A Novel Targeted Microtubules Transformable Nanopeptide System Yields Strong Anti-Prostate Cancer Effects by Suppressing Nuclear Translocation of Androgen Receptors.

The extended use of androgen deprivation therapy (ADT) may often lead to the progression from castration-sensitive prostate cancer (CSPC) to castration-resistant prostate cancer (CRPC) in prostate cancer. To address this, it is essential to inhibit the nuclear translocation of the androgen receptor (AR) as part of an effective disease-modifying strategy. Microtubules play a central role in facilitating AR nuclear translocation, highlighting their importance as a therapeutic target. In this regard, a designated as the targeted microtubules transformable nanopeptide system (MTN) is developed. This system is designed to disrupt microtubule structure and function through dual-targeting of prostate-specific membrane antigen (PSMA) and ß-tubulin. Initially, MTN targets prostate cells via PSMA and then specifically binds to ß-tubulin within microtubules, leading to the formation of nanofibers. These nanofibers subsequently induce the polymerization of microtubules, thereby disrupting AR transport. Notably, MTN exhibits efficient and prolonged suppression of prostate cancer across the spectrum from CSPC to CRPC, with a highly favorable safety profile in normal cells. These findings highlight the potential of MTN as a novel and promising approach for comprehensive prostate cancer therapy throughout its entire progression.

Periodontal health and oral hygiene of children with orofacial clefts in Eastern China.

To comparatively assess the periodontal condition and oral hygiene of children and adolescents at different ages presenting with different types of orofacial clefts (OFCs). A total of 1608 patients aged 6-18 years who had not previously undergone periodontal treatment were enrolled in this study. Participants were categorized into two age groups: 6-12 years (Group I) and 13-18 years (Group II). Participants in both age groups were further classified into one of the three OFC-type subgroups: cleft lip only (without or with alveolar cleft), cleft lip and cleft palate, and cleft palate only. Periodontal health was determined by evaluating plaque formation and gingival status with reference to the Silness and Loe plaque index (PI), Loe gingival index (GI), and community periodontal index (CPI). Periodontal health and oral hygiene were not significantly different between Groups I and II for cleft type (p > 0.05). A significant difference was not observed in PI for cleft type among the groups (p > 0.05). In Group II, GI and CPI were significantly higher than in Group I (p < 0.05). According to our results, cleft type does not influence periodontal health of children and adolescents with OFCs. Age, however, influences periodontal diseases' prevalence and severity.

Bacterial killing and the dimensions of bacterial death.

Bacteria can be dead, alive, or exhibit slowed or suspended life forms, making bacterial death difficult to establish. Here, agar-plating, microscopic-counting, SYTO9/propidium-iodide staining, MTT-conversion, and bioluminescence-imaging were used to determine bacterial death upon exposure to different conditions. Rank correlations between pairs of assay outcomes were low, indicating different assays measure different aspects of bacterial death. Principal-component analysis yielded two principal components, named "reproductive-ability" (PC1) and "metabolic-activity" (PC2). Plotting of these principal components in two-dimensional space revealed a dead region, with borders defined by the PC1 and PC2 values. Sensu stricto implies an unpractical reality that all assays determining PC1 and PC2 must be carried out in order to establish bacterial death. Considering this unpracticality, it is suggested that at least one assay determining reproductive activity (PC1) and one assay determining metabolic activity (PC2) should be used to establish bacterial death. Minimally, researchers should specifically describe which dimension of bacterial death is assessed, when addressing bacterial death.

Numerical Simulation and Microstructure Analysis of 30CrMnMoRe High-Strength Steel Welding.

Welding experiments were conducted under different currents for single-pass butt welding of high-strength steel flat plates. The microstructure of welded joints was characterized using OM, SEM, and EBSD, and the welding process was numerically simulated using a finite element method. According to the grain size obtained by electron microscope characterization and the temperature data obtained by simulation, the microstructure and mechanical properties of coarse grain and fine grain areas of the heat-affected zone were predicted by using the material microstructure and property simulation software. Finally, the results of mechanical properties simulation were verified through mechanical property testing.

Obstetric outcomes in the expectant management of cesarean scar pregnancy with fetal heart activity: a single-center retrospective cohort study.

Background: Cesarean scar pregnancy (CSP) is a high-risk complication characterized by the implantation of a pregnancy within a cesarean scar resulting from a previous delivery. Currently, clinical indicators guiding the expectant management of patients with CSP are lacking. We thus aimed to evaluate pregnancy and neonatal outcomes among women who underwent expectant CSP management and to investigate whether sonographic signs correlated with obstetric outcomes. Methods: We retrospective reviewed the electronic medical records and first-trimester transvaginal ultrasonography reports of consecutive patients diagnosed with CSP in the first trimester at the West China Second University Hospital from January 1, 2010 to December 31, 2022. Pregnancy outcomes (emergency surgery, blood loss, and rescue) and neonatal outcomes (gestational age at delivery, neonatal weight, and Apgar scores) were examined. A binary logistic regression analysis was conducted to identify independent risk factors that could predict severe complications. Results: The final analysis included 54 patients. The mean age of the pregnant women was 34±4 years. Among the 54 patients, 14 (25.9%) did not progress to 20 weeks of gestation. Pregnancy continued beyond 20 weeks in 40 patients, with 37 live births (92.5%) and 3 stillbirths (7.5%). Moreover, 7 (17.5%) and 33 (82.5%) patients delivered before and after 34 weeks, respectively. Placenta accreta spectrum (PAS) and placenta previa were confirmed in 29 (72.5%) and 17 (42.5%) patients, respectively. Hysterectomy, emergency cesarean section, and rescue surgery were performed in 5 (12.5%), 15 (37.5%), and 22 (55.5%) patients, respectively. Patients with a visible niche were significantly more likely to have preterm labor, PAS, placenta previa, low-birth-weight newborns, higher blood loss, intraoperative rescue, blood transfusion, and first-trimester vaginal bleeding than were those without one (all P values <0.05). Conclusions: Our study showed that expectant management of CSP to achieve live birth might be feasible. Patients with a visible niche exhibited worse outcomes, with a higher incidence of severe delivery complications.

Genomic insights into adaptive evolution of the species-rich cosmopolitan plant genus Rhododendron.

The species-rich cosmopolitan genus Rhododendron offers a good system for exploring the genomic mechanisms underlying adaptation to diverse habitats. Here, we report high-quality chromosomal-level genome assemblies of nine species, representing all five subgenera, different altitudinal distributions, and all flower color types of this genus. Further comprehensive genomic analyses indicate diverse adaptive strategies employed by Rhododendron, particularly adaptation to alpine and subalpine habitats by expansion/contraction of gene families involved in pathogen defense and oxidative phosphorylation, genomic convergent evolution, and gene copy-number variation. The convergent adaptation to high altitudes is further shown by population genomic analysis of R. nivale from the Himalaya-Hengduan Mountains. Moreover, we identify the genes involved in the biosynthesis of anthocyanins and carotenoids, which play a crucial role in shaping flower color diversity and environmental adaptation. Our study is significant for comprehending plant adaptive evolution and the uneven distribution of species diversity across different geographical regions.

Causal associations between frailty and low back pain: a bidirectional two-sample mendelian randomization study.

BACKGROUND: Previous observational studies have revealed a potentially robust bidirectional relationship between frailty and low back pain (LBP). However, the precise causal relationship remains unclear. METHODS: To examine the potential causal association between frailty and LBP, we conducted bidirectional two-sample Mendelian randomization analysis (MR) study. Genetic data on frailty index (FI) and LBP were acquired from publicly available genome-wide association studies (GWAS). Various MR methodologies were utilized, such as inverse variance weighting (IVW), weighted median, and MR-Egger, to evaluate causality. Additionally, sensitivity analyses were conducted to evaluate the robustness of the findings. RESULTS: Genetically predicted higher FI (IVW, odds ratio [OR] = 1.66, 95% CI 1.17-2.36, p = 4.92E-03) was associated with a higher risk of LBP. As for the reverse direction, genetic liability to LBP showed consistent associations with a higher FI (IVW, OR = 1.13, 95% CI 1.07-1.19, p = 2.67E-05). The outcomes from various MR techniques and sensitivity analyses indicate the robustness of our findings. CONCLUSION: Our research findings provide additional evidence bolstering the bidirectional causal relationship between frailty and LBP.

Hematite tailings to high-purity silica: Mechanistic studies and life cycle assessment analysis.

This study aimed to recover high-purity silica from hematite tailings (HTs) using superconducting high-gradient magnetic separation (S-HGMS) technology. This process involved converting silica into a silicone-rich concentrate and subsequently employing a fluorine-free mixed acid to leach the silicon-rich concentrate to remove impurities and achieve refinement and purification. The optimization of the S-HGMS process was conducted using the "Box-Behnken Design" method, resulting in the following optimal conditions: a pulp concentration of 50 g/L, a magnetic velocity ratio of 0.076 T s/m, and a pulp velocity of 500 mL/min. These conditions yielded a silica grade range of 61.905% in the HTs to 91.818% in the silicon-rich concentrate, with corresponding recovery rates of 53.031%. Under the optimized leaching process, this resulted in an increase in the silica content from 91.818% in the silicon-rich concentrate to 99.938% in high-purity silica. Additionally, by analyzing the production process of 1 kg of high-purity silica from HTs using the process LCA method, environmental hotspots were identified, and corresponding solutions were proposed. This approach is vital for efficient utilization of HTs as a resource. This process has low energy consumption and is environmentally friendly, enabling the reduction of hematite tailings. It has a wide range of applications and offers substantial economic benefits, rendering it a promising candidate for industrial applications.

Estrogen Status Influences Whole-Body Vibration Training-Induced Improvements on Muscle Mass and Strength in Female Ovariectomized Mice.

Estradiol (E2) deficiency arising from menopause is closely related to changes in body composition and declines of muscle mass and strength in elderly women. Whole-body vibration training (WBV) is an emerging approach expected to improve muscle mass and strength of older person, but the underlying mechanisms remain unclear. The balance between protein synthesis and degradation is a determining factor for muscle mass and strength, which is regulated by Akt-mTOR and FoxO1 signal pathway, respectively. In the present study, we firstly determined whether the effects of WBV on muscle mass and strength in ovariectomized female mice was affected by estrogen level, then investigated whether this was associated with Akt-mTOR and FoxO1 signal pathways. We found that (1) WBV, E2 supplementation (E) and WBV combined with E2 supplementation (WBV+E) significantly increased serum estradiol content, quadriceps muscle mass and grip strength in ovariectomized mice, accompanied with alterations of body composition (reducing fat content, increasing lean body mass and lean percent), furthermore, the altered degrees of these indicators by WBV+E were greater than WBV alone; (2) WBV, E and WBV+E remarkably increased the activities of Akt and mTOR and decreased FoxO1 activity, and the changed degrees by WBV+E were greater than WBV alone; (3) Pearson correlation coefficient revealed that serum estradiol content was positively correlated with Akt and mTOR activities, while inversely associated with FoxO1 activity. We concluded that WBV could significantly increase muscle mass and strength in ovariectomized mice, which might achieve through activating Akt-mTOR and suppressing FoxO1 signal pathways, and the improving effect of WBV on muscle mass and strength was better when in the presence of estrogen.

Corrigendum: PI-YOLO: dynamic sparse attention and lightweight convolutional based YOLO for vessel detection in pathological images.

[This corrects the article DOI: 10.3389/fonc.2024.1347123.].

HN1-mediated activation of lipogenesis through Akt-SREBP signaling promotes hepatocellular carcinoma cell proliferation and metastasis.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide, with more than 800,000 deaths each year, and its 5-year survival rate is less than 12%. The role of the HN1 gene in HCC has remained elusive, despite its upregulation in various cancer types. In our investigation, we identified HN1's heightened expression in HCC tissues, which, upon overexpression, fosters cell proliferation, migration, and invasion, unveiling its role as an oncogene in HCC. In addition, silencing HN1 diminished the viability and metastasis of HCC cells, whereas HN1 overexpression stimulated their growth and invasion. Gene expression profiling revealed HN1 silencing downregulated 379 genes and upregulated 130 genes, and suppressive proteins associated with the lipogenic signaling pathway networks. Notably, suppressing HN1 markedly decreased the expression levels of SREBP1 and SREBP2, whereas elevating HN1 had the converse effect. This dual modulation of HN1 affected lipid formation, hindering it upon HN1 silencing and promoting it upon HN1 overexpression. Moreover, HN1 triggers the Akt pathway, fostering tumorigenesis via SREBP1-mediated lipogenesis and silencing HN1 effectively curbed HCC tumor growth in mouse xenograft models by deactivating SREBP-1, emphasizing the potential of HN1 as a therapeutic target, impacting both external and internal factors, it holds promise as an effective therapeutic strategy for HCC.

Impact of positive CD4 cells on event-free survival in follicular lymphoma patients.

OBJECTIVE: Previous results about prognostic value of CD4+ T cells in follicular lymphoma (FL) remain controversial. METHODS: Immunohistochemistry was used to examine expression of positive CD4 cells in 103 patients with FL 1-3A. Early failure was described as failing to achieve event-free survival (EFS) at 12 or 24 months. RESULTS: There were 49 (47.6%) male and 54 (52.4%) females, with a median age of 54 years. Compared to patients with <20% of positive CD4 cells, patients with ≥20% of positive CD4 cells exhibited a significant lower risk of early failure (2-year EFS rate: 56.7% vs 73.5%, p = 0.047). When patients were stratified based on positive CD4 cell combined with FLIPI, the median EFS (p = 0.002) and median OS (p = 0.007) were significantly different. CONCLUSIONS: This study demonstrated that higher expression of positive CD4 cells predicts lower risk of early failure in follicular lymphoma, and combination analysis of CD4 and FLIPI could better predict disease relapse and survival outcome.

Emerging Roles of Adaptive Immune Response in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease and is characterized by progressive cognitive decline. Pathologically, this disease is associated with the accumulation of extracellular amyloid plaques, intracellular neurofibrillary tangles (NFTs), and neuroinflammation. Current drug treatments primarily focus on managing symptoms rather than stopping disease progression. Disease-modifying therapies target the clearance of amyloid plaques through active and passive immunity methods. Although successful in animal models, human trials have shown adverse effects, such as meningoencephalitis, in a small number of patients who received active immunity methods. The efficacy of active immunity methods in treating AD remains uncertain, but passive immunity methods amyloid-beta (Abeta)-specific monoclonal antibody therapies such as aducanumab and lecanemab have been approved by the FDA. Despite the limitations of immune-based therapies, T-cell, and chimeric antigen receptor-based treatments show promise, but new guidelines are necessary to address potential adverse events. Research into the relationship between adaptive immune responses and AD is expected to provide innovative treatment approaches.

PI-YOLO: dynamic sparse attention and lightweight convolutional based YOLO for vessel detection in pathological images.

Vessel density within tumor tissues strongly correlates with tumor proliferation and serves as a critical marker for tumor grading. Recognition of vessel density by pathologists is subject to a strong inter-rater bias, thus limiting its prognostic value. There are many challenges in the task of object detection in pathological images, including complex image backgrounds, dense distribution of small targets, and insignificant differences between the features of the target to be detected and the image background. To address these problems and thus help physicians quantify blood vessels in pathology images, we propose Pathological Images-YOLO (PI-YOLO), an enhanced detection network based on YOLOv7. PI-YOLO incorporates the BiFormer attention mechanism, enhancing global feature extraction and accelerating processing for regions with subtle differences. Additionally, it introduces the CARAFE upsampling module, which optimizes feature utilization and information retention for small targets. Furthermore, the GSConv module improves the ELAN module, reducing model parameters and enhancing inference speed while preserving detection accuracy. Experimental results show that our proposed PI-YOLO network has higher detection accuracy compared to Faster-RCNN, SSD, RetinaNet, YOLOv5 network, and the latest YOLOv7 network, with a mAP value of 87.48%, which is 2.83% higher than the original model. We also validated the performance of this network on the ICPR 2012 mitotic dataset with an F1 value of 0.8678, outperforming other methods, demonstrating the advantages of our network in the task of target detection in complex pathology images.

Discovery of Novel 2-Aminopyridine-Based and 2-Aminopyrimidine-Based Derivatives as Potent CDK/HDAC Dual Inhibitors for the Treatment of Refractory Solid Tumors and Hematological Malignancies.

Co-inhibition of histone deacetylase (HDAC) and cyclin-dependent kinase (CDK) synergizes to produce enhanced antitumor effects and potentially overcomes the drug resistance. In this work, we discovered a series of novel CDK9/HDACs dual inhibitors. Among them, compound 8e was identified to show potent CDK9 and HDAC1 inhibitory activities, with IC50 values at 88.4 and 168.9 nM, respectively, and exhibited antiproliferative capacities against hematological and solid tumor cells. Meanwhile, 8e showed high selectivity for CDK9 and HDAC1, remarkably induced MV-4-11 cell apoptosis and S cell cycle arrests. Furthermore, 8e possessed a significant antitumor potency with a T/C value of 29.98% in the MV-4-11 xenograft model. Interestingly, a potent FLT3/HDAC dual inhibitor 9e was also identified (FLT3/HDAC1/3 IC50 = 30.4/52.4/14.7 nM) and found to possess powerful apoptosis induction ability in MV-4-11 cell and potent antiproliferative capacities against FLT3 mutant-transformed BaF3 cells. Overall, our work provided valuable lead compounds for dual inhibitors with potent anticancer activity.

A case report of fifteen-and-a-half syndrome.

BACKGROUND: Fifteen-and-a-Half Syndrome is an uncommon clinical presentation characterized by the coexistence of one-and-a-half syndrome and bilateral facial palsy. In this study, we provide a comprehensive description of symptom evolution and imaging changes in a patient with Fifteen-and-a-Half Syndrome. CASE PRESENTATION: A 54-year-old male presented with sudden onset of one-and-a-half syndrome, which gradually progressed to fifteen-and-a-half syndrome. The final diagnosis was confirmed to be pontine infarction which occurred at the midline of the pontine tegmentum. CONCLUSION: This case highlights the diverse and progressive early clinical manifestations associated with Fifteen-and-a-half Syndrome. Currently, all reported cases of this syndrome are linked to brainstem infarction; however, early differential diagnosis is crucial to ensure prompt initiation of appropriate treatment for affected patients.

Long-Term Prediction and Risk Factors for Incident Visual Field Defect in Nonpathologic High Myopia.

Purpose: To investigate the long-term patterns and risk factors of visual field defect (VFD) development in nonpathologic high myopia (HM) over an 8-year follow-up. Methods: This was an observational cohort study. The VFD classification adhered to the Glaucoma Suspects with High Myopia Study Group. Logistic regression models with generalized estimating equations were used to identify risk factors for VFD development. Results: A total of 330 eyes from 194 patients were included. Among them, 49.4% of eyes developed VFD, with enlarged blind spot and nonspecific defect ranked as the most common VFDs, followed by partial arcuate defect, vertical step, nasal step, paracentral defect, and combined defects. Longer axial length (odds ratio [OR] = 1.43 per 1-mm increase; 95% CI, 1.04-1.95; P = 0.026), thinner central corneal thickness (OR = 1.01 per 1-µm decrease; 95% CI, 1.003-1.02; P = 0.013), worse mean deviation of visual field (OR = 1.51 per 1-dB decrease; 95% CI, 1.14-2.00; P = 0.004), and the presence of peripapillary γ-zone (OR = 5.57; 95% CI, 3.06-10.15; P < 0.001) at baseline correlated with the development of any VFD. By incorporating these factors, the prediction models achieved area under the curves of 0.789 (95% CI, 0.726-0.853) and 0.828 (95% CI, 0.714-0.943) for discriminating the development of any VFD and moderate/severe VFD, respectively, with good calibration power. Conclusions: The development of VFD occurred frequently in individuals with nonpathologic HM and can be effectively predicted using relevant metrics. The findings will aid in expanding our knowledge of optic neuropathy in HM.

Impact of early caffeine administration on respiratory outcomes in very preterm infants initially receiving invasive mechanical ventilation.

OBJECTIVE: The guidelines recommend early caffeine administration for preterm infants requiring non-invasive mechanical ventilation since earlier treatment is associated with better outcomes. The objective was to evaluate the impact of early caffeine therapy (within 24 hours after birth) on respiratory outcomes in very preterm infants who were initially receiving invasive mechanical ventilation. METHODS: This was an observation cohort study from 1 January 2018 to 31 December 2022 based on a database that was prospectively collected and maintained. Infants who initially received invasive mechanical ventilation were divided into two groups based on the timing of caffeine initiation: within the first 24 hours after birth (early) and within 48 hours of birth or later (late). Generalised linear mixed models with a random effect model for the centre were used to assess the impact of different caffeine initiation times on neonatal outcomes. RESULTS: Among the cohort of 9880 infants born at <32 weeks gestation, 2381 were eligible for this study (early initiation: 1758 (73.8%) and late initiation: 623 (26.2%)). For infants born at more than 28 weeks of gestation, the adjusted generalised linear mixed model showed that the duration of invasive mechanical ventilation was 1.34 (95% CI -2.40 to -0.27) days shorter and the incidence of moderate-to-severe bronchopulmonary dysplasia (BPD) was lower (adjusted OR 0.63; 95% CI 0.41 to 0.96) in the early caffeine group compared with the late caffeine group. CONCLUSION: In very preterm infants who initially receive invasive mechanical ventilation, early administration of caffeine within 24 hours after birth can shorten the duration of invasive mechanical ventilation, reduce the incidence of moderate-to-severe BPD and improve respiratory outcomes. The very early initiation of caffeine treatment does not appear to be associated with any adverse outcomes. TRIAL REGISTRATION NUMBER: ChiCTR1900025234.

Corrigendum: Paclitaxel-incorporated nanoparticles improve functional recovery after spinal cord injury.

[This corrects the article DOI: 10.3389/fphar.2022.957433.].

Impact of Gold-Standard Label Errors on Evaluating Performance of Deep Learning Models in Diabetic Retinopathy Screening: Nationwide Real-World Validation Study.

BACKGROUND: For medical artificial intelligence (AI) training and validation, human expert labels are considered the gold standard that represents the correct answers or desired outputs for a given data set. These labels serve as a reference or benchmark against which the model's predictions are compared. OBJECTIVE: This study aimed to assess the accuracy of a custom deep learning (DL) algorithm on classifying diabetic retinopathy (DR) and further demonstrate how label errors may contribute to this assessment in a nationwide DR-screening program. METHODS: Fundus photographs from the Lifeline Express, a nationwide DR-screening program, were analyzed to identify the presence of referable DR using both (1) manual grading by National Health Service England-certificated graders and (2) a DL-based DR-screening algorithm with validated good lab performance. To assess the accuracy of labels, a random sample of images with disagreement between the DL algorithm and the labels was adjudicated by ophthalmologists who were masked to the previous grading results. The error rates of labels in this sample were then used to correct the number of negative and positive cases in the entire data set, serving as postcorrection labels. The DL algorithm's performance was evaluated against both pre- and postcorrection labels. RESULTS: The analysis included 736,083 images from 237,824 participants. The DL algorithm exhibited a gap between the real-world performance and the lab-reported performance in this nationwide data set, with a sensitivity increase of 12.5% (from 79.6% to 92.5%, P<.001) and a specificity increase of 6.9% (from 91.6% to 98.5%, P<.001). In the random sample, 63.6% (560/880) of negative images and 5.2% (140/2710) of positive images were misclassified in the precorrection human labels. High myopia was the primary reason for misclassifying non-DR images as referable DR images, while laser spots were predominantly responsible for misclassified referable cases. The estimated label error rate for the entire data set was 1.2%. The label correction was estimated to bring about a 12.5% enhancement in the estimated sensitivity of the DL algorithm (P<.001). CONCLUSIONS: Label errors based on human image grading, although in a small percentage, can significantly affect the performance evaluation of DL algorithms in real-world DR screening.