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1.
ACS Med Chem Lett ; 15(6): 958-964, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38894918

RESUMO

SOS1, a guanine nucleotide exchange factor (GEF), plays a critical role in catalyzing the conversion of KRAS from its GDP- to GTP-bound form, regardless of KRAS mutation status, and represents a promising new drug target to treat all KRAS-driven tumors. Herein, we employed a scaffold hopping strategy to design, synthesize, and optimize a series of novel binary ring derivatives as SOS1 inhibitors. Among them, compound 10f (HH0043) displayed potent activities in both biochemical and cellular assays and favorable pharmacokinetic profiles. Oral administration of HH0043 resulted in a significant tumor inhibitory effect in a subcutaneous KRAS G12C-mutated NCI-H358 (human lung cancer cell line) xenograft mouse model, and the tumor inhibitory effect of HH0043 was superior to that of BI-3406 at the same dose (total growth inhibition, TGI: 76% vs 49%). On the basis of these results, HH0043, with a novel 1,7-naphthyridine scaffold that is distinct from currently reported SOS1 inhibitors, is nominated as the lead compound for this discovery project.

2.
Nat Commun ; 15(1): 5169, 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38886390

RESUMO

The effectiveness of national policies for air pollution control has been demonstrated, but the relative effectiveness of short-term emission reduction measures in comparison with national policies has not. Here we show that short-term abatement measures during important international events substantially reduced PM2.5 concentrations, but air quality rebounded to pre-event levels after the measures ceased. Long-term adherence to strict emission reduction policies led to successful decreases of 54% in PM2.5 concentrations in Beijing, and 23% in atmospheric nitrogen deposition in China from 2012 to 2020. Incentivized by "blue skies" type campaigns, economic development and reactive nitrogen pollution are quickly decoupled, showing that a combination of inspiring but aggressive short-term measures and effective but durable long-term policies delivers sustainable air quality improvement. However, increased ammonia concentrations, transboundary pollutant flows, and the complexity to achieving reduction targets under climate change scenarios, underscore the need for the synergistic control of multiple pollutants and inter-regional action.

3.
Bioresour Technol ; : 131002, 2024 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-38889869

RESUMO

A continuous chemical-free green approach was investigated for the comprehensive reutilization of all components in herbal extraction residues (HERs), taking Glycyrrhiza uralensis residue (GUR) as an example. The GUR structural changes induced by mechanical extrusion which improve the specific surface area and enzyme accessibility of GUR. With 3 % pretreated GUR loading of high-tolerance Penicillium oxalicum G2. The reducing sugar yield of 11.45 g/L was achieved, along with an 81.06 % in situ enzymatic hydrolysis. Finally, 8.23 g/L bioethanol (0.40 g/g total sugar) was produced from GUR hydrolysates after 24 h fermentation of Pichia stipitis G32. The amount of functional medicinal ingredients extracted from GUR after hydrolysis (39.63 mg/g) was 37.69 % greater than that of un-pretreated GUR. In total, 1.49 g flavonoids, 294.36 U cellulase, and 14.13 g ethanol could be produced from 100 g GUR using this process, illustrating that this green and efficient process has the potential for industrial production.

4.
Artigo em Inglês | MEDLINE | ID: mdl-38866616

RESUMO

BACKGROUND AND AIM: Currently, the relationship between dynamic changes in dietary manganese (Mn) intake and risk of hyperuricemia (HU) is still unclear. This study aimed to identify dietary Mn consumption trajectories in the Chinese adults and assess their relation with the risk of HU. METHODS AND RESULTS: Cohort data from the China Health and Nutrition Survey (CHNS) 1997-2009 were employed in this study. Overall, 6886 adult participants were included. Participants were designated into subgroups based on the trajectories of dietary Mn consumption by sex. Cox proportional hazard models were used to explore the associations between different trajectories and the risk of HU. For men, compared with low stable trajectory group, moderate to high trajectory group was significantly related to reduced risk of HU (HR = 0.61, 95% CI: 0.38 to 0.98) with adjustment for covariates. TC, HDL-C, ApoB, and TG exerted partial regulation function between trajectories and HU. For women, compared with low stable trajectory group, high stable trajectory group was significantly related to reduced risk of HU (HR = 0.76, 95% CI: 0.60 to 0.95) with adjustment for covariates. Similarly, TC, HDL-C, ApoB, and ApoA exerted partial regulation function between trajectories and HU. CONCLUSIONS: Long-term relatively high dietary Mn consumption may have a protective effect against HU in Chinese adults. The differences in HU-related factors among different dietary Mn intake trajectories partially regulated the association between these trajectories and HU.

5.
Artigo em Inglês | MEDLINE | ID: mdl-38862429

RESUMO

DNA sequencers have become increasingly important research and diagnostic tools over the past 20 years. In this study, we developed a single-molecule desktop sequencer, GenoCare 1600 (GenoCare), which utilizes amplification-free library preparation and two-color sequencing-by-synthesis chemistry, making it more user-friendly compared with previous single-molecule sequencing platforms for clinical use. Using the GenoCare platform, we sequenced an Escherichia coli standard sample and achieved a consensus accuracy exceeding 99.99%. We also evaluated the sequencing performance of this platform in microbial mixtures and coronavirus disease 2019 (COVID-19) samples from throat swabs. Our findings indicate that the GenoCare platform allows for microbial quantitation, sensitive identification of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, and accurate detection of virus mutations, as confirmed by Sanger sequencing, demonstrating its remarkable potential in clinical application.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , COVID-19/virologia , COVID-19/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Análise de Sequência de DNA/métodos , Escherichia coli/genética , Mutação
6.
Orphanet J Rare Dis ; 19(1): 232, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38863016

RESUMO

BACKGROUND: Pulmonary high-grade neuroendocrine carcinomas(pHGNEC) encompassing small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) are clinically aggressive tumors with poor prognosis. The role of surgery and prognostic factors guiding management remain unclear. We aimed to analyze prognosis following resection and identify predictive variables. METHODS: This retrospective study analyzed 259 patients undergoing pHGNEC resection from 2001-2023. Overall survival (OS) and disease-free survival (DFS) were evaluated using Kaplan-Meier curves. Prognostic factors were assessed with Cox regression and visualized using nomogram tools. RESULTS: Minimally invasive surgery was associated with better OS (p = 0.001) and DFS (p = 0.001). Higher T stage predicted worse OS (T2 p = 0.044, T4 p = 0.007) and DFS (T2 p = 0.020, T4 p = 0.004). Advanced TNM stage III (OS p = 0.018; DFS p = 0.015) and IV (OS p < 0.001; DFS p < 0.001) also correlated with poorer prognosis. In the SCLC subgroup, elevated preoperative CEA independently predicted worse OS (p = 0.012) and DFS (p = 0.004). T4 disease (OS p < 0.001; DFS p = 0.002) and advanced TNM staging (stage III OS p = 0.043; DFS p = 0.045; stage IV OS p < 0.001, DFS p < 0.001) were associated with worse outcomes. In LCNEC patients, VATS resection improved OS (p = 0.048) and DFS (p = 0.027) despite conversion. Prior malignancy predicted worse OS (p < 0.001). Advanced TNM disease (stage III OS p = 0.047; stage IV OS p = 0.003, DFS p = 0.005) were also negative prognostic factors. The prognostic nomogram incorporating above variables effectively stratified risk. Calibration plots revealed good correlation between predicted and actual survival. CONCLUSIONS: We identified minimally invasive surgery, early TNM stage, younger age, and normal preoperative CEA as positive prognostic factors following pHGNEC resection. Our study provides an applicable prognostic nomogram to facilitate personalized pHGNEC management.


Assuntos
Carcinoma Neuroendócrino , Neoplasias Pulmonares , Nomogramas , Humanos , Feminino , Masculino , Carcinoma Neuroendócrino/cirurgia , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/mortalidade , Pessoa de Meia-Idade , Estudos Retrospectivos , Prognóstico , Neoplasias Pulmonares/cirurgia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/mortalidade , Idoso , Adulto , Idoso de 80 Anos ou mais
7.
Artigo em Inglês | MEDLINE | ID: mdl-38870522

RESUMO

The commonly-used drug susceptibility testing (DST) relies on bacterial culture and faces shortcomings such as long turnaround time and clone/subclone selection. We developed a targeted deep amplification sequencing (DAS) method directly applied to clinical specimens. In this DAS panel, we examined 941 drug-resistant mutations associated with 20 anti-tuberculosis drugs with an initial amount of 4 pg DNA and reduced clinical testing time from 20 days to two days. A prospective study was conducted using 115 clinical specimens mainly with Xpert® Mycobacterium tuberculosis/rifampicin (Xpert MTB/RIF) assay positive to evaluate drug-resistant mutation detection. DAS was performed on culture-free specimens, while culture-dependent isolates were used for phenotypic DST, DAS, and whole-genome sequencing (WGS). For in silico molecular DST, our result based on DAS panel revealed the similar accuracy to three published reports based on WGS. For 82 isolates, application of DAS showed better sensitivity (93.03% vs. 92.16%), specificity (96.10% vs. 95.02%), and accuracy (91.33% vs. 90.62%) than Mykrobe software using WGS. Compared to culture-dependent WGS, culture-free DAS provides a full picture of sequence variation at population level, exhibiting in detail the gain-and-loss variants caused by bacterial culture. Our study performs a systematic verification of the advantages of DAS in clinical applications and comprehensively illustrates the discrepancy in Mycobacterium tuberculosis before and after culture.

8.
J Clin Anesth ; 97: 111525, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38870701

RESUMO

STUDY OBJECTIVE: Few studies have focused on the effect of virtual reality (VR) exposure on postoperative acute pain in adult female patients undergoing gynecology surgery. DESIGN: A randomized control trial (RCT) study. SETTING: At Beijing Fuxing Hospital. PATIENTS: 115 patients aged between 20 and 60 years, American Society of Anesthesiologists (ASA) physical status I - II were consecutively enrolled and randomly divided into VR group (n = 58) or control group (n = 57). INTERVENTIONS: Patients in the VR group received 15 min of VR video viewing before surgery. MEASUREMENTS: The primary outcome was acute postoperative pain at 8 h which was measured by the Visual Analogue Scale (VAS) scores. The secondary outcomes including the use of analgesic drugs, the incidence of moderate pain and postoperative recovery which were recorded 24 h after surgery. The Hospital Anxiety and Depression Scale (HADS) was also used to evaluate patients' emotional status before surgery. MAIN RESULTS: The VAS scores at 30 min [2 (1,2) vs. 3 (2,3)], 2 h [2 (2,3) vs. 4 (3,4)], 4 h [3 (2,4) vs. 4 (4,5)], 8 h [3 (2,4) vs. 4 (4,5)], 12 h [2 (2,3) vs. 4 (3,4)], 24 h [1 (1,2) vs. 3 (2,3)] after surgery. Generalized estimation equation (GEE) indicated that VR intervention was negatively correlated with postoperative VAS values (ß = -0.830, S.E = 0.199, 95%CI (-1.220,-0.439), Wald χ2 = 17.359, p<0.05), in the meanwhile, VR also lower the incidence of moderate pain (VAS > 4) at 8 h postoperatively (12.1% vs 31.0%, p = 0.013). However, the 24 h tramadol usage remained unchanged. Patients in the VR group had better sleep quality (6.33 ± 2.3 vs. 4.12 ± 2.5, p < 0.001) and lower incidence of nausea (43.1% vs. 63.2%, p < 0.05), dizziness (0% vs. 14.0%, p < 0.05), and headache (12.1% vs. 29.8%, p < 0.05). VR could reduce the median HADS scores (9.81 ± 6.1 vs 3.14 ± 3.9, p < 0.001) and blood pressure preoperatively. CONCLUSIONS: VR intervention can reduce acute postoperative pain with better postoperative recovery and lower preoperative anxiety level in adult female patients undergoing laparoscopic gynecology surgery.

9.
Phys Med ; 123: 103393, 2024 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-38852363

RESUMO

BACKGROUND AND PURPOSE: One of the current roadblocks to the widespread use of Total Marrow Irradiation (TMI) and Total Marrow and Lymphoid Irradiation (TMLI) is the challenging difficulties in tumor target contouring workflow. This study aims to develop a hybrid neural network model that promotes accurate, automatic, and rapid segmentation of multi-class clinical target volumes. MATERIALS AND METHODS: Patients who underwent TMI and TMLI from January 2018 to May 2022 were included. Two independent oncologists manually contoured eight target volumes for patients on CT images. A novel Dual-Encoder Alignment Network (DEA-Net) was developed and trained using 46 patients from one internal institution and independently evaluated on a total of 39 internal and external patients. Performance was evaluated on accuracy metrics and delineation time. RESULTS: The DEA-Net achieved a mean dice similarity coefficient of 90.1 % ± 1.8 % for internal testing dataset (23 patients) and 91.1 % ± 2.5 % for external testing dataset (16 patients). The 95 % Hausdorff distance and average symmetric surface distance were 2.04 ± 0.62 mm and 0.57 ± 0.11 mm for internal testing dataset, and 2.17 ± 0.68 mm, and 0.57 ± 0.20 mm for external testing dataset, respectively, outperforming most of existing state-of-the-art methods. In addition, the automatic segmentation workflow reduced delineation time by 98 % compared to the conventional manual contouring process (mean 173 ± 29 s vs. 12168 ± 1690 s; P < 0.001). Ablation study validate the effectiveness of hybrid structures. CONCLUSION: The proposed deep learning framework achieved comparable or superior target volume delineation accuracy, significantly accelerating the radiotherapy planning process.

10.
Food Chem ; 456: 139965, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38852460

RESUMO

Pasteurisation and spray drying are critical steps to ensure the safety and shelf-life of formulae, but these treatments also induce formation of some potentially harmful Maillard reaction products. In this study, the occurrence of potentially harmful Maillard reaction products and proximate compositions in different commercial formulae were analysed. Our results showed that infant formulae had significantly higher concentrations of furosine, Nε-(carboxymethyl)lysine (CML) and Nε-(carboxyethyl)lysine (CEL) than follow-on/toddler formula. Specialty formulae had higher concentrations of glyoxal and CML than other types of formulae. Correlation analysis indicated that concentrations of 5-hydroxymethylfurfural, 3-deoxyglucosone, CML and CEL were closely related to fat contents. These results provided insight into concentrations of potentially harmful Maillard reaction products in different types of formulae and provide a theoretical basis for further optimisation of processing.

11.
World J Surg Oncol ; 22(1): 150, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38844951

RESUMO

PURPOSE: To evaluate the predictors for short and long term urinary continence (UC) recovery after laparoscopic radical prostatectomy (LRP) from clinical and oncological variables. METHODS: We retrospectively collected data from 142 prostate cancer patients who underwent LRP between September 2014 and June 2021 at a tumor specialist diagnosis and treatment center in China. The rate of post-prostatectomy incontinence (PPI) was evaluated from immediate and at 3, 6 and 12 mo after LRP, and UC was defined as the use of no or one safety pad. Sixteen clinical and oncological variables were analyzed by univariate and multivariate regression analysis to determine whether they were associated with short (3 mo) or long term (12 mo) UC recovery after LRP. RESULTS: After eliminating patients who were lost to follow-up, 129 patients were eventually included. The mean ± SD age was 68 ± 6.3 years. The UC rates of immediate, 3, 6 and 12 mo after the operation were 27.9%, 54.3%, 75.2% and 88.4%, respectively. Multivariate analyses revealed that membranous urethral length (MUL) was a protective predictor of UC after catheter extraction(P < 0.001), and at 3 mo (P < 0.001), 6 mo (P < 0.001) and 12 mo (P = 0.009) after surgery. CONCLUSION: MUL is a significant independent factor that can contribute to short and long term UC recovery post-LRP, which may assist clinicians and their patients in counseling of treatment.


Assuntos
Laparoscopia , Complicações Pós-Operatórias , Prostatectomia , Neoplasias da Próstata , Incontinência Urinária , Humanos , Masculino , Prostatectomia/efeitos adversos , Prostatectomia/métodos , Laparoscopia/efeitos adversos , Laparoscopia/métodos , Neoplasias da Próstata/cirurgia , Incontinência Urinária/etiologia , Incontinência Urinária/epidemiologia , Idoso , Estudos Retrospectivos , China/epidemiologia , Complicações Pós-Operatórias/etiologia , Seguimentos , Prognóstico , Pessoa de Meia-Idade , Recuperação de Função Fisiológica
12.
Eur J Radiol ; 177: 111521, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38850722

RESUMO

PURPOSE: To develop two bone status prediction models combining deep learning and radiomics based on standard-dose chest computed tomography (SDCT) and low-dose chest computed tomography (LDCT), and to evaluate the effect of tube voltage on reproducibility of radiomics features and predictive efficacy of these models. METHODS: A total of 1508 patients were enrolled in this retrospective study. LDCT was conducted using 80 kVp, tube current ranging from 100 to 475 mA. On the other hand, SDCT was performed using 120 kVp, tube current ranging from 100 to 520 mA. We developed an automatic thoracic vertebral cancellous bone (TVCB) segmentation model. Subsequently, 1184 features were extracted and two classifiers were developed based on LDCT and SDCT images. Based on the diagnostic results of quantitative computed tomography examination, the first-level classifier was initially developed to distinguish normal or abnormal BMD (including osteoporosis and osteopenia), while the second-level classifier was employed to identify osteoporosis or osteopenia. The Dice coefficient was used to evaluate the performance of the automated segmentation model. The Concordance Correlation Coefficients (CCC) of radiomics features were calculated between LDCT and SDCT, and the performance of these models was evaluated. RESULTS: Our automated segmentation model achieved a Dice coefficient of 0.98 ± 0.01 and 0.97 ± 0.02 in LDCT and SDCT, respectively. Alterations in tube voltage decreased the reproducibility of the extracted radiomic features, with 85.05 % of the radiomic features exhibiting low reproducibility (CCC < 0.75). The area under the curve (AUC) using LDCT-based and SDCT-based models was 0.97 ± 0.01 and 0.94 ± 0.02, respectively. Nonetheless, cross-validation with independent test sets of different tube voltage scans suggests that variations in tube voltage can impair the diagnostic efficacy of the model. Consequently, radiomics models are not universally applicable to images of varying tube voltages. In clinical settings, ensuring consistency between the tube voltage of the image used for model development and that of the acquired patient image is critical. CONCLUSIONS: Automatic bone status prediction models, utilizing either LDCT or SDCT images, enable accurate assessment of bone status. Tube voltage impacts reproducibility of features and predictive efficacy of models. It is necessary to account for tube voltage variation during the image acquisition.

13.
Anal Chem ; 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38874382

RESUMO

Dysregulation of protein core-fucosylation plays a pivotal role in the onset, progression, and immunosuppression of cancer. However, analyzing core-fucosylation, especially the accurate determination of the core-fucosylation (CF) site occupancy ratio, remains challenging. To address these problems, we developed a truncation strategy that efficiently converts intact glycopeptides with hundreds of different glycans into two truncated forms, i.e., a monosaccharide HexNAc and a disaccharide HexNAc+core-fucose. Further combination with data-independent analysis to form an integrated platform allowed the measurement of site-specific core-fucosylation abundances and the determination of the CF occupancy ratio with high reproducibility. Notably, three times CF sites were identified using this strategy compared to conventional methods based on intact glycopeptides. Application of this platform to characterize protein core-fucosylation in two breast cancer cell lines, i.e., MDA-MB-231 and MCF7, yields a total of 1615 unique glycosites and about 900 CF sites from one single LC-MS/MS analysis. Differential analysis unraveled the distinct glycosylation pattern for over 201 cell surface drug targets between breast cancer subtypes and provides insights into developing new therapeutic strategies to aid precision medicine. Given the robust performance of this platform, it would have broad application in discovering novel biomarkers based on the CF glycosylation pattern, investigating cancer mechanisms, as well as detecting new intervention targets.

14.
Int J Surg ; 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38874488

RESUMO

BACKGROUND: Limited studies have explored the joint effect of physical activity (PA) and dietary quality (DQ) on the mortality outcomes of the cancer population. We aim to investigate the separate and joint prognostic effect of PA and DQ on the survival of US cancer survivors. METHODS: Data of cancer survivors (n=3,007, representing 22 million cancer survivors) were from the National Health and Nutrition Examination Survey (NHANES) between 2007 and 2018. PA was assessed using the self-reported Global Physical Activity Questionnaire (GPAQ) and DQ was evaluated through the Health Eating Index-2015 (HEI-2015). Kaplan-Meier (KM) curves and the Cox proportional hazard model were used to evaluate the associations between separate and joint prognostic effects of PA and DQ with mortality outcomes among cancer survivors. RESULTS: In the joint analyses, cancer survivors with sufficiently active PA (≥600 MET-min/week) and qualified DQ (≥60) presented reduced risks of all-cause mortality (HR 0.45, 95% CI 0.35-0.59) as compared with each lifestyle intervention separately. Meanwhile, the joint effects of either insufficiently or sufficiently active PA (>0 MET-min/week) and qualified DQ (≥60) were associated with lower risks for cancer (HR 0.60, 95% CI 0.40-0.90) and non-cancer mortality (HR 0.43, 95% CI 0.32-0.59). CONCLUSIONS: Our study highlights the combination of active PA and qualified DQ was strongly associated with reduced mortality risk of cancer survivors. Our findings might help to refine the lifestyle intervention recommendations for this population.

15.
ISA Trans ; 2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38834422

RESUMO

The formation tracking of the leader-follower multi-agent systems (MASs) under switching topologies is investigated. The considered system is exposed to both the mismatched and matched disturbances in the dynamics of the leader and followers, which places higher requirements for the robustness of the control protocol. In the presence of disturbances and leader's unknown control input, an innovative distributed observer embedded with robust terms is designed firstly to estimate leader's states in finite time. Taking account of the switching topologies, a novel analysis scheme that divides the convergence process into two stages is proposed to establish the finite-time (FT) convergence of estimation errors. Then, by virtue of a constructed auxiliary variable, a FT controller with an event-triggered mechanism is put forward, in which multiple robust feedback terms are designed wisely to suppress the mismatched and matched disturbances effectively. As a result, the FT formation tracking can be achieved with saved resources, despite perturbed environments and switching topologies. Simulation examples are presented to confirm the effectiveness of the proposed algorithm.

16.
World Neurosurg ; 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38878892

RESUMO

OBJECTIVE: To develop and validate natural language processing (NLP)-driven artificial intelligence (AI) models for the diagnosis of lumbar disc herniation (LDH) with L5 and S1 radiculopathy using electronic health records (EHRs). METHODS: EHRs of patients undergoing single-level Percutaneous Endoscopic Lumbar Discectomy (PELD) for the treatment of LDH at the L4/5 or L5/S1 level between June 1, 2013, and December 31, 2021, were collected. The primary outcome was LDH with L5 and S1 radiculopathy, which was defined as nerve root compression recorded in the operative notes. Datasets were created using the history of present illness (HPI) text and positive symptom (PS) text with radiculopathy (L5 or S1), respectively. The datasets were randomly split into a training set and a testing set in a 7:3 ratio. Two machine learning (ML) models, the Long Short-Term Memory (LSTM) network and Extreme Gradient Boosting (XGBoost), were developed using the training set. Performance evaluation of the models on the testing set was done using measures such as the receiver operating characteristic (ROC) curve, area under the curve (AUC), accuracy, recall, F1-score, and precision. RESULTS: The study included a total of 1681 patients, with 590 patients having L5 radiculopathy and 1091 patients having S1 radiculopathy. Among the four models developed, the LSTM model based on PS text showed the best discrimination in the testing set, with precision (0.9054), recall (0.9405), accuracy (0.8950), F1-score (0.9226), and AUC (0.9485). CONCLUSIONS: This study provides preliminary validation of the concept that NLP-driven AI models can be used for the diagnosis of lumbar disease using EHRs. This study could pave the way for future research that may develop more comprehensive and clinically impactful AI-driven diagnostic systems.

17.
Animals (Basel) ; 14(11)2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38891605

RESUMO

Haemaphysalis longicornis is a common tick species that carries several pathogens. There are few reports on the influence of different hosts on the structure of midgut microflora in H. longicornis. In this study, midgut contents of fully engorged female H. longicornis were collected from the surface of tiger (Panthera tigris) and deer (Dama dama). The bacterial genomic DNA of each sample was extracted, and the V3-V4 regions of the bacterial 16S rRNA were sequenced using the Illumina NovaSeq sequencing. The diversity of the bacterial community of the fully engorged female H. longicornis on the surface of tiger was higher than that of deer. In total, 8 phyla and 73 genera of bacteria annotations were detected in the two groups. At the phylum level, the bacterial phyla common to the two groups were Proteobacteria, Firmicutes, and Actinobacteriota. At the genus level, there were 20 common bacterial genera, among which the relative abundances of Coxiella, Morganella, Diplorickettsia, and Acinetobacter were high. The Morganella species was further identified to be Morganella morganii. The alpha diversity index indicated that the bacterial diversity of the tiger group was higher than that of the deer group. Bacteroidota, Patescibacteria, Desulfobacterota, Verrucomicrobiota, and Cyanobacteria were solely detected in the tiger group. A total of 52 bacterial genera were unique in the tiger group, while one bacterial genus was unique in the deer group. This study indicates that there are differences in the structure of the gut bacteria of the same tick species among different hosts. Further culture-based methods are needed to provide a more comprehensive understanding of the tick microbiota parasitizing different hosts.

18.
Eur J Intern Med ; 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38876929

RESUMO

BACKGROUND: Alcohol use disorder (AUD) is among the leading causes of morbidity and mortality worldwide, and over 95 million people live with alcohol dependence globally. The estimated heritability of AUD is 50-60 %, and multiple genes are thought to contribute to various endophenotypes of the disease. Previous clinical trials support a precision medicine approach using ondansetron (AD04, a 5-HT3 antagonist) by segregating AUD populations by the bio-genetic endophenotype of specific serotonergic genotypes and the bio-psychosocial endophenotype of the severity of drinking or both. By targeting the modulation of biogenetic signaling within the biopsychosocial context of AUD, low-dose AD04 holds promise in reducing alcohol consumption among affected individuals while minimizing adverse effects. METHODS: This was a phase III, 6-month, 25-site, randomized, placebo-controlled clinical trial using AD04 to treat DSM-V-categorized AUD individuals who were pre-stratified into the endophenotypes of heavy or very heavy drinking individuals and possessed a pre-defined profile of genetic variants related to the serotonin transporter and serotonin-3AB receptor. Participants (N = 303) presented moderate to severe AUD, >80 % were men, mostly in their fifties, and >95 % were of European descent. Low-dose AD04 (approx. 033 mg twice daily) or a matching placebo was administered twice daily for 6 months. Brief Behavioral Compliance Enhancement Treatment (BBCET [53]) was administered every two weeks to enhance medication compliance and clinic attendance. RESULTS: There was a significant reduction in the monthly percentage of heavy drinking days, PHDD (-46·7 % (2·7 %), 95 %CI: -52·1 % to -41·2 % vs. -38·1 % (2·9 %), 95 %CI: -43·8 % to -32·5 %, respectively; LS mean difference=-8·5 %; p = 0.03) among AD04-treated vs. placebo-receiving heavy drinking individuals at month 6. Heavy drinking individuals were also less likely to be diagnosed with AUD [Month 1: -32·0 % (2·8 %), 95 %CI: -37·5 % to -26·5 % vs. -23·2 % (2·9 %), 95 %CI: -28·9 to -17·5 %; LS mean difference= -8·8 %; p = 0·026)], and improved on the WHO quality of life BREF scale with a significant effect for at least a 1-level downward shift (OR = 3.4; 95 % CI: 1·03-11·45, p = 0·044). Importantly, heavy drinking individuals, as distinct from very heavy drinking individuals, were the bio-psychosocial endophenotype more predictive of therapeutic response to AD04. AD04 had an exceptional safety and tolerability profile, like the placebo's. CONCLUSIONS: In this Phase 3 clinical trial, AD04 was shown to be a promising treatment for currently drinking heavy drinking individuals with AUD who also possess a specific genotypic profile in the serotonin transporter and serotonin-3AB receptor complex. Using AD04 to reduce the harm of AUD in heavy drinking individuals who are currently drinking, without the necessity of abstinence or detoxification from alcohol use, is an important advance in the field of precision medicine. AD04's adverse events profile, which was like placebo, should enhance accessibility and acceptance of modern medical treatment for AUD by lowering the incorrect but commonly perceived stigma of personal failure.

19.
Mol Cell Biochem ; 2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38896203

RESUMO

Triple-negative breast cancer (TNBC) poses a formidable challenge in oncology due to its aggressive nature and limited treatment options. Although doxorubicin, a widely used chemotherapeutic agent, shows efficacy in TNBC treatment, acquired resistance remains a significant obstacle. Our study explores the role of MALSU1, a regulator of mitochondrial translation, in TNBC and its impact on cell proliferation and doxorubicin resistance. We observed increased MALSU1 expression in TNBC, correlating with poor patient prognosis. MALSU1 knockdown in TNBC cells significantly reduced proliferation, indicating its pivotal role in sustaining cell growth. Mechanistically, MALSU1 depletion resulted in decreased activities of mitochondrial respiratory chain complexes, cellular ATP levels, and mitochondrial respiration. Notably, exogenous addition of normal mitochondria restored proliferation and mitochondrial respiration in MALSU1-depleted TNBC cells. Importantly, MALSU1 knockdown enhanced the sensitivity of doxorubicin-resistant TNBC cells to doxorubicin treatment. Furthermore, pharmacological inhibition of mitochondrial translation using tigecycline and chloramphenicol mimicked the effects of MALSU1 knockdown, suggesting mitochondrial translation as a potential therapeutic target. Taken together, our findings not only elucidate the intricate role of MALSU1 in TNBC biology and doxorubicin resistance but also lay the groundwork for future investigations targeting MALSU1 and/or mitochondrial translation as a promising avenue for developing innovative therapeutic strategies against TNBC.

20.
Cancer Med ; 13(11): e7350, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38859683

RESUMO

BACKGROUND AND OBJECTIVE: High-grade glioma (HGG) is known to be characterized by a high degree of malignancy and a worse prognosis. The classical treatment is safe resection supplemented by radiotherapy and chemotherapy. Tumor treating fields (TTFields), an emerging physiotherapeutic modality that targets malignant solid tumors using medium-frequency, low-intensity, alternating electric fields to interfere with cell division, have been used for the treatment of new diagnosis of glioblastoma, however, their administration in HGG requires further clinical evidence. The efficacy and safety of TTFields in Chinese patients with HGG were retrospectively evaluated by us in a single center. METHODS: We enrolled and analyzed 52 patients with newly diagnosed HGG undergoing surgery and standard chemoradiotherapy regimens from December 2019 to June 2022, and followed them until June 2023. Based on whether they used TTFields, they were divided into a TTFields group and a non-TTFields group. Progression-free survival (PFS) and overall survival (OS) were compared between the two groups. RESULTS: There were 26 cases in the TTFields group and 26 cases in the non-TTFields group. In the TTFields group, the median PFS was 14.2 months (95% CI: 9.50-18.90), the median OS was 19.7 months (95% CI: 14.95-24.25) , the median interval from surgery to the start of treatment with TTFields was 2.47 months (95% CI: 1.47-4.13), and the median duration of treatment with TTFields was 10.6 months (95% CI: 9.57-11.63). 15 (57.69%) patients experienced an adverse event and no serious adverse event was reported. In the non-TTFields group, the median PFS was 9.57 months (95% CI: 6.23-12.91) and the median OS was 16.07 months (95% CI: 12.90-19.24). There was a statistically significant difference in PFS (p = 0.005) and OS (p = 0.007) between the two groups. CONCLUSIONS: In this retrospective analysis, TTFields were observed to improve newly diagnosed HGG patients' median PFS and OS. Compliance was much higher than reported in clinical trials and safety remained good.


Assuntos
Neoplasias Encefálicas , Glioma , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Quimiorradioterapia/métodos , China , População do Leste Asiático , Terapia por Estimulação Elétrica/métodos , Glioma/terapia , Glioma/patologia , Glioma/mortalidade , Gradação de Tumores , Intervalo Livre de Progressão , Estudos Retrospectivos , Resultado do Tratamento
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