Search

Intrinsic breast cancer molecular subtyping (IBCMS) provides significant prognostic information for patients with breast cancer and helps determine treatment. This study compared IBCMS methods on various gene-expression platforms in PALOMA-2 and PALLET trials. PALOMA-2 tumor samples were profiled using EdgeSeq and nanostring and subtyped with AIMS, PAM50, and research-use-only (ruo)Prosigna. PALLET tumor biopsies were profiled using mRNA sequencing and subtyped with AIMS and PAM50. In PALOMA-2 (n = 222), a 54% agreement was observed between results from AIMS and gold-standard ruoProsigna, with AIMS assigning 67% basal-like to HER2-enriched. In PALLET (n = 224), a 69% agreement was observed between results from PAM50 and AIMS. Different IBCMS methods may lead to different results and could misguide treatment selection; hence, a standardized clinical PAM50 assay and computational approach should be used.Trial number: NCT01740427.

Abstract Background Post-stroke cognitive impairment (PSCI) not only increases patient mortality and disability, but also adversely affects motor function and the ability to perform routine daily activities. Current therapeutic approaches for, PSCI lack specificity, primarily relying on and medication and traditional cognitive therapy supplemented by a limited array of tools. Both transcranial direct current stimulation (tDCS) and virtual reality (VR) training have demonstrated efficacy in improving cognitive performance among PSCI patients. Previous findings across various conditions suggest that implementing a therapeutic protocol combining tDCS and VR (tDCS - VR) may yield superior in isolation. Despite this, to our knowledge, no clinical investigation combining tDCS and VR for PSCI rehabilitation has been conducted. Thus, the purpose of this study is to explore the effects of tDCS - VR on PSCI rehabilitation. Methods This 4-week, single-center randomized clinical trial protocol will recruit 200 patients who were randomly assigned to one of four groups: Group A (tDCS + VR), Group B (tDCS + sham VR), Group C (sham tDCS + VR), Group D (sham tDCS + sham VR). All four groups will receive conventional cognitive rehabilitation training. The primary outcome measurement utilizes the Mini-Mental State Examination (MMSE). Secondary outcome measures include the Montreal Cognitive Assessment, Frontal Assessment Battery, Clock Drawing Test, Digital Span Test, Logic Memory Test, and Modified Barthel Index. Additionally, S-YYZ-01 apparatus for diagnosis and treating language disorders assesses subjects’ speech function. Pre- and post-four-week intervention assessments are conducted for all outcome measures. Functional near-infrared spectroscopy (fNIRS) is employed to observe changes in oxygenated hemoglobin (HbO), deoxy-hemoglobin (HbR), and total hemoglobin (HbT) in the cerebral cortex. Discussion Our hypothesis posits that the tDCS - VR therapy, in opposed to individual tDCS or VR interventions, could enhance cognitive function, speech ability and daily living skills in PSCI patients while concurrently augmenting frontal cortical activity. This randomized study aims to provide a robust theoretical foundation supported by scientific evidence for the practical implementation of the tDCS - VR combination as a secure and efficient PSCI rehabilitation approach. Trial registration Chictr.org.cn Identifier: ChiCTR2300070580. Registered on 17th April 2023.

Abstract Pedunculoside and rotundic acid, the most abundant components in plants of the genus Ilex L. (Aquifoliaceae), exhibit biological and pharmacological significance in the treatment of cardiovascular diseases. However, there have been few studies on their metabolism. This study performed a systematic metabolism study of pedunculoside and rotundic acid and evaluated their potential for herb–drug interaction. Pedunculoside or rotundic acid was incubated with human liver microsomes and recombinant human metabolic enzymes, and analyzed using LC‐Q‐TOF/MS and LC–MS/MS. Pedunculoside was found to be the most stable in human liver microsomes, whereas rotundic acid was easily metabolized. Eight pedunculoside metabolites and six rotundic acid metabolites were detected and tentatively identified through hydroxylation, glucuronidation, acetylation, and glucose conjugation. Hydroxylation of pedunculoside is mainly catalyzed by CYP3A4/5 and partly by CYP2C8. Hydroxylation of rotundic acid is almost exclusively catalyzed by CYP3A4/5, and its glucuronidation reaction is mediated by UGT1A4. Neither pedunculoside nor rotundic acid showed CYP inhibition (IC50 values > 50 μM) with the probe substrates of major CYP isoforms during incubation with human liver microsomes. This study is the first investigation into the in vitro metabolism of pedunculoside and rotundic acid using human liver microsomes. It also aims to assess their potential as perpetrators of drug–drug interactions involving CYP enzymes. The comprehensive metabolism and drug interaction studies of pedunculoside and rotundic acid enable us to evaluate and manage potential risks with their use in pharmacotherapy.

ObjectiveTo observe the efficacy and safety of pelvic floor magnetic stimulation (PFMS) combined with mirabegron in female patients with refractory overactive bladder (OAB) symptoms.Patients and methodsA total of 160 female patients with refractory OAB symptoms were prospectively randomized into two groups. Eighty cases in the combination group accepted PFMS and mirabegron therapy and 80 cases as control only accepted mirabegron therapy (The clinical trial registry number: ChiCTR2200070171). The lower urinary tract symptoms, OAB questionnaire (OAB-q) health-related quality of life (HRQol), symptom bother score and OABSS between two groups were compared at the 1st, 2nd and 4th week ends.ResultsAll of 160 patients were randomly assigned to two groups, of which 80 patients were included in the combination group and 80 in the mirabegron group. The incidences of LUTS, including urgency, frequent urination, and incontinence episodes, in the 2nd week and the 4th week after combination treatment were significantly lower than those in the mirabegron group (p 0.05). With respect to secondary variables, the OAB-q HRQol score in the combination group was statistically superior in comparison with that in the mirabegron group between the 2nd week and the 4th week (p

Purpose: This study aims to investigate the potential of Oregon grape root extracts to modulate the activity of P-glycoprotein.Methods: We performed 3H-CsA or 3H-digoxin transport experiments in the absence or presence of two sources of Oregon grape root extracts (E1 and E2), berberine or berbamine in Caco-2 and MDCKII-MDR1 cells. In addition, real time quantitative polymerase chain reaction (RT-PCR) was performed in Caco-2 and LS-180 cells to investigate the mechanism of modulating P-glycoprotein.Results: Our results showed that in Caco-2 cells, Oregon grape root extracts (E1 and E2) (0.1–1 mg/mL) inhibited the efflux of CsA and digoxin in a dose-dependent manner. However, 0.05 mg/mL E1 significantly increased the absorption of digoxin. Ten µM berberine and 30 µM berbamine significantly reduced the efflux of CsA, while no measurable effect of berberine was observed with digoxin. In the MDCKII-MDR1 cells, 10 µM berberine and 30 µM berbamine inhibited the efflux of CsA and digoxin. Lastly, in real time RT-PCR study, Oregon grape root extract (0.1 mg/mL) up-regulated mRNA levels of human MDR1 in Caco-2 and LS-180 cells at 24 h.Conclusion: Our study showed that Oregon grape root extracts modulated P-glycoprotein, thereby may affect the bioavailability of drugs that are substrates of P-glycoprotein.

Dendrobium, a highly effective traditional Chinese medicinal herb, exhibits significant variations in efficacy and price among different varieties. Therefore, achieving an efficient classification of Dendrobium is crucial. However, most of the existing identification methods for Dendrobium make it difficult to simultaneously achieve both non-destructiveness and high efficiency, making it challenging to truly meet the needs of industrial production. In this study, we combined Laser-Induced Breakdown Spectroscopy (LIBS) with multivariate models to classify 10 varieties of Dendrobium. LIBS spectral data for each Dendrobium variety were collected from three circular medicinal blocks. During the data analysis phase, multivariate models to classify different Dendrobium varieties first preprocess the LIBS spectral data using Gaussian filtering and stacked correlation coefficient feature selection. Subsequently, the constructed fusion model is utilized for classification. The results demonstrate that the classification accuracy of 10 Dendrobium varieties reached 100%. Compared to Support Vector Machine (SVM), Random Forest (RF), and K-Nearest Neighbors (KNN), our method improved classification accuracy by 14%, 20%, and 20%, respectively. Additionally, it outperforms three models (SVM, RF, and KNN) with added Principal Component Analysis (PCA) by 10%, 10%, and 17%. This fully validates the excellent performance of our classification method. Finally, visualization analysis of the entire research process based on t-distributed Stochastic Neighbor Embedding (t-SNE) technology further enhances the interpretability of the model. This study, by combining LIBS and machine learning technologies, achieves efficient classification of Dendrobium, providing a feasible solution for the identification of Dendrobium and even traditional Chinese medicinal herbs.

Cannabinoid use has surged in the past decade, with a growing interest in expanding cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) applications into special populations. Consequently, the increased use of CBD and THC raises the risk of drug–drug interactions (DDIs). Nevertheless, DDIs for cannabinoids, especially in special populations, remain inadequately investigated. While some clinical trials have explored DDIs between therapeutic drugs like antiepileptic drugs and CBD/THC, more potential interactions remain to be examined. This review summarizes the published studies on CBD and THC–drug interactions, outlines the mechanisms involved, discusses the physiological considerations in pharmacokinetics (PK) and DDI studies in special populations (including pregnant and lactating women, pediatrics, older adults, patients with hepatic or renal impairments, and others), and presents modeling approaches that can describe the DDIs associated with CBD and THC in special populations. The PK of CBD and THC in special populations remain poorly characterized, with limited studies investigating DDIs involving CBD/THC in these populations. Therefore, it is critical to evaluate potential DDIs between CBD/THC and medications that are commonly used in special populations. Modeling approaches can aid in understanding these interactions.

Background: Failure to restore missing teeth in time can easily lead to the mesial tilting of the distal abutment teeth. However, a fixed partial denture (FPD) can improve stress conduction and distribution and prevent periodontal injuries. In these more complex cases, it is necessary to consider various factors comprehensively to improve conventional treatment planning and achieve better results. Methods: We selected a patient with a missing first molar and a mesial inclination of the second molar, leaving inadequate space or bone mass for implant denture restoration, necessitating an FPD for restoration. Three-dimensional finite element analysis (3D-FEA) combined with photoelastic analysis were used to explore how the inclination angle (0 ‒ 30°) and different dental restoration materials (zirconia, lithium disilicate, polymer-infiltrated ceramic network, and resin composite) affect the biomechanical behaviour of FPD‒abutments‒periodontal tissue complex. Results: The stress was easily concentrated in the FPD connectors, enamel shoulder collar, periapical area, and root bifurcation. The stress on FPD and the periodontal ligament (PDL) of the second premolar increased with an increase in the elastic modulus of FPD, with an opposite trend in the abutments, the alveolar bone, and the PDL of the second molar. The stress on the FPD and alveolar bone increased with increased inclination angle of the distal abutment. The stress on two abutments and their PDL were positively correlated with the inclination angle in two stages; however, when the inclination angle > 12°, the second premolar and its PDL showed a negative correlation. Conclusions: FPDs can be used for restoration within 24° of distal abutment inclination, but protecting the abutments (< 12° especially) and the periodontal tissue (> 12° especially) must be taken seriously. For this purpose, an FPD material with higher strength is recommended. [ABSTRACT FROM AUTHOR]

Epithelial ovarian cancer (EOC) presents considerable difficulties in prognostication and treatment strategy development. Bevacizumab, an anti-angiogenic medication, has demonstrated potential in enhancing progression-free survival (PFS) in EOC patients. Nevertheless, the identification of individuals at elevated risk of disease progression following treatment remains a challenging task. This study was to develop and validate a deep learning (DL) model using retrospectively collected computed tomography (CT) plain scans of inoperable and recurrent EOC patients receiving bevacizumab treatment diagnosed between January 2013 and January 2024. A total of 525 patients from three different institutions were retrospectively included in the study and divided into training set (N = 400), internal test set (N = 97) and external test set (N = 28). The model's performance was evaluated using Harrell's C-index. Patients were categorized into high-risk and low-risk group based on a predetermined cutoff in the training set. Additionally, a multimodal model was evaluated, incorporating the risk score generated by the DL model and the pretreatment level of carbohydrate antigen 125 as input variables. The Net Reclassification Improvement (NRI) metric quantified the reclassification performance of our optimal model in comparison to the International Federation of Gynecology and Obstetrics (FIGO) staging model. The results indicated that DL model achieved a PFS predictive C-index of 0.73 in the internal test set and a C-index of 0.61 in the external test set, along with hazard ratios of 34.24 in the training set (95% CI: 21.7, 54.1; P < 0.001) and 8.16 in the internal test set (95% CI: 2.5, 26.8; P < 0.001). The multimodal model demonstrated a C-index of 0.76 in the internal test set and a C-index of 0.64 in the external test set. Comparative analysis against FIGO staging revealed an NRI of 0.06 (P < 0.001) for the multimodal model. The model presents opportunities for prognostic assessment, treatment strategizing, and ongoing patient monitoring. [ABSTRACT FROM AUTHOR]

Background: Acral melanoma presents distinct biological characteristics compared to cutaneous melanoma. While adjuvant therapeutic strategies for high-risk resected acral melanoma closely resemble those for cutaneous melanoma, the evidence supporting the clinical application of adjuvant therapy for acral melanoma remains inadequate. Our aim was to systematically analyze the efficacy and safety profile of adjuvant therapy in acral melanoma. Methods: This systematic review adhered to a pre-registered protocol. We comprehensively searched four electronic databases and reference lists of included articles to identify eligible studies. The primary outcome was therapeutic efficacy, and the secondary outcome was adverse events (AEs). Results: This systematic review included 11 studies with 758 acral melanoma patients undergoing adjuvant therapy. High-dose interferon α-2b (IFN) regimens showed no significant difference in recurrence-free survival (RFS), though the longer regimen was linked to increased hepatotoxicity. Adjuvant anti-PD-1 therapy demonstrated varying efficacy, with improved RFS in patients who experienced immune-related AEs. Targeted therapy with dabrafenib plus trametinib achieved high 12-month RFS in patients with BRAF-mutated acral melanoma. Comparative studies suggested that adjuvant anti-PD-1 therapy is similarly effective to IFN in prolonging survival for high-risk acral melanoma patients. Additionally, prior treatment with pegylated IFN enhanced RFS in patients receiving adjuvant pembrolizumab. Conclusion: High-dose IFN was widely used as adjuvant therapy for acral melanoma, but serious AEs prompted the search for alternatives. Adjuvant anti-PD-1 therapy shows promise, though it may be less effective than in non-acral melanoma. Further prospective studies are needed to determine the optimal adjuvant treatment for acral melanoma. [ABSTRACT FROM AUTHOR]

Working conditions exert an important influence on the tribological properties of protective coatings, thus affecting the wear resistance of workpieces. In this work, a TiAlSiN hardness-modulated multilayer coating with a good match of strength and toughness was deposited on WC-Co substrates. The adhesive wear played a predominant role under the condition of a larger normal load and lower velocity, leading to the formation of a third body layer composed of compressed and lubricating oxides. As a result, the wear rate of the coating tested at 20 N reduced by 23% of that tested at 5 N. Instead, abrasive wear was more manifest, leading to the formation of big-size abrasives, and thus the wear rate increased by 2.8 times while the velocity elevated from 4 mm/s to 16 mm/s. A full factorial analysis of the wear behaviors, including the nanohardness and roughness of the wear track, and the friction coefficient and wear rate of the coating, offered good guidance for the comprehension of the wear form of the TiAlSiN multilayer coating. The results demonstrated the optimization of multilayer structures for TiAlSiN coatings to attain better wear resistance under coupling conditions of normal load and velocity: harder or more lubricated sublayers. [ABSTRACT FROM AUTHOR]

Every year, over 12 million people are enduring the persistent pain resulting from wound infections. In these chronic wounds, concealed infections may be covered up by scabs or granulation, which impeding accurate diagnosis and treatment. To address such clinical challenges, inspired by corals, a biomimetic microneedle patch (HepMi‐PCL) is developed to indicate and treat infections within wound. Relying on high‐precision 3D printing technology, each polycaprolactone microneedle own an equally sized porous shell and cavity with heparin‐based functional hydrogel filling in. After penetrating through the scab, HepMi‐PCL can absorb exudate in wound through surficial guide grooves and pores microstructure on its microneedle, thereby indicating whether anti‐infection is needed. Upon the identification of a positive chronic infection, HepMi‐PCL will smartly activate to release drugs rapidly. Subsequently, when the infection is effectively managed and the exudate progressively decreases, the drug delivery will correspondingly slow down or cease altogether. By leveraging autonomous response and therapeutic capabilities, HepMi‐PCL demonstrates the potential to expedite the diagnosis and treatment of infections, resulting in an enhancement of healing speed for infected wounds by over 200%. Thus, the integration of diagnostic and therapeutic functions of the microneedle patch is anticipated to offer novel approaches in addressing the management of chronic wounds. [ABSTRACT FROM AUTHOR]

Summary: The exploitation of heterosis to integrate parental advantages is one of the fastest and most efficient ways of rice breeding. The genomic architecture of heterosis suggests that the grain yield is strongly correlated with the accumulation of numerous rare superior alleles with positive dominance. However, the improvements in yield of hybrid rice have shown a slowdown or even plateaued due to the limited availability of complementary superior alleles. In this study, we achieved a considerable increase in grain yield of restorer lines by inducing an alternative splicing event in a heterosis gene OsMADS1 through CRISPR‐Cas9, which accounted for approximately 34.1%–47.5% of yield advantage over their corresponding inbred rice cultivars. To achieve a higher yield in hybrid rice, we crossed the gene‐edited restorer parents harbouring OsMADS1GW3p6 with the sterile lines to develop new rice hybrids. In two‐line hybrid rice Guang‐liang‐you 676 (GLY676), the yield of modified hybrids carrying the homozygous heterosis gene OsMADS1GW3p6 significantly exceeded that of the original hybrids with heterozygous OsMADS1. Similarly, the gene‐modified F1 hybrids with heterozygous OsMADS1GW3p6 increased grain yield by over 3.4% compared to the three‐line hybrid rice Quan‐you‐si‐miao (QYSM) with the homozygous genotype of OsMADS1. Our study highlighted the great potential in increasing the grain yield of hybrid rice by pyramiding a single heterosis gene via CRISPR‐Cas9. Furthermore, these results demonstrated that the incomplete dominance of heterosis genes played a major role in yield‐related heterosis and provided a promising strategy for breeding higher‐yielding rice varieties above what is currently achievable. [ABSTRACT FROM AUTHOR]

Background: Tabes dorsalis is a late manifestation of neurosyphilis, characterized by progressive ataxia, lightning pains, loss of proprioception, and urinary incontinence. The absence of a definitive diagnostic standard and the non-specific clinical manifestations have led to a significant rate of misdiagnoses. Methods: Hospitalized patients with tabes dorsalis at Peking Union Medical College Hospital between January 2010 and December 2023 were reviewed. Results: A total of 13 patients were included, with 10 males and 3 females. The median age was 50 years (range, 34– 64). The most frequent initial symptoms were limb numbness (30.8%) and lightning pains (30.8%). Eleven patients (84.6%) received misdiagnoses prior to the final diagnosis. The most frequently observed physical sign was positive Romberg's sign (84.6%). Notably, Argyll Robertson pupil was presented in 7 subjects (53.8%). Serological tests revealed positive rapid plasma regain (RPR) and Treponema pallidum particle agglutination (TPPA) for all patients. All CSF samples were TPPA-reactive. Intramedullary hyperintensity on T2-weighted imaging of spinal MRI was found in 5 patients (38.5%). All patients received anti-syphilitic treatment, with effective treatment recorded in five cases. Conclusion: This study underscores the importance of neurological symptoms and signs in diagnosing tabes dorsalis. Individuals with progressive ataxia and positive Romberg's sign should be closely monitored for potential neurosyphilis. Integrating clinical features, laboratory tests, and neuroimaging could reduce misdiagnosis and expedite the initiation of anti-syphilitic therapy. [ABSTRACT FROM AUTHOR]

Chronic diabetic wounds have been an urgent clinical problem, and wound dressings play an important role in their management. Due to the design of traditional dressings, it is difficult to achieve adaptive adhesion and on-demand removal of complex diabetic wounds, real-time monitoring of wound status, and dynamic adjustment of drug release behavior according to the wound microenvironment. Smart hydrogels, as smart dressings, can respond to environmental stimuli and achieve more precise local treatment. Here, we review the latest progress of smart hydrogels in wound bandaging, dynamic monitoring, and drug delivery for treatment of diabetic wounds. It is worth noting that we have summarized the most important properties of smart hydrogels for diabetic wound healing. In addition, we discuss the unresolved challenges and future prospects in this field. We hope that this review will contribute to furthering progress on smart hydrogels as improved dressing for diabetic wound healing and practical clinical application. [ABSTRACT FROM AUTHOR]

In recent years, there has been growing concern over the rising incidence of liver diseases, with increasing exposure to environmental toxins as a significant contributing factor. However, the mechanisms of liver injury induced by environmental pollutants are largely unclear. Here, using tetrabromobisphenol A (TBBPA), a widely used brominated flame retardant, as an example, environmental toxin‐induced liver toxicity in mice is characterized via single‐cell sequencing technology. Heterogeneous gene expression profiles after exposure to TBBPA in major cell types of the liver are demonstrated. In hepatocytes, pathway analysis of differentially expressed genes reveals the enhanced interferon response and diminished metabolic processes. The disrupted endothelial functions in TBBPA‐treated cells are then shown. Moreover, the activation of M2‐polarization in Kupffer cells, as well as activated effector T and B cells are unveiled in TBBPA‐treated cells. Finally, ligand‐receptor pair analysis shows that TBBPA disrupts cell‐cell communication and induces an inflammatory microenvironment. Overall, the results reveal that TBBPA‐induced dysfunction of hepatocytes and endothelial cells may then activate and recruit other immune cells such as Kuffer cells, and T/NK cells into the liver, further increasing inflammatory response and liver injury. Thus, the results provide novel insight into undesiring environmental pollutant‐induced liver injury. [ABSTRACT FROM AUTHOR]