a low detection limit (0.05%), a rapid time response (response time of ~150 ms; relaxation time of ~100 ms), and excellent response stability even after 2000 s at a strain of 1.0% or 8.0%. These findings unequivocally show that flexible wearable sensors based on LIG have significant potential for capturing human motion posture, wrist pulse rates, and eye blinking patterns. Moreover, the sensors can capture various physiological signals for pilots to provide real-time capturing.


Assuntos
Grafite , Dispositivos Eletrônicos Vestíveis , Humanos , Captura de Movimento , Eletrônica , Lasers
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