DN-ODE: Data-driven neural-ODE modeling for breast cancer tumor dynamics and progression-free survivals.

Pharmacokinetic/Pharmacodynamic (PK/PD) modeling is crucial in the development of new drugs. However, traditional population-based PK/PD models encounter challenges when modeling for individual patients. We aim to explore the potential of constructing a pharmacodynamic model for individual breast cancer pharmacodynamics leveraging only limited data from early clinical trial phases. While previous studies on Neural Ordinary Differential Equations (ODEs) suggest promising results in clinical trial practices, they primarily focused on theoretical applications or independent PK/PD modeling. PD modeling from complex and irregular clinical trial data, especially when interacting with PK parameters, is still unclear. To achieve that, we introduce a Data-driven Neural Ordinary Differential Equation (DN-ODE) modeling for breast cancer tumor dynamics and progression-free survival data. To validate this approach, experiments are conducted with early-phase clinical trial data from the Amcenestrant (an oral treatment for breast cancer) dataset (AMEERA 1-2), aiming to predict pharmacodynamics in the later phase (AMEERA 3). DN-ODE model achieves RMSE scores of 8.78 and 0.21 in tumor size and progression-free survival, respectively, with R2 scores over 0.9 for each task. Compared to PK/PD methodologies, DN-ODE is able to predict robust individual tumor dynamics with only limited cycle data. We also introduce Principal Component Analysis visualizations for encoder results, demonstrating the DN-ODE's capability to discern individual distributions and diverse tumor growth patterns. Therefore, DN-ODE facilitates comprehensive drug efficacy assessments, pinpoints potential responders, and aids in trial design.

Enhancing siRNA efficacy in vivo with extended nucleic acid backbones.

Therapeutic small interfering RNA (siRNA) requires sugar and backbone modifications to inhibit nuclease degradation. However, metabolic stabilization by phosphorothioate (PS), the only backbone chemistry used clinically, may be insufficient for targeting extrahepatic tissues. To improve oligonucleotide stabilization, we report the discovery, synthesis and characterization of extended nucleic acid (exNA) consisting of a methylene insertion between the 5'-C and 5'-OH of a nucleoside. exNA incorporation is compatible with common oligonucleotide synthetic protocols and the PS backbone, provides stabilization against 3' and 5' exonucleases and is tolerated at multiple oligonucleotide positions. A combined exNA-PS backbone enhances resistance to 3' exonuclease by ~32-fold over the conventional PS backbone and by >1,000-fold over the natural phosphodiester backbone, improving tissue exposure, tissue accumulation and efficacy in mice, both systemically and in the brain. The improved efficacy and durability imparted by exNA may enable therapeutic interventions in extrahepatic tissues, both with siRNA and with other oligonucleotides such as CRISPR guide RNA, antisense oligonucleotides, mRNA and tRNA.

Protein arginine methyltransferase 6 mediates antiviral immunity in plants.

Viral suppressor RNA silencing (VSR) is essential for successful infection. Nucleotide-binding and leucine-rich repeat (NLR)-based and autophagy-mediated immune responses have been reported to target VSR as counter-defense strategies. Here, we report a protein arginine methyltransferase 6 (PRMT6)-mediated defense mechanism targeting VSR. The knockout and overexpression of PRMT6 in tomato plants lead to enhanced and reduced disease symptoms, respectively, during tomato bush stunt virus (TBSV) infection. PRMT6 interacts with and inhibits the VSR function of TBSV P19 by methylating its key arginine residues R43 and R115, thereby reducing its dimerization and small RNA-binding activities. Analysis of the natural tomato population reveals that two major alleles associated with high and low levels of PRMT6 expression are significantly associated with high and low levels of viral resistance, respectively. Our study establishes PRMT6-mediated arginine methylation of VSR as a mechanism of plant immunity against viruses.

An oil-in-gel type of organohydrogel loaded with methylprednisolone for the treatment of secondary injuries following spinal cord traumas.

The secondary injuries following traumatic spinal cord injury (SCI) is a multiphasic and complex process that is difficult to treat. Although methylprednisolone (MP) is the only available pharmacological regime for SCI treatment, its efficacy remains controversial due to its very narrow therapeutic time window and safety concerns associated with high dosage. In this study, we have developed an oil-in-gel type of organohydrogel (OHG) in which the binary oleic-water phases coexist, for the local delivery of MP. This new OHG is fabricated by a glycol chitosan/oxidized hyaluronic acid hydrophilic network that is uniformly embedded with a biocompatible oil phase, and it can be effectively loaded with MP or other hydrophobic compounds. In addition to spatiotemporally control MP release, this biodegradable OHG also provides a brain tissue-mimicking scaffold that can promote tissue regeneration. OHG remarkably decreases the therapeutic dose of MP in animals and extends its treatment course over 21 d, thereby timely manipulating microglia/macrophages and their associated with signaling molecules to restore immune homeostasis, leading to a long-term functional improvement in a complete transection SCI rat model. Thus, this OHG represents a new type of gel for clinical treatment of secondary injuries in SCI.

Correction: Asymmetric catalytic [1,3]- or [3,3]-sigmatropic rearrangement of 3-allyloxy-4H-chromenones and their analogues.

[This corrects the article DOI: 10.1039/D4SC02201G.].

The first large scale rDNA amplicon database of soil microbiomes from Pamir Plateau, China.

The Eastern Pamir, distinguished with high altitude, extremely arid and cold climate, limited nutrients and sparse vegetation, is a unique ecological reservoir. Microbial communities play a central role in maintaining Eastern Pamir's ecosystem functioning. Despite the ecological significance, due to the difficulty of sample collection and microbial isolation, the microbial diversity and its functionality at the Pamir Plateau have been rarely documented. To fill this gap, 80 soil samples from 17 sites across different elevations were collected, performed the rDNA amplicon sequencing to present the first large-scale overview of bacterial, archaeal, and fungal communities in the Eastern Pamir. Microbiome analysis revealed that the bacteria Actinobacteria, Alphaproteobacteria and Bacteroidia, alongside such as archaea Nitrososphaeria and Halobacteria, and fungi including Dothideomycetes, Sordariomycetes and Eurotiomycetes were dominant lineages at class level in soil microbial communities. The community structure and biodiversity of soil microorganisms provided by this dataset would be pivotal for future studies aimed at understanding the biogeographical distribution, ecological functions and environmental responses of microbial communities of the Pamir Plateau.

Divergent Roles of the Auxin Response Factors in Lemongrass (Cymbopogon flexuosus (Nees ex Steud.) W. Watson) during Plant Growth.

Auxin Response Factors (ARFs) make up a plant-specific transcription factor family that mainly couples perception of the phytohormone, auxin, and gene expression programs and plays an important and multi-faceted role during plant growth and development. Lemongrass (Cymbopogon flexuosus) is a representative Cymbopogon species widely used in gardening, beverages, fragrances, traditional medicine, and heavy metal phytoremediation. Biomass yield is an important trait for several agro-economic purposes of lemongrass, such as landscaping, essential oil production, and phytoremediation. Therefore, we performed gene mining of CfARFs and identified 26 and 27 CfARF-encoding genes in each of the haplotype genomes of lemongrass, respectively. Phylogenetic and domain architecture analyses showed that CfARFs can be divided into four groups, among which groups 1, 2, and 3 correspond to activator, repressor, and ETTN-like ARFs, respectively. To identify the CfARFs that may play major roles during the growth of lemongrass plants, RNA-seq was performed on three tissues (leaf, stem, and root) and four developmental stages (3-leaf, 4-leaf, 5-leaf. and mature stages). The expression profiling of CfARFs identified several highly expressed activator and repressor CfARFs and three CfARFs (CfARF3, 18, and 35) with gradually increased levels during leaf growth. Haplotype-resolved transcriptome analysis revealed that biallelic expression dominance is frequent among CfARFs and contributes to their gene expression patterns. In addition, co-expression network analysis identified the modules enriched with CfARFs. By establishing orthologous relationships among CfARFs, sorghum ARFs, and maize ARFs, we showed that CfARFs were mainly expanded by whole-genome duplications, and that the duplicated CfARFs might have been divergent due to differential expression and variations in domains and motifs. Our work provides a detailed catalog of CfARFs in lemongrass, representing a first step toward characterizing CfARF functions, and may be useful in molecular breeding to enhance lemongrass plant growth.

Effects of polysaccharide from Pueraria lobata on osteoarthritis in rats.

The effects of Pueraria lobata polysaccharide (PPL-1) on osteoarthritis (OA) disease were comprehensively evaluated by using chondrocytes and synoviocytes extracted from the joints of SD rats based on in vitro cell experiments and by establishing pathological models of OA rats. The results showed that concentrations of 1.25-10 and 0.2-1.6 µg/mL, PPL-1 did not inhibit or promote chondrocytes and synoviocytes in vitro. However, at concentrations of 1.25-10 and 0.2-1.6 µg/mL, it can promote cartilage and synovial membrane cells after LPS stimulation of cell activity and inhibite LPS-induced apoptosis. The results of animal experiments showed that PPL-1 can reduce the symptoms of joint swelling in OA rats, decrease the production of serum inflammatory cytokines TNF-α, IL-1ß, and IL-6, and slow down the occurrence of inflammation. Therefore, from the perspective of symptoms, inflammatory factors and pathology, PPL-1 has therapeutic effects on OA rats and alleviates the development of inflammation. It indicated that PPL-1 has the potential to be developed into an OA therapeutic drug with anti-inflammatory properties that protects and activates chondrocytes.

Robot-assisted radical nephroureterectomy using the KangDuo Surgical Robot-01 Sys-tem versus the da Vinci System: a multicenter prospective randomized controlled trial.

INTRODUCTION: We aim to compare the safety and effectiveness of the KangDuo (KD)-Surgical Robot-01 (KD-SR-01) system and the da Vinci (DV) system for robot-assisted radical nephroureterectomy (RARNU). MATERIALS AND METHODS: This multicenter prospective randomized controlled trial was conducted between March 2022 and September 2023. Group 1 included 29 patients undergoing KD-RARNU. Group 2 included 29 patients undergoing DV-RARNU. Patient demographic and clinical characteristics, perioperative data, and follow-up outcomes were collected prospectively and compared between the two groups. RESULTS: There were no significant differences in patient baseline demographic and preoperative characteristics between the two groups. The success rates in both groups were 100% without conversion to open or laparoscopic surgery or positive surgical margins. No significant difference was observed in docking time [242 (120-951) s vs 253 (62-498) s, P = 0.780], console time [137 (55-290) min vs 105 (62-220) min, P = 0.114], operative time [207 (121-460) min vs 185 (96-305) min, P = 0.091], EBL [50 (10-600) mL vs 50 (10-700) mL, P = 0.507], National Aeronautics and Space Administration Task Load Index scores, and postoperative serum creatinine levels between the two groups. None of the patients showed evidence of distant metastasis, local recurrence, or equipment-related adverse events during the four-week follow-up. One (3.4%) patient in Group 2 experienced postoperative enterovaginal and enterovesical fistulas (Clavien-Dindo grade III). CONCLUSIONS: The KD-SR-01 system is safe and effective for RARNU compared to the DV Si or Xi system. Further randomized controlled studies with larger sample sizes and longer durations are required.

The Effect of Cuproptosis-Related Proteins on Macrophage Polarization in Mesothelioma is Revealed by scRNA-seq.

High invasiveness mesothelioma is a malignant tumor of the peritoneum or pleura. The effect of cuproptosis on mesothelioma (MESO) is still unknown, though. The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) datasets were used to identify differential genes linked to cuproptosis in mesothelioma. Multigene features were then created to assess the course of the disease. Use single-cell data and in vitro validation to uncover crucial gene regulation mechanisms. In MESO, we found nine differentially expressed genes linked to cuproptosis. Using univariate Cox and LASSO regression techniques, a 3-gene feature (P < 0.05) was created, showing a good predictive potential for survival time. According to the risk score, patients in the low-risk subset had a considerably greater survival rate than those in the high-risk subset (P = 0). The similar survival pattern and prediction performance are also seen in the validation queue. The findings of the drug sensitivity research indicate that in high-risk patients, vinblastine, paclitaxel, gefitinib, and erlotinib are sensitive medications (P < 0.05). Classical monocytes were identified as core cells connected to cuproptosis by the CellChat results. SLC31A1 is implicated in the positive regulation of M2 macrophage polarization, according to cell subtype analysis and in vitro confirmation. Genes linked to cuproptosis have a major influence on tumor immunity and can predict how MESO will progress.

Single-cell transcriptomics reveals writers of RNA modification-mediated immune microenvironment and cardiac resident Macro-MYL2 macrophages in heart failure.

BACKGROUND: Heart failure (HF), which is caused by cardiac overload and injury, is linked to significant mortality. Writers of RNA modification (WRMs) play a crucial role in the regulation of epigenetic processes involved in immune response and cardiovascular disease. However, the potential roles of these writers in the immunological milieu of HF remain unknown. METHODS: We comprehensively characterized the expressions of 28 WRMs using datasets GSE145154 and GSE141910 to map the cardiac immunological microenvironment in HF patients. Based on the expression of WRMs, the immunological cells in the datasets were scored. RESULTS: Single-cell transcriptomics analysis (GSE145154) revealed immunological dysregulation in HF as well as differential expression of WRMs in immunological cells from HF and non-HF (NHF) samples. WRM-scored immunological cells were positively correlated with the immunological response, and the high WRM score group exhibited elevated immunological cell infiltration. WRMs are involved in the differentiation of T cells and myeloid cells. WRM scores of T cell and myeloid cell subtypes were significantly reduced in the HF group compared to the NHF group. We identified a myogenesis-related resident macrophage population in the heart, Macro-MYL2, that was characterized by an increased expression of cardiomyocyte structural genes (MYL2, TNNI3, TNNC1, TCAP, and TNNT2) and was regulated by TRMT10C. Based on the WRM expression pattern, the transcriptomics data (GSE141910) identified two distinct clusters of HF samples, each with distinct functional enrichments and immunological characteristics. CONCLUSION: Our study demonstrated a significant relationship between the WRMs and immunological microenvironment in HF, as well as a novel resident macrophage population, Macro-MYL2, characterized by myogenesis. These results provide a novel perspective on the underlying mechanisms and therapeutic targets for HF. Further experiments are required to validate the regulation of WRMs and Macro-MYL2 macrophage subtype in the cardiac immunological milieu.

Clinical Diagnostic Value of Shear-Wave Elastography in Detecting Malignant Nipple Retraction.

OBJECTIVES: In recent years, the use of shear-wave elastography (SWE) as a diagnostic tool for detecting malignant breast lesions has shown promising results. This study aims to determine the clinical diagnostic value of SWE in detecting malignant nipple retraction. METHODS: Both US and SWE (Philips EPIQ7 system) were performed for 41 consecutive patients with nipple retraction (56 nipples). The mean, median, and maximum tissue elasticity values (in kilopascals) were determined for each nipple by using SWE. The sensitivity, specificity, and overall accuracy of each measurement was determined by using the surgical pathology results or clinical diagnosis as the gold standard. RESULTS: Of the 56 retracted nipples, 32 were due to benign lesions, and 24 were due to malignant lesions. No significant differences in dimensions or echo features were found between the benign and malignant groups. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the color Doppler flow imaging (CDFI) pattern were 63.89% (23/36), 95% (19/20), 95.83 (23/24), 59.38 (19/32), and 75% (42/56), respectively; the corresponding values for median elasticity on SWE were 88.46% (23/26), 96.67% (29/30), 95.83 (23/24), 90.63 (29/32), and 92.85 (52/56), respectively. CONCLUSIONS: The addition of SWE to conventional US could help differentiate benign from malignant lesions associated with nipple retraction.

Characteristics and risk differences of different tumor sizes on distant metastases of pancreatic neuroendocrine tumors: A retrospective study in the SEER database.

BACKGROUND: The rate of distant metastasis in patients with pancreatic neuroendocrine tumors (PNETs) is 20%-50% at the time of initial diagnosis. However, whether tumor size can predict distant metastasis for PNETs remains unknown up to date. METHODS: We used Surveillance, Epidemiology, and End Results (SEER) population-based data to collect 6089 patients with PNETs from 2010 to 2019. The optimal cut-off point of tumor size to predict distant metastasis was calculated by Youden's index. Multivariate logistic regression analysis was used to figure out the association between tumor size and distant metastasis patterns. RESULTS: The most common metastatic site was liver (27.2%), followed by bone (3.0%), lung (2.3%) and brain (0.4%). Based on an optimal cut-off value of tumor size (25.5 mm) for predicting distant metastasis determined by Youden's index, patients were categorized into groups of tumor size < 25.5 mm and ≥ 25.5 mm. Multivariate logistic regression analyses showed that, compared with < 25.5 mm, tumor size ≥ 25.5 mm was an independent risk predictor of overall distant metastasis [odds ratio (OR) = 4.491, 95% confidence interval (CI): 3.724-5.416, P < 0.001] and liver metastasis (OR = 4.686, 95% CI: 3.886-5.651, P < 0.001). CONCLUSIONS: Tumor size ≥ 25.5 mm was significantly associated with more overall distant and liver metastases. Timely identification of distant metastasis for tumor size ≥ 25.5 mm may provide survival benefit for timely and precise treatment.

Opportunities and Challenges in the Development of Antibody-Drug Conjugate for Triple-Negative Breast Cancer: The Diverse Choices and Changing Needs.

Triple-negative breast cancer (TNBC) is a highly heterogeneous breast cancer subtype, which is also characterized by the aggressive phenotype, high recurrence rate, and poor prognosis. Antibody-drug conjugate (ADC) is a monoclonal antibody with a cytotoxic payload connected by a linker. ADC is gaining more and more attention as a targeted anti-cancer agent. Clinical studies of emerging ADC drugs such as sacituzumab govitecan and trastuzumab deruxtecan in patients with metastatic breast cancer (including TNBC) are progressing rapidly. In view of its excellent clinical efficacy and good tolerability, Sacituzumab govitecan gained accelerated approval by the FDA for the treatment of advanced metastatic TNBC in 2020. This review discusses the treatment status and challenges in TNBC, with an emphasis on the current status of ADC development and clinical trials in TNBC and metastatic breast cancer. We also summarize the clinical experience and future exploration directions of ADC development for TNBC patients.

Inherited glycosylphosphatidylinositol deficiency: a review from molecular and clinical perspectives.

Glycosylphosphatidylinositol (GPI) is a highly conserved post-translational modification in eukaryotes, which is essential for anchoring various proteins to the cell surface. Dysfunction of GPI biogenesis leads to human diseases, such as inherited GPI deficiency (IGD) caused by germline mutations in GPI-related genes. With accumulating reports on individuals with IGD, there has been increasing interest and studies on disease mechanism, diagnosis, and therapy. This review outlines the biosynthetic pathway of GPI-anchored proteins (GPI-APs) and summarizes clinical IGD cases from a molecular perspective. We also review current diagnostic and therapeutic approaches for IGD. Finally, we discuss future research directions to facilitate the understanding and treatment of GPI-related disorders.

UPLC-MS/MS reveals the differences in lipids composition of Camellia oleifera from northern margin distribution area.

The lipids accumulation characteristics in 23Camellia oleifera lines from northern margin distribution area were investigated through quantitative lipidomics. Combined lipids content-function analysis indicated that NQ1, HT1, HT2, ZA2, ZB1, ZB2, and SN2 lines had potential to develop functional foods due to abundant glycerolipids (GLs), glycerophospholipids (GPs), fatty acids (FAs), and prenol lipids (PRs). 673 lipids components were detected, and 293 differential components were identified in NQ1, ZA2, HB1, and HT1. 4 kinds free fatty acids (FFAs) were higher in NQ1, 5 triglycerides (TGs) were higher in HT1, and 2 phosphatidyl serines (PSs) and 1 phosphatidyl glycerol (PG) were higher in ZA2. GLs, GPs, and FFAs had strong relation at intra- and inter-category level. Glycerolipid metabolism, glycerophospholipid metabolism, and fatty acid biosynthesis were the significantly differential lipids pathways. Our study elucidated lipids differences of 23 C. oleifera lines, and offered valuable references for lipids biosynthesis, directional breeding, and lipids utilization.

Tirzepatide shows neuroprotective effects via regulating brain glucose metabolism in APP/PS1 mice.

Tirzepatide (LY3298176), a GLP-1 and GIP receptor agonist, is fatty-acid-modified and 39-amino acid linear peptide, which ameliorates learning and memory impairment in diabetic rats. However, the specific molecular mechanism remains unknown. In the present study, we investigated the role of tirzepatide in the neuroprotective effects in Alzheimer's disease (AD) model mice. Tirzepatide was administrated intraperitoneal (i.p.) APP/PS1 mice for 8 weeks with at 10 nmol/kg once-weekly, it significantly decreased the levels of GLP-1R, and GFAP protein expression and amyloid plaques in the cortex, it also lowered neuronal apoptosis induced by amyloid-ß (Aß), but did not affect the anxiety and cognitive function in APP/PS1 mice. Moreover, tirzepatide reduced the blood glucose levels and increased the mRNA expression of GLP-1R, SACF1, ATF4, Glu2A, and Glu2B in the hypothalamus of APP/PS1 mice. Tirzepatide increased the mRNA expression of glucose transporter 1, hexokinase, glucose-6-phosphate dehydrogenase, and phosphofructokinase in the cortex. Lastly, tirzepatide improved the energetic metabolism by regulated reactive oxygen species production and mitochondrial membrane potential caused by Aß, thereby decreasing mitochondrial function and ATP levels in astrocytes through GLP-1R. These results provide valuable insights into the mechanism of brain glucose metabolism and mitochondrial function of tirzepatide, presenting potential strategies for AD treatment.

A multi-classifier system integrated by clinico-histology-genomic analysis for predicting recurrence of papillary renal cell carcinoma.

Integrating genomics and histology for cancer prognosis demonstrates promise. Here, we develop a multi-classifier system integrating a lncRNA-based classifier, a deep learning whole-slide-image-based classifier, and a clinicopathological classifier to accurately predict post-surgery localized (stage I-III) papillary renal cell carcinoma (pRCC) recurrence. The multi-classifier system demonstrates significantly higher predictive accuracy for recurrence-free survival (RFS) compared to the three single classifiers alone in the training set and in both validation sets (C-index 0.831-0.858 vs. 0.642-0.777, p < 0.05). The RFS in our multi-classifier-defined high-risk stage I/II and grade 1/2 groups is significantly worse than in the low-risk stage III and grade 3/4 groups (p < 0.05). Our multi-classifier system is a practical and reliable predictor for recurrence of localized pRCC after surgery that can be used with the current staging system to more accurately predict disease course and inform strategies for individualized adjuvant therapy.

Neurodevelopmental toxicity of a ubiquitous disinfection by-product, bromoacetic acid, in Zebrafish (Danio rerio).

Disinfection of public drinking water and swimming pools is crucial for preventing waterborne diseases, but it can produce harmful disinfection by-products (DBPs), increasing the risk of various diseases for those frequently exposed to such environments. Bromoacetic acid (BAA) is a ubiquitous DBP, with toxicity studies primarily focused on its in vitro cytotoxicity, and insufficient research on its neurodevelopmental toxicity. Utilizing zebrafish as a model organism, this study comprehensively explored BAA's toxic effects and uncovered the molecular mechanisms through neurobehavioral analysis, in vivo two-photon imaging, transcriptomic sequencing, pharmacological intervention and molecular biological detection. Results demonstrated BAA induced significant changes on various indicators in the early development of zebrafish. Furthermore, BAA disrupted behavioral patterns in zebrafish larvae across locomotion activity, light-dark stimulation, and vibration stimulation paradigms. Subsequent investigation focused on larvae revealed BAA inhibited neuronal development, activated neuroinflammatory responses, and altered vascular morphology. Transcriptomic analysis revealed BAA-stressed zebrafish exhibited downregulation of visual transduction-related genes and activation of ferroptosis and cellular apoptosis. Neurobehavioral disorders were recovered by inhibiting ferroptosis and apoptosis. This study elucidates the neurodevelopmental toxicity associated with BAA, which is crucial for understanding health risks of DBPs and for the development of more effective detection methods and regulatory strategies.