LTe2 induces cell apoptosis in multiple myeloma by suppressing AKT phosphorylation at Thr308 and Ser473

Multiple myeloma (MM) is a highly heterogeneous hematological malignancy originating from B lymphocytes, with a high recurrence rate primarily due to drug resistance. 2-((1H-indol-3-yl)methyl)-3-((3-((1H-indol-3-yl)methyl)-1H-indol-2-yl)methyl)-1H-indole (LTe2), a tetrameric indole oligomer, possesses a wide range of anticancer activities through various mechanisms. Here, we aim to explore the anti-tumor efficiency and potential downstream targets of LTe2 in MM. Its bioactivity was assessed by employing MTT assays, flow cytometry, and the 5TMM3VT mouse model. Additionally, transcriptomic RNA-seq analysis and molecular dynamics (MD) experiments were conducted to elucidate the mechanism underlying LTe2 induced MM cell apoptosis. The results demonstrated that LTe2 significantly inhibited MM cell proliferation both in vitro and in vivo, and revealed that LTe2 exerts its effect by inhibiting the phosphorylation of AKT at the Thr308 and Ser473 sites. In summary, our findings highlight the potential of LTe2 as a novel candidate drug for MM treatment and provided a solid foundation for future clinical trials involving LTe2

Comparison of PET/CT and MRI in the Diagnosis of Bone Metastasis in Prostate Cancer Patients: A Network Analysis of Diagnostic Studies

Background: Accurate diagnosis of bone metastasis status of prostate cancer (PCa) is becoming increasingly more important in guiding local and systemic treatment. Positron emission tomography/computed tomography (PET/CT) and magnetic resonance imaging (MRI) have increasingly been utilized globally to assess the bone metastases in PCa. Our meta-analysis was a high-volume series in which the utility of PET/CT with different radioligands was compared to MRI with different parameters in this setting. Materials and Methods: Three databases, including Medline, Embase, and Cochrane Library, were searched to retrieve original trials from their inception to August 31, 2019 according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. The methodological quality of the included studies was assessed by two independent investigators utilizing Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). A Bayesian network meta-analysis was performed using an arm-based model. Absolute sensitivity and specificity, relative sensitivity and specificity, diagnostic odds ratio (DOR), and superiority index, and their associated 95% confidence intervals (CI) were used to assess the diagnostic value. Results: Forty-five studies with 2,843 patients and 4,263 lesions were identified. Network meta-analysis reveals that 68Ga-labeled prostate membrane antigen (68Ga-PSMA) PET/CT has the highest superiority index (7.30) with the sensitivity of 0.91 and specificity of 0.99, followed by 18F-NaF, 11C-choline, 18F-choline, 18F-fludeoxyglucose (FDG), and 18F-fluciclovine PET/CT. The use of high magnetic field strength, multisequence, diffusion-weighted imaging (DWI), and more imaging planes will increase the diagnostic value of MRI for the detection of bone metastasis in prostate cancer patients. Where available, 3.0-T high-quality MRI approaches 68Ga-PSMA PET/CT was performed in the detection of bone metastasis on patient-based level (sensitivity, 0.94 vs. 0.91; specificity, 0.94 vs. 0.96; superiority index, 4.43 vs. 4.56). Conclusions: 68Ga-PSMA PET/CT is recommended for the diagnosis of bone metastasis in prostate cancer patients. Where available, 3.0-T high-quality MRI approaches 68Ga-PSMA PET/CT should be performed in the detection of bone metastasis

Impact of Prolonged Mechanical Ventilation on Ferroptosis in Renal Ischemia/Reperfusion Injury in Rats

We here investigated the impact of mechanical ventilation (MV) time on ferroptosis in a rat renal ischemia/reperfusion injury (IRI) model. Thirty-two male adult Sprague Dawley rats were divided into four groups (n=8/group): the sham group, IRI group, IRI+MV-4 h group, and IRI+MV-12 h group. Rats in the IRI group were subjected to 45 min bilateral renal ischemia. Rats in the IRI+MV groups were additionally mechanically ventilated with tracheal intubation after 45 min bilateral renal ischemia. Morphological changes associated with kidney injury and ferroptosis were assessed by hematoxylin and eosin staining and electron microscopy. Levels of the central regulator of ferroptosis, glutathione peroxidase 4 (GPX4), and lipid peroxidation markers 4-hydroxynonenal (4HNE) and superoxide dismutase 2 (SOD2) were determined in the kidney tissue by western blotting. Glutathione (GSH) levels were assessed in the serum and kidney homogenate. Scr levels in the IRI+MV-12 h group were significantly higher than those in the sham, IRI, and IRI+MV-4 h groups (all P IRI group > IRI+MV-4 h group > IRI+MV-12 h group (P<0.05 for all comparisons). By contrast, the 4HNE levels progressively increased in the kidney, with the highest values in the IRI+MV-12 h group (P<0.05, vs. the IRI group and vs. the IRI+MV-4 h group). Further, the GSH levels in the serum and kidney homogenates were significantly reduced in the IRI+MV-12 h group (P<0.01, vs. IRI group and vs. the IRI+MV-4 h group). A significant positive correlation was observed between the serum and kidney GSH levels (r2=0.542, P=0.03). These observations suggested that prolonged MV may exacerbate renal function failure, already initiated by IRI, by ferroptosis. Depletion of GSH may contribute to this effect, which requires further investigation

Exploring the Potential of Plant-Derived Exosome-like Nanovesicle as Functional Food Components for Human Health: A Review

Plant-derived exosome-like nanovesicles (PELNs) are bilayer membrane-enclosed nanovesicles secreted by plant cells, serving as carriers of various substances such as proteins, RNA, and metabolites. The mounting evidence suggests that PELN plays a crucial role in transmembrane signaling, nutrient transportation, apoptosis, and regulation of gut microbiota composition. This makes it a promising “dark nutrient” for plants to modulate human physiology and pathogenesis. A comprehensive understanding of PELN formation, uptake, and functional mechanisms can offer novel insights into plant nutrition and functional properties, thereby facilitating the precise development of plant-based foods and drugs. This article provides a summary of PELN extraction and characterization, as well as absorption and delivery processes. Furthermore, it focuses on the latest discoveries and underlying physiological mechanisms of PELN’s functions while exploring future research directions

PALI-NLP at SemEval-2022 Task 4: Discriminative Fine-tuning of Transformers for Patronizing and Condescending Language Detection

Patronizing and condescending language (PCL) has a large harmful impact and is difficult to detect, both for human judges and existing NLP systems. At SemEval-2022 Task 4, we propose a novel Transformer-based model and its ensembles to accurately understand such language context for PCL detection. To facilitate comprehension of the subtle and subjective nature of PCL, two fine-tuning strategies are applied to capture discriminative features from diverse linguistic behaviour and categorical distribution. The system achieves remarkable results on the official ranking, including 1st in Subtask 1 and 5th in Subtask 2. Extensive experiments on the task demonstrate the effectiveness of our system and its strategies.Comment: 8 pages, submitted in SemEval-2022 Workshop (co-located with NAACL

Incidence of traumatic sciatic nerve injury in patients with acetabular fractures and factors affecting recovery: a retrospective study

Abstract Background Reports on traumatic sciatic nerve injury associated with acetabular fracture are rare. In this study, we investigated the demographics of these injuries, their clinical characteristics, management, and factors potentially influencing neurological recovery. Methods We retrospectively reviewed all patients diagnosed to have acetabular fracture at our trauma center between January 2014 and June 2021. Data on patient demographics, characteristics of sciatic nerve injury, neurological recovery, factors potentially influencing neurological recovery were analyzed. Results Eighteen patients (bilateral in one case) met the diagnostic criteria. All these injuries involved the posterior wall or posterior column, and most patients had posterior dislocation of the hip joint. Four of the 19 sides with traumatic sciatic nerve injury involved the common peroneal nerve division and 15 involved both the common peroneal and tibial nerve divisions. Seventeen patients (18 sides) underwent intraoperative nerve exploration, which revealed abnormalities in 7 sides and no obvious abnormality in 11 sides. At the last follow-up, 10 sides (52.6%) had complete recovery and 9 (47.4%) had partial recovery; the difference was statistically significant between those with or without abnormal nerve damage during exploration (P = 0.046). Linear regression analysis showed that a nerve abnormality detected intraoperatively was a predictor of nerve recovery (P = 0.009). The mean recovery time was significantly longer for partial recovery than for complete recovery (13.78 months vs. 6.70 months; P = 0.001). Conclusions All the injuries in this series involved the posterior wall or posterior column, and most patients had posterior dislocation of the hip joint. Damage to the common peroneal nerve division was more severe than that to the tibial nerve division preoperatively. However, the degree of recovery of the common peroneal division was not worse than that of the tibial division. There was a relationship between the degree of neurological recovery and whether there was an abnormality at the time of intraoperative nerve exploration. Patients with partial recovery took longer to recover

Classification and Design of HIV-1 Integrase Inhibitors Based on Machine Learning

A key enzyme in human immunodeficiency virus type 1 (HIV-1) life cycle, integrase (IN) aids the integration of viral DNA into the host DNA, which has become an ideal target for the development of anti-HIV drugs. A total of 1785 potential HIV-1 IN inhibitors were collected from the databases of ChEMBL, Binding Database, DrugBank, and PubMed, as well as from 40 references. The database was divided into the training set and test set by random sampling. By exploring the correlation between molecular descriptors and inhibitory activity, it is found that the classification and specific activity data of inhibitors can be more accurately predicted by the combination of molecular descriptors and molecular fingerprints. The calculation of molecular fingerprint descriptor provides the additional substructure information to improve the prediction ability. Based on the training set, two machine learning methods, the recursive partition (RP) and naive Bayes (NB) models, were used to build the classifiers of HIV-1 IN inhibitors. Through the test set verification, the RP technique accurately predicted 82.5% inhibitors and 86.3% noninhibitors. The NB model predicted 88.3% inhibitors and 87.2% noninhibitors with correlation coefficient of 85.2%. The results show that the prediction performance of NB model is slightly better than that of RP, and the key molecular segments are also obtained. Additionally, CoMFA and CoMSIA models with good activity prediction ability both were constructed by exploring the structure-activity relationship, which is helpful for the design and optimization of HIV-1 IN inhibitors