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1.
Cell Mol Biol (Noisy-le-grand) ; 70(6): 61-65, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38836683

RESUMO

This experiment aimed to explore the influence mechanism of external fixator on open fracture. A total of 128 patients with open tibiofibular fractures were included in this study. The patients were randomly divided into external fixator group (n=64) and control group (n=64) according to the order of admission. Double-blind controlled observation was used. The levels of osteocalcin (BGP), ß-CTX, P1 NP, BALP, including haptoglobin (Hp), ceruloplasmin (CER), serum adrenocorticotropic hormone (ACTH), cortisol (COR), C-reactive protein (CRP), white blood cell (WBC) and interleukin-6 (IL-6) were recorded in different groups. The postoperative VAS score and quality of life were recorded. Log-rank was used to analyze the difference in postoperative adverse reaction rates among different groups. External fixation stent treatment increased BGP, PINP, and BALP expression and decreased ß-CTX, Hp, CER, ACTH, COR, CRP, WBC, and IL-6 levels. Patients in the external fixation stent group had significantly lower VAS score quality of life scores and incidence of adverse events than the control group. External fixation stents protect open fracture patients by promoting bone metabolism.


Assuntos
Osso e Ossos , Proteína C-Reativa , Fixadores Externos , Osteocalcina , Qualidade de Vida , Humanos , Masculino , Feminino , Adulto , Osteocalcina/sangue , Osteocalcina/metabolismo , Pessoa de Meia-Idade , Osso e Ossos/metabolismo , Proteína C-Reativa/metabolismo , Fraturas Expostas/cirurgia , Fraturas Expostas/metabolismo , Interleucina-6/sangue , Interleucina-6/metabolismo , Pró-Colágeno/sangue , Pró-Colágeno/metabolismo , Método Duplo-Cego , Colágeno Tipo I/metabolismo , Colágeno Tipo I/sangue , Hormônio Adrenocorticotrópico/sangue , Hormônio Adrenocorticotrópico/metabolismo , Fragmentos de Peptídeos/sangue , Extremidades/cirurgia , Extremidades/lesões , Peptídeos , Hidrocortisona/sangue
2.
Head Neck ; 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38770972

RESUMO

BACKGROUND: The current study presents the effort of a global collaborative group to review the management and outcomes of malignant tumors of the skull base worldwide. PATIENTS AND METHODS: A total of 28 institutions contributed data on 3061 patients. Analysis evaluated clinical variables, survival outcomes, and multivariable factors associated with outcomes. RESULTS: The median age was 56 years (IQR 44-67). The open surgical approach was used in 55% (n = 1680) of cases, endoscopic resection was performed in 36% (n = 1087), and the combined approach in 9.6% (n = 294). With a median follow-up of 7.1 years, the 5-year OS DSS and RFS were 65%, 71.7% and 53%, respectively. On multivariable analysis, older age, comorbidities, histology, dural/intracranial involvement, positive margins, advanced stage, and primary site were independent prognostic factors for OS, DSS, and RFS. Adjuvant RT was a protective prognostic factor. CONCLUSION: The progress across various disciplines may have contributed to improved OS and DSS in this study compared to previous reports.

3.
J Pain Res ; 17: 1651-1661, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38736679

RESUMO

Purpose: Patients undergoing arthroscopic hip surgery (AHS) require good analgesia and early rehabilitation after surgery, and there is no consensus on the optimal nerve block. We aimed to compare the efficacy of the pericapsular nerve group (PENG) block with lateral femoral cutaneous nerve (LFCN) block compared to fascia iliaca compartment block (FICB) in patients with AHS. Patients and Methods: A total of 80 patients receiving AHS under general anesthesia were randomized to receive either FICB (group F) or PENG block in combination with LFCN block (group P). The primary outcomes were the rate of quadriceps weakness after block on the afflicted side, as well as muscle strength grading and pain score after block, and the quality of recovery on the second postoperative day. Results: Compared with group F, group P had a lower incidence of quadriceps weakness 48 h after block (76.9% vs 28.2%, P < 0.001), and had less impact on muscle strength grade and lower static pain score at 6, 12, 18, 24, 36, and 48 h after block (P < 0.001), and a lower dynamic pain score at 6 and 12 h after block in group P (p < 0.05). The quality of recovery on the second postoperative day improved (p < 0.05). Conclusion: In comparison to FICB, PENG block in combination with LFCN block can affect less quadriceps muscle strength and reduce the use of postoperative analgesics, which is beneficial for the postoperative recovery of AHS patients.

4.
Europace ; 2024 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-38801673

RESUMO

AIM: Radiofrequency ablation (RFA) is used as a first-line therapy for accessory pathways (APs). However, data regarding the effects of pulsed field ablation (PFA) on APs are limited. We sought to evaluate the acute procedural and 6-month success and safety of PFA in a cohort of patients with APs. METHODS AND RESULTS: A focal contact-force sensing PFA catheter was used for patients with APs. PFA generator generated a bipolar and biphasic waveform (± 1000 V) with a duration of 100 ms from the tip of PFA catheter. 100% acute procedural success was achieved in 10 conscious patients with APs (7 left anterolateral, 2 left inferolateral, and 1 right posteroseptal APs) including 6 (60%) patients after an initial application. The average total ablation time was 6.3 ± 4.9 seconds for 4.7 ± 1.8 ablation sites (ASs), including 3.1 ± 2.4 seconds at targets and 3.2 ± 2.9 seconds at 3.2 ± 2 bolus ASs. The mean skin-to-skin time was 59.3 ± 15.5 minutes, and PFA catheter dwell time was 29.4 ± 7.8 minutes. One patient encountered transient sinus arrest during PFA due to parasympathetic overexcitation. Sinus rhythm was restored in all patients without any significant adverse events during short-term follow-up. CONCLUSIONS: PFA of APs was feasible, effective, and safe. Its efficiency was remarkable for its ultrarapid termination of AP conduction. Further studies are warranted to prove whether utilization of PFA with current parameters can extend to manifold APs ablation.

5.
Int J Gen Med ; 17: 1833-1843, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38715746

RESUMO

Purpose: To determine the current status of vitamin D status and the associated factors for its deficiency among Chinese hospital staff. Methods: The physical examination data of 2509 hospital staff members was analyzed alongside that of 1507 patients who visited the hospital during the corresponding period of the examination. Serum concentration of 25-hydroxyvitamin D (25(OH)D) were measured in the participants. The hospital staff also completed surveys about general information, laboratory examination, and occupational characteristics. Results: The median vitamin D status (serum 25(OH)D concentration) of the participants was 9.0 ng/mL, ranging from 6.5 to 44.7 ng/mL, and the prevalence of deficiency (<12.3 ng/mL) was 81.47% (2044/2509). The multivariable logistic regression revealed that nurses (OR = 1.54, 95% CI 1.09-2.19, p = 0.015), BMI below 18 (OR = 2.39, 95% CI 1.02-5.58, p = 0.045) associated with higher prevalence of vitamin D deficiency. In the contrast, age above 30 (OR = 0.69, 95% CI 0.53-0.91, p = 0.009) and a high level of uric acid (OR = 0.56, 95% CI 0.41-0.78, p = 0.001) associated with lower prevalence of vitamin D deficiency. The prevalence of vitamin D deficiency was higher among the hospital staff (81.47%) compared to the patients who visited the hospital during the same time period (65.69%). A substantial disparity was observed in the propensity score matching dataset (69.14% vs 79.94%, p < 0.001). Conclusion: Hospital staff are a high-risk group for vitamin D deficiency. Paying attention to vitamin D status and supplementation of this vitamin are pertinent aspects of hospital staff health care. Outdoor activities, vitamin D supplementation, and foods rich in vitamin D should be advocated.

6.
ACS Med Chem Lett ; 15(5): 714-721, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38746903

RESUMO

We herein report the discovery, synthesis, and evolution of a series of indazoles and azaindazoles as CNS-penetrant IRAK4 inhibitors. Described is the use of structure-based and property-based drug design strategically leveraged to guide the property profile of a key series into a favorable property space while maintaining potency and selectivity. Our rationale that led toward functionalities with potency improvements, CNS-penetration, solubility, and favorable drug-like properties is portrayed. In vivo evaluation of an advanced analogue showed significant, dose-dependent modulation of inflammatory cytokines in a mouse model. In pursuit of incorporating a highly engineered bridged ether that was crucial to metabolic stability in this series, significant synthetic challenges were overcome to enable the preparation of the analogues.

7.
Artigo em Inglês | MEDLINE | ID: mdl-38780901

RESUMO

OBJECTIVE: Hard-to-heal diabetic foot ulcers (DFUs) are associated with higher mortality rates and an increased medical burden for patients. ON101, a new topical cream, exhibited better healing efficacy than the control dressing in a Phase III trial. In this post-hoc analysis, we further identify whether ON101 can improve the healing of ulcers with hard-to-heal risk factors in this cohort of DFU patients. APPROACH: To compare the efficacy of ON101 with absorbent dressing among various hard-to-heal wounds in patients with DFU, a post hoc analysis of a randomized phase III trial included 276 DFU patients was performed by subgrouping those patients based on ulcer depth, location, size, duration, and patients' glycated hemoglobin (HbA1c) levels and body mass index (BMI). RESULTS: In the full analysis set, the proportion of patients achieving healing was 61.7% in the ON101 group and 37.0% in the comparator (P =0.0001). In sub-group analysis according to risk factors, ON101 demonstrated superior healing capacity on Wagner grade 2 ulcers (P < 0.0001); plantar ulcers (P = 0.0016), ulcers size ≥5 cm² (P = 0.0122), ulcers duration ≥3 months (P = 0.0043); for patients with HbA1c ≥9% (P = 0.0285); and patients with BMI ≥25 (P = 0.0005). INNOVATION: ON101, a novel therapeutic drug, can modulate the functions of macrophages and demonstrate superior healing rates to conventional absorbent dressing in patients with hard-to-heal DFUs. CONCLUSIONS: The results of this post hoc study suggest that ON101 is a better therapeutic option than conventional dressing used in treatment for DFU patients with higher HbA1c, BMI, or ulcers with complex conditions such as longer duration, deeper wounds, larger size, and plantar location.

8.
J Med Chem ; 67(10): 8383-8395, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38695469

RESUMO

Interleukin receptor associated kinase 4 (IRAK4) plays an important role in innate immune signaling through Toll-like and interleukin-1 receptors and represents an attractive target for the treatment of inflammatory diseases and cancer. We previously reported the development of a potent, selective, and brain-penetrant imidazopyrimidine series of IRAK4 inhibitors. However, lead molecule BIO-7488 (1) suffered from low solubility which led to variable PK, compound accumulation, and poor in vivo tolerability. Herein, we describe the discovery of a series of pyridone analogs with improved solubility which are highly potent, selective and demonstrate desirable PK profiles including good oral bioavailability and excellent brain penetration. BIO-8169 (2) reduced the in vivo production of pro-inflammatory cytokines, was well tolerated in safety studies in rodents and dog at margins well above the predicted efficacious exposure and showed promising results in a mouse model for multiple sclerosis.


Assuntos
Encéfalo , Quinases Associadas a Receptores de Interleucina-1 , Inibidores de Proteínas Quinases , Animais , Cães , Masculino , Camundongos , Ratos , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Descoberta de Drogas , Encefalomielite Autoimune Experimental/tratamento farmacológico , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/farmacologia , Pirimidinas/química , Pirimidinas/farmacocinética , Pirimidinas/síntese química , Pirimidinas/uso terapêutico , Relação Estrutura-Atividade
9.
Environ Int ; 186: 108639, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38603815

RESUMO

Antimicrobial resistance is considered to be one of the biggest public health problems, and airborne transmission is an important but under-appreciated pathway for the spread of antibiotic resistance genes (ARGs) in the environment. Previous research has shown pharmaceutical factories to be a major source of ARGs and antibiotic resistant bacteria (ARB) in the surrounding receiving water and soil environments. Pharmaceutical factories are hotspots of antibiotic resistance, but the atmospheric transmission and its environmental risk remain more concerns. Here, we conducted a metagenomic investigation into the airborne microbiome and resistome in three pharmaceutical factories in China. Soil (average: 38.45%) and wastewater (average: 28.53%) were major contributors of airborne resistome. ARGs (vanR/vanS, blaOXA, and CfxA) conferring resistance to critically important clinically used antibiotics were identified in the air samples. The wastewater treatment area had significantly higher relative abundances of ARGs (average: 0.64 copies/16S rRNA). Approximately 28.2% of the detected airborne ARGs were found to be associated with plasmids, and this increased to about 50% in the wastewater treatment area. We have compiled a list of high-risk airborne ARGs found in pharmaceutical factories. Moreover, A total of 1,043 viral operational taxonomic units were identified and linked to 47 family-group taxa. Different CRISPR-Cas immune systems have been identified in bacterial hosts in response to phage infection. Similarly, higher phage abundance (average: 2451.70 PPM) was found in the air of the wastewater treatment area. Our data provide insights into the antibiotic resistance gene profiles and microbiome (bacterial and non-bacterial) in pharmaceutical factories and reveal the potential role of horizontal transfer in the spread of airborne ARGs, with implications for human and animal health.


Assuntos
Microbiologia do Ar , Antibacterianos , Microbiota , Águas Residuárias , Microbiota/genética , Microbiota/efeitos dos fármacos , China , Antibacterianos/farmacologia , Águas Residuárias/microbiologia , Bactérias/genética , Bactérias/efeitos dos fármacos , Resistência Microbiana a Medicamentos/genética , Farmacorresistência Bacteriana/genética
10.
Nurs Open ; 11(4): e2162, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38581183

RESUMO

AIM: To evaluate the psychometric properties of the Advance Care Planning Readiness Scale (ACPRS-C) within the context of community-dwelling older adults with chronic diseases residing in suburban counties in China. DESIGN: Descriptive, cross-sectional survey. METHODS: The research method employed in this study is characterized as a methodological study. Self-reported survey data were collected among community-dwelling older adults with chronic diseases residing in suburban counties in China. Including the following psychometric characteristics, item analysis was performed using the decision value method and Pearson's correlation analysis. Content validity was assessed through expert panel evaluation. The internal consistency of the questionnaire was determined by calculating Cronbach's alpha coefficient and corrected item-total correlation. Additionally, confirmatory factor analysis (CFA) was utilized to assess the construct validity of the ACPRS-C. RESULTS: A total of 228 older adults participated in this psychometric study from August to October 2023. The item content validity index ranged from 0.80 to 1.00, while the scale content validity index was 0.945. The scale demonstrated excellent internal consistency (Cronbach's alpha = 0.931), and the correlation between items and total score was satisfactory. The structural validity was deemed robust (CFA model fit: chi-square/df = 1.121, comparative fit index = 0.992). CONCLUSION: The ACPRS-C is a scale with strong psychometric properties to assess the ACP readiness within the context of community-dwelling older adults with chronic diseases residing in suburban counties in China. Its reliability and validity hold considerable significance for both research and clinical practice.


Assuntos
Vida Independente , Humanos , Idoso , Psicometria , Estudos Transversais , Reprodutibilidade dos Testes , Doença Crônica
11.
Arch Toxicol ; 98(7): 2269-2279, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38662237

RESUMO

Tobacco carcinogens metabolism-related genes (TCMGs) could generate reactive metabolites of tobacco carcinogens, which subsequently contributed to multiple diseases. However, the association between genetic variants in TCMGs and bladder cancer susceptibility remains unclear. In this study, we derived TCMGs from metabolic pathways of polycyclic aromatic hydrocarbons and tobacco-specific nitrosamines, and then explored genetic associations between TCMGs and bladder cancer risk in two populations: a Chinese population of 580 cases and 1101 controls, and a European population of 5930 cases and 5468 controls, along with interaction and joint analyses. Expression patterns of TCMGs were sourced from Nanjing Bladder Cancer (NJBC) study and publicly available datasets. Among 43 TCMGs, we observed that rs7087341 T > A in AKR1C2 was associated with a reduced risk of bladder cancer in the Chinese population [odds ratio (OR) = 0.84, 95% confidence interval (CI) = 0.72-0.97, P = 1.86 × 10-2]. Notably, AKR1C2 rs7087341 showed an interaction effect with cigarette smoking on bladder cancer risk (Pinteraction = 5.04 × 10-3), with smokers carrying the T allele increasing the risk up to an OR of 3.96 (Ptrend < 0.001). Genetically, rs7087341 showed an allele-specific transcriptional regulation as located at DNA-sensitive regions of AKR1C2 highlighted by histone markers. Mechanistically, rs7087341 A allele decreased AKR1C2 expression, which was highly expressed in bladder tumors that enhanced metabolism of tobacco carcinogens, and thereby increased DNA adducts and reactive oxygen species formation during bladder tumorigenesis. These findings provided new insights into the genetic mechanisms underlying bladder cancer.


Assuntos
Carcinógenos , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/induzido quimicamente , Carcinógenos/toxicidade , Carcinógenos/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Estudos de Casos e Controles , Povo Asiático/genética , China/epidemiologia , Nicotiana , Idoso , População Branca/genética , Fumar Cigarros/efeitos adversos , Fumar Cigarros/genética , Nitrosaminas/toxicidade , Hidroxiesteroide Desidrogenases
12.
Atherosclerosis ; 392: 117527, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38583286

RESUMO

BACKGROUND AND AIMS: Diabetic atherosclerotic vascular disease is characterized by extensive vascular calcification. However, an elevated blood glucose level alone does not explain this pathogenesis. We investigated the metabolic markers underlying diabetic atherosclerosis and whether extracellular Hsp90α (eHsp90α) triggers vascular endothelial calcification in this particular metabolic environment. METHODS: A parallel human/animal model metabolomics approach was used. We analyzed 40 serum samples collected from 24 patients with atherosclerosis and from the STZ-induced ApoE-/- mouse model. A multivariate statistical analysis of the data was performed, and mouse aortic tissue was collected for the assessment of plaque formation. In vitro, the effects of eHsp90α on endothelial cell calcification were assessed by serum analysis, Western blotting and immunoelectron microscopy. RESULTS: Diabetic ApoE-/- mice showed more severe plaque lesions and calcification damage. Stearamide, oleamide, l-thyroxine, l-homocitrulline and l-citrulline are biomarkers of diabetic ASVD; l-thyroxine was downregulated in both groups, and the thyroid sensitivity index was correlated with serum Hsp90α concentration. In vitro studies showed that eHsp90α increased Runx2 expression in endothelial cells through the LRP1 receptor. l-thyroxine reduced the increase in Runx2 levels caused by eHsp90α and affected the distribution and expression of LRP1 through hydrogen bonding with glutamine at position 1054 in the extracellular segment of LRP1. CONCLUSIONS: This study provides a mechanistic link between characteristic serum metabolites and diabetic atherosclerosis and thus offers new insight into the role of extracellular Hsp90α in promoting vascular calcification.


Assuntos
Diabetes Mellitus Experimental , Proteínas de Choque Térmico HSP90 , Camundongos Knockout para ApoE , Placa Aterosclerótica , Tiroxina , Calcificação Vascular , Humanos , Animais , Proteínas de Choque Térmico HSP90/metabolismo , Calcificação Vascular/metabolismo , Calcificação Vascular/patologia , Masculino , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Tiroxina/sangue , Feminino , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Pessoa de Meia-Idade , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Camundongos , Aterosclerose/metabolismo , Aterosclerose/patologia , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/patologia , Angiopatias Diabéticas/etiologia , Metabolômica/métodos , Células Endoteliais/metabolismo , Células Endoteliais/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Idoso , Camundongos Endogâmicos C57BL , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Doenças da Aorta/sangue , Biomarcadores/sangue , Células Endoteliais da Veia Umbilical Humana/metabolismo
13.
J Cancer Res Clin Oncol ; 150(3): 118, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38466436

RESUMO

PURPOSE: Human epidermal growth factor receptor 2 (HER2)-positive breast cancer cases are among the most aggressive breast tumor subtypes. Accurately assessing HER2 expression status is vital to determining whether patients will benefit from targeted anti-HER2 treatment. HER2-targeted positron emission tomography (PET/CT) is noninvasive, enabling the real-time evaluation of breast cancer patient HER2 status with accuracy. METHODS: We summarize the research progress of PET/CT targeting HER2 in breast cancer, focusing on PET/CT molecular probes targeting HER2 and their clinical application in the management of advanced breast cancer. RESULTS: At present, a variety of different HER2 targeted molecular probes for PET/CT imaging have been developed, including nucleolin-labeled antibodies, antibody fragments, nanobodies, and peptides of various affinities, among others. HER2-targeted PET/CT can relatively accurately evaluate HER2 expression status in advanced breast cancer patients. It has good performance in the early detection of small HER2-positive lesions, evaluation of HER2 status in lesions that cannot be readily biopsied, evaluation of the heterogeneity of multiple metastases, identification of lesions with altered HER2 status, and evaluation of the efficacy of anti-HER2 drugs. CONCLUSION: HER2-targeted PET/CT offers a promising noninvasive approach for real-time assessment of HER2 status,which can be guide targeted treatment for HER2-positive breast cancer patients. Future prospective clinical studies will be invaluable for fully evaluating the importance of HER2-targeted molecular imaging in the management of breast cancer.


Assuntos
Neoplasias da Mama , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Feminino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Neoplasias da Mama/metabolismo , Tomografia por Emissão de Pósitrons , Receptor ErbB-2/metabolismo , Estudos Prospectivos
14.
Sci Total Environ ; 927: 171991, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38547976

RESUMO

Landfill leachate is a hotspot in antibiotic resistance development. However, little is known about antibiotic resistome and host pathogens in leachate and their effects on surrounding groundwater. Here, metagenomic sequencing was used to explore profiles, host bacteria, environmental risks and influencing factors of antibiotic resistome in raw and treated leachate and surrounding groundwater of three landfills. Results showed detection of a total of 324 antibiotic resistance genes (ARGs). The ARGs conferring resistance to multidrug (8.8 %-25.7 %), aminoglycoside (13.1 %-39.2 %), sulfonamide (10.0 %-20.9 %), tetracycline (5.7 %-34.4 %) and macrolide-lincosamide-streptogramin (MLS, 5.3 %-29.5 %) were dominant in raw leachate, while multidrug resistance genes were the major ARGs in treated leachate (64.1 %-83.0 %) and groundwater (28.7 %-76.6 %). Source tracking analysis suggests non-negligible influence of leachate on the ARGs in groundwater. The pathogens including Acinetobacter pittii, Pseudomonas stutzeri and P. alcaligenes were the major ARG-carrying hosts. Variance partitioning analysis indicates that the microbial community, abiotic variables and their interaction contributed most to the antibiotic resistance development. Our results shed light on the dissemination and driving mechanisms of ARGs from leachate to the groundwater, indicating that a comprehensive risk assessment and efficient treatment approaches are needed to deal with ARGs in landfill leachate and nearby groundwater. ENVIRONMENTAL IMPLICATIONS: Antibiotic resistance genes are found abundant in the landfill sites, and these genes could be disseminated into groundwater via leaching of wastewater and infiltration of leachate. This results in deterioration of groundwater quality and human health risks posed by these ARGs and related pathogens. Thus measures should be taken to minimize potential negative impacts of landfills on the surrounding environment.


Assuntos
Água Subterrânea , Instalações de Eliminação de Resíduos , Poluentes Químicos da Água , Água Subterrânea/microbiologia , Água Subterrânea/química , Poluentes Químicos da Água/análise , Resistência Microbiana a Medicamentos/genética , Antibacterianos/farmacologia , Monitoramento Ambiental , Bactérias/efeitos dos fármacos , Bactérias/genética
15.
Sci Total Environ ; 923: 171475, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38453063

RESUMO

Climbazole is an azole biocide that has been widely used in formulations of personal care products. Climbazole can cause developmental toxicity and endocrine disruption as well as gut disturbance in aquatic organisms. However, the mechanisms behind gut toxicity induced by climbazole still remain largely unclear in fish. Here, we evaluate the gut effects by exposing grass carp (Ctenopharyngodon idella) to climbazole at levels ranging from 0.2 to 20 µg/L for 42 days by evaluating gene transcription and expression, biochemical analyses, correlation network analysis, and molecular docking. Results showed that climbazole exposure increased cyp1a mRNA expression and ROS level in the three treatment groups. Climbazole also inhibited Nrf2 and Keap1 transcripts as well as proteins, and suppressed the transcript levels of their subordinate antioxidant molecules (cat, sod, and ho-1), increasing oxidative stress. Additionally, climbazole enhanced NF-κB and iκBα transcripts and proteins, and the transcripts of NF-κB downstream pro-inflammatory factors (tnfα, and il-1ß/6/8), leading to inflammation. Climbazole increased pro-apoptosis-related genes (fadd, bad1, and caspase3), and decreased anti-apoptosis-associated genes (bcl2, and bcl-xl), suggesting a direct reaction to apoptosis. The molecular docking data showed that climbazole could form stable hydrogen bonds with CYP1A. Mechanistically, our findings suggested that climbazole can induce inflammation and oxidative stress through CYP450s/ROS/Nrf2/NF-κB pathways, resulting in cell apoptosis in the gut of grass carp.


Assuntos
Carpas , Suplementos Nutricionais , Imidazóis , Animais , Suplementos Nutricionais/análise , Dieta , NF-kappa B , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Imunidade Inata , Azóis/toxicidade , Fator 2 Relacionado a NF-E2/metabolismo , Simulação de Acoplamento Molecular , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Inflamação/induzido quimicamente , Inflamação/veterinária , Estresse Oxidativo , Apoptose , Carpas/metabolismo
16.
J Med Chem ; 67(6): 4676-4690, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38467640

RESUMO

Interleukin receptor-associated kinase 4 (IRAK4) is a key node of signaling within the innate immune system that regulates the production of inflammatory cytokines and chemokines. The presence of damage-associated molecular patterns (DAMPs) after tissue damage such as stroke or traumatic brain injury (TBI) initiates signaling through the IRAK4 pathway that can lead to a feed-forward inflammatory loop that can ultimately hinder patient recovery. Herein, we describe the first potent, selective, and CNS-penetrant IRAK4 inhibitors for the treatment of neuroinflammation. Lead compounds from the series were evaluated in CNS PK/PD models of inflammation, as well as a mouse model of ischemic stroke. The SAR optimization detailed within culminates in the discovery of BIO-7488, a highly selective and potent IRAK4 inhibitor that is CNS penetrant and has excellent ADME properties.


Assuntos
Quinases Associadas a Receptores de Interleucina-1 , AVC Isquêmico , Camundongos , Animais , Humanos , Transdução de Sinais , Citocinas , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico
17.
Nanomaterials (Basel) ; 14(5)2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38470724

RESUMO

The mesophase pitch-based carbon fiber interface material (TIM) with a vertical array was prepared by using mesophase pitch-based short-cut fibers (MPCFs) and 3016 epoxy resin as raw materials and carbon nanotubes (CNTs) as additives through electrostatic flocking and resin pouring molding process. The microstructure and thermal properties of the interface were analyzed by using a scanning electron microscope (SEM), laser thermal conductivity and thermal infrared imaging methods. The results indicate that the plate spacing and fusing voltage have a significant impact on the orientation of the arrays formed by mesophase pitch-based carbon fibers. While the orientation of the carbon fiber array has a minimal impact on the shore hardness of TIM, it does have a direct influence on its thermal conductivity. At a flocking voltage of 20 kV and plate spacing of 12 cm, the interface material exhibited an optimal thermal conductivity of 24.47 W/(m·K), shore hardness of 42 A and carbon fiber filling rate of 6.30 wt%. By incorporating 2% carbon nanotubes (CNTs) into the epoxy matrix, the interface material achieves a thermal conductivity of 28.97 W/(m·K) at a flocking voltage of 30 kV and plate spacing of 10 cm. This represents a 52.1% increase in thermal conductivity compared to the material without TIM. The material achieves temperature uniformity within 10 s at the same heat source temperatures, which indicates a good application prospect in IC packaging and electronic heat dissipation.

18.
Toxicology ; 504: 153782, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38493947

RESUMO

Tobacco carcinogens are recognized as critical hazard factors for bladder tumorigenesis, affecting the prognosis of patients through aromatic amines components. However, the specific function of tobacco carcinogens and systematic assessment models in the prognosis of bladder cancer remains poorly elucidated. We retrieved bladder cancer specific tobacco carcinogens-related genes from Comparative Toxicogenomic Database, our Nanjing Bladder Cancer cohort and TCGA database. Gene×Gene interaction method was utilized to establish a prognostic signature. Integrative assessment of immunogenomics, tumor microenvironments and single-cell RNA-sequencing were performed to illustrate the internal relations of key events from different levels. Finally, we comprehensively identified 33 essential tobacco carcinogens-related genes to construct a novel prognostic signature, and found that high-risk patients were characterized by significantly worse overall survival (HR=2.25; Plog-rank < 0.01). Single-cell RNA-sequencing and multi-omics analysis demonstrated that cancer-associated fibroblasts mediated the crosstalk between epithelial-mesenchymal transition progression and immune evasion. Moreover, an adverse outcome pathway framework was established to facilitate our understanding to the tobacco carcinogens-triggered bladder tumorigenesis. Our study systematically provided immune microenvironmental alternations for smoking-induced adverse survival outcomes in bladder cancer. These findings facilitated the integrative multi-omics insights into risk assessment and toxic mechanisms of tobacco carcinogens.


Assuntos
Fibroblastos Associados a Câncer , Transição Epitelial-Mesenquimal , Microambiente Tumoral , Neoplasias da Bexiga Urinária , Humanos , Fibroblastos Associados a Câncer/imunologia , Fibroblastos Associados a Câncer/patologia , Fibroblastos Associados a Câncer/efeitos dos fármacos , Carcinógenos/toxicidade , Regulação Neoplásica da Expressão Gênica , Evasão da Resposta Imune , Multiômica , Prognóstico , Análise de Célula Única , Fumar/efeitos adversos , Microambiente Tumoral/imunologia , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/patologia
19.
Drug Des Devel Ther ; 18: 583-595, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38436039

RESUMO

Background: Remifentanil-induced hyperalgesia (RIH) increases the risk of persistent postoperative pain, making early postoperative analgesic therapy ineffective and affecting postoperative patient satisfaction. This study aimed to verify the effects of gradual withdrawal of remifentanil combined with postoperative pump infusion of remifentanil on postoperative hyperalgesia and pain in patients undergoing laparoscopic hysterectomy. Methods: This trial was a factorial design, double-blind, randomized controlled trial. Patients undergoing laparoscopic hysterectomy were randomly allocated to the control group, postoperative pump infusion of remifentanil group, gradual withdrawal of remifentanil group, or gradual withdrawal plus postoperative pump infusion of remifentanil group (n = 35 each). The primary outcome was postoperative mechanical pain thresholds in the medial forearm. The secondary outcomes included postoperative mechanical pain thresholds around the incision, pain numeric rating scale scores, analgesic utilization, awakening agitation or sedation scores, a 15-item quality of recovery survey, and postoperative complications. Results: Gradual withdrawal of remifentanil significantly increased postoperative pain thresholds versus abrupt discontinuation (P < 0.05), whereas postoperative infusion did not show significant differences compared to the absence of infusion (P > 0.05). The combined gradual withdrawal and postoperative infusion group exhibited the highest thresholds and had the lowest postoperative pain scores and analgesic requirements as well as the highest quality of recovery scores (P < 0.05). No significant differences were observed for agitation scores, sedation scores, or complication rates (P > 0.05). Conclusion: The novel combined gradual withdrawal and postoperative infusion of remifentanil uniquely attenuates postoperative hyperalgesia, pain severity, analgesic necessity, and improves recovery quality after laparoscopic hysterectomy.


Assuntos
Hiperalgesia , Laparoscopia , Feminino , Humanos , Remifentanil , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Método Duplo-Cego , Histerectomia/efeitos adversos , Dor Pós-Operatória/tratamento farmacológico , Analgésicos , Laparoscopia/efeitos adversos
20.
Materials (Basel) ; 17(5)2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38473456

RESUMO

Carbon-based composite materials, denoted as C/C composites and possessing high thermal conductivity, were synthesized utilizing a three-dimensional (3D) preform methodology. This involved the orthogonal weaving of mesophase pitch-based fibers in an X (Y) direction derived from low-temperature carbonization, and commercial PAN-based carbon fibers in a Z direction. The 3D preforms were saturated with mesophase pitch in their raw state through a hot-pressing process, which was executed under relatively low pressure at a predetermined temperature. Further densification was achieved by successive stages of mesophase pitch impregnation (MPI), followed by impregnation with coal pitch under high pressure (IPI). The microstructure and thermal conductivity of the C/C composites were systematically examined using a suite of analytical techniques, including Scanning Electron Microscopy (SEM), X-ray Diffraction (XRD), and PLM, amongst others. The findings suggest that the volumetric fraction of fibers and the directional alignment of the mesophase pitch molecules can be enhanced via hot pressing. The high graphitization degree of the mesophase pitch matrix results in an increased microcrystalline size and thus improved thermal conductivity of the C/C composite. Conversely, the orientation of the medium-temperature coal pitch matrix is relatively low, which compensates for the structural inadequacies of the composite material, albeit contributing minimally to the thermal conductivity of the resultant C/C composites. Following several stages of impregnation with mesophase pitch and subsequent impregnation with medium-temperature coal pitch, the 3D C/C composites yielded a density of 1.83 and 2.02 g/cm3. The thermal conductivity in the X (Y) direction was found to be 358 and 400 W/(m·K), respectively.

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