A review of dose escalation for FDA-approved products treating solid tumors and hematological malignancies in first-in-human trials.

First-in-human (FIH) dose-escalation trials on oncology should prioritize safety and emphasize efficacy. We reviewed the FIH trials of 67 anti-tumor products approved by the Food and Drug Administration between 2018 and 2023 and found that the "3 + 3" design remains the predominant dose-escalation method (66.2%). The number of patients receiving sub-therapeutic doses is positively correlated with the maximum tolerated dose (MTD) or maximum dose (MD) to starting dose ratio (P = 0.056) and the number of dose levels in trials (P < 0.001). In addition, the proportion of products with a high ratio in antibody drugs is higher than that in small molecules (P < 0.001). The MTD or MD exceeded the label dose by three or more doses in 22.03% of the products. In conclusion, optimizing the starting dose selection method, refining the way of determining doses, and finding alternative indicators to replace toxicity as the endpoints will increase the effectiveness and broaden the beneficiary scope.

Color components determination and full-length comparative transcriptomic analyses reveal the potential mechanism of carotenoid synthesis during Paphiopedilum armeniacum flowering.

Background: Paphiopedilum armeniacum (P. armeniacum), an ornamental plant native to China, is known for its distinctive yellow blossoms. However, the mechanisms underlying P. armeniacum flower coloration remain unclear. Methods: We selected P. armeniacum samples from different flowering stages and conducted rigorous physicochemical analyses. The specimens were differentiated based on their chemical properties, specifically their solubilities in polar solvents. This key step enabled us to identify the main metabolite of flower color development of P. armeniacum, and to complete the identification by High-performance liquid chromatography (HPLC) based on the results. Additionally, we employed a combined approach, integrating both third-generation full-length transcriptome sequencing and second-generation high-throughput transcriptome sequencing, to comprehensively explore the molecular components involved. Results: We combined physical and chemical analysis with transcriptome sequencing to reveal that carotenoid is the main pigment of P. armeniacum flower color. Extraction colorimetric method and HPLC were used to explore the characteristics of carotenoid accumulation during flowering. We identified 28 differentially expressed carotenoid biosynthesis genes throughout the flowering process, validated their expression through fluorescence quantification, and discovered 19 potential positive regulators involved in carotenoid synthesis. Among these candidates, three RCP2 genes showed a strong potential for governing the PDS and ZDS gene families. In summary, our study elucidates the fundamental mechanisms governing carotenoid synthesis during P. armeniacum flowering, enhancing our understanding of this process and providing a foundation for future research on the molecular mechanisms driving P. armeniacum flowering.

RNA-binding protein NOVA1 promotes acute T-lymphocyte leukemia progression by stabilizing USP44 mRNA.

Acute T-lymphocyte leukemia (T-ALL) is a malignant tumor disease. RNA-binding protein neotumor ventral antigen-1 (NOVA1) is highly expressed in bone marrow mononuclear cells of T-ALL patients, while the role of NOVA1 in T-ALL progression remains unknown. The gain- and loss-of-function studies for NOVA1 were performed in Jurkat and CCRF-CEM cells. NOVA1 overexpression promoted cell proliferation and cell cycle progression. NOVA1 knockdown increased the apoptosis rate of T-ALL cells. Ubiquitin-specific protease 44 (USP44), a nuclear protein with deubiquitinase catalytic activity, has been reported to play an oncogene role in human T-cell leukemia. USP44 expression was positively associated with NOVA1, and RNA immunoprecipitation assay verified the binding of NOVA1 to the mRNA of USP44. USP44 knockdown partially abolished NOVA1-induced cell proliferation and inhibition of apoptosis. The in vivo xenograft experiment was performed by injection of T-ALL tumor cells into the tail vein of NOD/SCID mice. The knockdown of NOVA1 had lower tumorigenicity. NOVA1 knockdown alleviated pathological changes in lung and spleen tissues, and increased the overall survival period and the weight of T-ALL mice. Thus, NOVA1 acts as an accelerator in T-ALL, and its function might be achieved by binding to and stabilizing USP44 mRNA.

Fiber Characteristics and Mechanical Properties of Oxytenanthera abyssinica.

Unlike the culm hollow structure of most bamboo species, Oxytenanthera abyssinica has a unique solid or semi-solid culm, which may endow it with superior mechanical performance. In this study, the variation in fiber morphology and micro-mechanical properties across the radial regions of bamboo culm was examined by optical microscopy, scanning electron microscopy, X-ray diffraction, and nanoindentation. Results showed that the mean values of vascular bundle frequency and fiber tissue proportion were 1.76 pcs/mm2 and 21.04%, respectively, both of which increased gradually from inner to outer. The mean length, diameter, and length-diameter ratio of the fiber were 2.10 mm, 21.54 µm, and 101.41 respectively. The mean indentation modulus of elasticity (IMOE) and hardness were 21.34 GPa and 545.88 MPa. The IMOE exhibited a significant increase from the inner to the middle region, and little change was observed from the middle to the outer region. There were slight fluctuations in hardness along the radial direction. The mean crystallinity and microfibril angle(MFA) of the fibers was 68.12% and 11.26 degrees, respectively. There is a positive correlation between cellulose crystallinity and the IMOE and hardness, while there is a negative correlation between the MFA and the IMOE and the hardness.

Emergence of Corona Is Independent of the Four Whorls of Floral Organs in Narcissus tazetta.

Plants of the genus Narcissus are well-known for their characteristic corona morphology, which structural origins have been a bone of contention among scholars. With "Jinzhanyintai" (JZ) and "Yulinglong" (YLL)-two major close-originated cultivars of Chinese narcissus (Narcissus tazetta L. var. chinensis Roem)-as materials, anatomic observation was made on floral organs during corona morphogenesis by dissection with hands under a stereomicroscope, paraffin section, scanning electron microscopy, and high-resolution X-ray tomography. It was uncovered that corona primordia of both cultivars appeared following the end of the differentiation of other floral organs, with differentiation sites located at the inner wall of the juncture of the base of tepals and the upper margin of the hypanthium. Affected by staminal filaments, the corona primordia of JZ experienced a three-stage differentiation process, namely blockage from the second whorl of stamens, blockage from the first whorl of stamens, and healing of corona primordia. However, the expanded spatial structure of the first whorl of petal-like stamens blocked the path of differentiation of YLL corona primordia, giving rise to slow differentiation of the corona primordia at the base of the first whorl of petal-like stamens and malformed differentiation of the corona primordia in the interval between the two whorls of petal-like stamens. Thus, a fragmented structure consisting of typical and fragmented coronas was formed. Furthermore, petal-like stamens of YLL in the lower part had a corona-like morphology. The spatio-temporal specificity of corona differentiation convincingly demonstrates that the corona is a structure independent of and different from the typical four whorls of floral organs, but also highly correlated with stamen.

Identification and transcriptome data analysis of ARF family genes in five Orchidaceae species.

The Orchidaceae is a large family of perennial herbs especially noted for the exceptional diversity of specialized flowers. Elucidating the genetic regulation of flowering and seed development of orchids is an important research goal with potential utility in orchid breeding programs. Auxin Response Factor (ARF) genes encode auxin-responsive transcription factors, which are involved in the regulation of diverse morphogenetic processes, including flowering and seed development. However, limited information on the ARF gene family in the Orchidaceae is available. In this study, 112 ARF genes were identified in the genomes of 5 orchid species (Apostasia shenzhenica, Dendrobium catenatum, Phalaenopsis aphrodite, Phalaenopsis equestris and Vanilla planifolia,). These genes were grouped into 7 subfamilies based on their phylogenetic relationships. Compared with the ARF family in model plants, such as Arabidopsis thaliana and Oryza sativa, one group of ARF genes involved in pollen wall synthesis has been lost during evolution of the Orchidaceae. This loss corresponds with absence of the exine in the pollinia. Through mining of the published genomic and transcriptomic data for the 5 orchid species: the ARF genes of subfamily 4 may play an important role in flower formation and plant growth, whereas those of subfamily 3 are potentially involved in pollen wall development. the study results provide novel insights into the genetic regulation of unique morphogenetic phenomena of orchids, which lay a foundation for further analysis of the regulatory mechanisms and functions of sexual reproduction-related genes in orchids.

Tandem Efficient Bromine Removal and Silver Recovery by Resorcinol-Formaldehyde Resin Nanoparticles.

Halogen wastewater greatly threatens the health of human beings and aquatic organisms due to its severe toxicity, corrosiveness, and volatility. Efficient bromine removal is therefore urgently required, while existing Br2-capture materials often face challenges from limited water stability and possible halogen leaking. We report a facile and efficient aqueous Br2 removal method using submicron resorcinol-formaldehyde (RF) resin nanoparticles (NPs). The abundant aromatic groups dominate the Br2 removal by substitution reactions. An excellent Br2 conversion capacity of 7441 mg gRF-1 was achieved by RF NPs that outperform state-of-the-art materials by ∼2-fold, along with advantages including good water stability, low cost, and easy fabrication. Two recycling-coupled (electrochemical or H2O2-involved) Br2 removal routes further reveal the feasibility of in-depth halogen removal by RF NPs. The brominated resin can be downstream upcycled for silver recovery, realizing the harvesting of precious metal, reducing of heavy-metal pollution, and resource utilization of brominated resin.

Network Pharmacology and Integrated Molecular Docking Study on the Mechanism of the Therapeutic Effect of Fangfeng Decoction in Osteoarthritis.

BACKGROUND: At present, there are no effective pharmacologic therapies for attenuating the course of osteoarthritis (OA) in humans and current therapies are geared to mitigating symptoms. Fangfeng decoction (FFD) is a traditional Chinese medicine prescribed for the treatment of OA. In the past, FFD has achieved positive clinical outcomes in alleviating the symptoms of OA in China. However, its mechanism of action has not yet been clarified. OBJECTIVE: The objective of this study is to investigate and explore the mechanism of FFD and how the compound interacts with the target of OA; network pharmacology and molecular docking methods were applied in this study. METHODS: The active components of FFD were screened by Traditional Chinese Medicine Systems Pharmacology (TCMSP) database according to the inclusion criteria as oral bioactivity (OB) ≥ 30% and drug likeness (DL) ≥ 0.18. Then, gene name conversion was performed through the UniProt website. The related target genes of OA were obtained from the Genecards database. Core components, targets, and signaling pathways were obtained through compound-target-pathway (C-T-P) and protein-protein interaction (PPI) networks were built using Cytoscape 3.8.2 software. Matescape database was utilized to get gene ontology (GO) function enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment of gene targets. The interactions of key targets and components were analyzed by molecular docking in Sybyl 2.1 software. RESULTS: A total of 166 potential effective components, 148 FFD-related targets, and 3786 OA-related targets were obtained. Finally, 89 common potential target genes were confirmed. Pathway enrichment results showed that HIF-1 and CAMP signaling pathways were considered key pathways. The screening of core components and targets was achieved through the CTP network. The core targets and active components were obtained according to the CTP network. The molecular docking results showed that quercetin, medicarpin, and wogonin of FFD could bind to NOS2, PTGS2, and AR, respectively. CONCLUSION: FFD is effective in the treatment of OA. It may be caused by the effective binding of the relevant active components of FFD to the targets of OA.

Transcriptome analysis of floral bud development and function analysis of a novel CO gene in Paeonia × lemoinei 'High Noon'.

Paeonia × lemoinei 'High Noon' is one of the most important cultivars in tree peony (Paeonia sect. Moutan), a traditional horticultural plant in China, with a re-blooming characteristic which was quite different from other cultivars. So, the genetic resources in 'High Noon' were incredibly valuable in flowering-time-modified molecular breeding in tree peony. However, the molecular mechanism underlying the floral bud formation of 'High Noon' was not clear yet. To explore the molecular mechanism in this process, the transcriptomes of three stages during floral bud development were deeply analyzed in this study. As a result, a total of 5816 differentially expressed genes (DEGs) were identified between the three developmental stages, and pathways including ''DNA replication'', ''metabolic pathways'', ''circadian rhythm'', and ''plant hormone signal transduction'' were mostly enriched in the functional enrichment and expression pattern analysis. Furthermore, a total of 584 genes related to the photoperiod pathway were further identified and a novel CO homolog gene PlCO was identified to be a stable hydrophilic protein, which contained both CCT domain and B-box domain. Over-expression of PlCO in Arabidopsis resulted in early flowering, which suggested a promotion role of flowering. The PlCO protein localized in nucleus and possessed a transcription activity ability, which implied that PlCO might function as a transcription factor. The transcriptome analysis revealed pathways involved in floral bud development in tree peony and provided new insight into the regulatory network underlying the floral bud development. The gene identification in 'High Noon' provided new valuable candidate genes for flowering-time-modified molecular breeding in tree peony.

Citrullination: A modification important in the pathogenesis of autoimmune diseases.

Peptidyl arginine deiminase (PAD) which mediates citrullination catalyzes the conversion of arginine residues of protein peptide chains to citrulline residues. Citrullination can be involved in the process of apoptosis, embryo development, regulation of myelin sheath function and other physiological processes. Besides, it can regulate the process of cell death, affect the formation of neutrophil extracellular traps (NETs) and produce anti-citrullinated protein antibody (ACPA) to participate in autoimmune diseases. In this manuscript, the regulatory effects of citrullination in normal physiology and autoimmune diseases are reviewed, and the effects of citrullination on immune cells in autoimmune diseases are discussed in detail.

Universal chimeric antigen receptor T cell therapy - The future of cell therapy: A review providing clinical evidence.

Autologous CAR-T therapy has shown promising outcomes in the treatment of tumors, particularly hematological malignancies over the past years. However, the application of autologous CAR-T therapy is limited, due to undesirable patient and/or peripheral blood characteristics, the high cost and long time period of manufacturing, and other challenges. Universal CAR-T therapy could overcome major limitations of autologous CAR-T therapy. In this review, we described the research and development status of universal CAR-T therapy for hematological malignancies. In addition, we also summarized the challenges had been encountered and the current solutions.

The miR166-mRNA network regulates vascular tissue differentiation in Moso bamboo.

miR166s play an important role in plant tissue differentiation. However, the functions of miR166s in the differentiation of vascular tissue in bamboo have not yet been elucidated. Here, we showed that five miR166s are overexpressed (tags per million reads > 2,000) in underground shoot samples of wild-type (WT) Moso bamboo (Phyllostachys edulis) and a thick-walled variant (P. edulis "Pachyloen") throughout the developmental process. Potential targets of these miR166s include some genes encoding homeodomain-leucine zipper (HD-ZIP) transcription factors and protein kinases. Cleavage sites for miR166s were identified in seven PeHD-ZIP homologs and a protein kinase gene via degradome sequencing (p < 0.05). Dual-luciferase and transient expression assays confirmed the binding of miR166s to PeHOXs. Fluorescence in situ hybridization revealed that miR166s were localized to the xylem of the leaf, root, and internode of 2-month-old pot seedlings of WT Moso bamboo. Overall, these findings reveal that miR166s are regulators of vascular tissue differentiation in bamboo. The miR166s identified in our study provide novel targets for bamboo breeding.

All-optical demonstration of a scalable super-resolved magnetic vortex core.

We first present the all-optical realization of a scalable super-resolved magnetic vortex core (MVC) by tightly focusing two modulated counter-propagating radially polarized doughnut Gaussian beams based on the vectoial diffraction theory and the inverse Faraday effect. It is shown that by imposing spiral phase plates (SPPs) on the incident vectorial beams, single three-dimensional (3D) super-resolved (λ3/22) MVC can be achieved in the 4π focusing setup, which is radically different from that produced with a single lens focusing. Furthermore, the light-induced MVC texture turns to be richer and more complex when the radially polarized beams are tailored by the SPPs and judiciously designed multi-ring filters all together. In this case, we are able to garner not only transverse super-resolved (0.447λ) MVC needle with an uniformly extended area (40λ) in the single lens focusing system, but also the multiple uniform 3D super-resolved (λ3/24) chain-like MVC cells in the 4π focusing system, thus giving rise to the tunable and scalable super-resolved MVC extension. The related physical mechanisms to trigger such peculiar magnetization polarization topologies are unraveled as well. These resultant achievements would pave the way for the integrated transfer and storage of optomagnetic information, atomic trapping, and beyond.

Transcriptome and miRNAome analysis reveals components regulating tissue differentiation of bamboo shoots.

Primary thickening determines bamboo yield and wood property. However, little is known about the regulatory networks involved in this process. This study identified a total of 58,652 genes and 150 miRNAs via transcriptome and small RNA sequencing using the underground thickening shoot samples of wild-type (WT) Moso bamboo (Phyllostachys edulis) and a thick wall (TW) variant (P. edulis "Pachyloen") at five developmental stages (WTS1/TWS1-WTS5/TWS5). A total of 14,029 (65.17%) differentially expressed genes and 68 (45.33%) differentially expressed miRNAs were identified from the WT, TW, and WTTW groups. The first two groups were composed of four pairwise combinations, each between two successive stages (WTS2/TWS2_versus_WTS1/TWS1, WTS3/TWS3_versus_WTS2/TWS2, WTS4/TWS4_versus_WTS3/TWS3, and WTS5/TWS5_versus_WTS4/TWS4), and the WTTW group was composed of five combinations, each between two relative stages (TWS1-5_versus_WTS1-5). Additionally, among the phytohormones, zeatin showed more remarkable changes in concentrations than indole-3-acetic acid, gibberellic acid, and abscisic acid throughout the five stages in the WT and the TW groups. Moreover, 125 cleavage sites were identified for 387 miRNA-mRNA pairs via degradome sequencing (P < 0.05). The dual-luciferase reporter assay confirmed that 13 miRNAs bound to 12 targets. Fluorescence in situ hybridization localized miR166 and miR160 in the shoot apical meristem and the procambium of Moso bamboo shoots at the S1 stage. Thus, primary thickening is a complex process regulated by miRNA-gene-phytohormone networks, and the miRNAome and transcriptome dynamics regulate phenotypic plasticity. These findings provide insights into the molecular mechanisms underlying wood formation and properties and propose targets for bamboo breeding.

Longitudinal magnetization superoscillation enabled by high-order azimuthally polarized Laguerre-Gaussian vortex modes.

We present an all-optical scheme for the generation of longitudinal magnetization superoscillation based on the vectorial diffraction theory and the inverse Faraday effect. To achieve this, an azimuthally polarized high-order Laguerre-Gaussian vortex mode is firstly focused by a high numerical aperture (NA) objective and then impinges on an isotropic magneto-optical material. It is found that, by judiciously controlling the intrinsic arguments (radial mode index (p) and truncation parameter (ß)) of such a configurable vectorial vortex beam, the longitudinal magnetic domain induced in the focal plane can be switched from a peak sub-wavelength magnetization (> 0.36λ/NA), via the fastest Fourier magnetization component (∼0.36λ/NA), to a super-oscillation magnetization hotspot (< 0.36λ/NA). We further examine the dependence of the transverse size, the side lobe, and the energy conversion efficiency within the focal magnetization domain on both the p and ß of the initial vortex modes, confirming that the higher-order structured vortex beams are preferable alternatives to trigger robust longitudinal magnetization superoscillation. In addition, the underlying mechanisms behind the well-defined magnetization phenomena are unveiled. The ultra-small-scale longitudinal magnetization demonstrated here may hold massive potential applications in high-density all-optical magnetic recording/storage, super-resolution magnetic resonance imaging, atom trapping and spintronics.

Analysis of 427 genomes reveals moso bamboo population structure and genetic basis of property traits.

Moso bamboo (Phyllostachys edulis) is an economically and ecologically important nontimber forestry species. Further development of this species as a sustainable bamboo resource has been hindered by a lack of population genome information. Here, we report a moso bamboo genomic variation atlas of 5.45 million single-nucleotide polymorphisms (SNPs) from whole-genome resequencing of 427 individuals covering 15 representative geographic areas. We uncover low genetic diversity, high genotype heterozygosity, and genes under balancing selection underlying moso bamboo population adaptation. We infer its demographic history with one bottleneck and its recently small population without a rebound. We define five phylogenetic groups and infer that one group probably originated by a single-origin event from East China. Finally, we conduct genome-wide association analysis of nine important property-related traits to identify candidate genes, many of which are involved in cell wall, carbohydrate metabolism, and environmental adaptation. These results provide a foundation and resources for understanding moso bamboo evolution and the genetic mechanisms of agriculturally important traits.

Local Variations in Carbohydrates and Matrix Lignin in Mechanically Graded Bamboo Culms.

The mechanical performance of bamboo is highly dependent on its structural arrangement and the properties of biomacromolecules within the cell wall. The relationship between carbohydrates topochemistry and gradient micromechanics of multilayered fiber along the diametric direction was visualized by combined microscopic techniques. Along the radius of bamboo culms, the concentration of xylan within the fiber sheath increased, while that of cellulose and lignin decreased gradually. At cellular level, although the consecutive broad layer (Bl) of fiber revealed a relatively uniform cellulose orientation and concentration, the outer Bl with higher lignification level has higher elastic modulus (19.59-20.31 GPa) than that of the inner Bl close to the lumen area (17.07-19.99 GPa). Comparatively, the cell corner displayed the highest lignification level, while its hardness and modulus were lower than that of fiber Bl, indicating the cellulose skeleton is the prerequisite of cell wall mechanics. The obtained cytological information is helpful to understand the origin of the anisotropic mechanical properties of bamboo.

The association of 14-year dietary cholesterol trajectories with the risk of cardio-metabolic diseases, all-cause mortality and serum lipids.

OBJECTIVES: The effect of dietary cholesterol consumption on health effects and serum lipids remains controversial. This study aimed to examine the association of dietary cholesterol trajectories over 14 years in China with the risk of cardio-metabolic diseases and all-cause mortality and serum lipids. METHODS: This study used weighted longitudinal data of 8952 adults from the China Health and Nutrition Survey, and subgroup analyses included 5466 adults who provided blood samples. Latent class trajectory modelling was performed to examine cholesterol trajectories. Cox regression models and general linear regressions were performed to examine the association between trajectories and outcomes. RESULTS: Compared to the participants with persistently low dietary cholesterol intake, participants with gradually increasing cholesterol intake throughout adulthood were more likely to have hypertension (HR = 1.14, 95% CI: 1.03, 1.28) and to die due to all causes (HR = 2.19, 95% CI: 1.57, 3.05). Moreover, participants with persistently high cholesterol intake were more likely to die due to all causes (HR = 2.26, 95% CI 1.47, 3.47). The total cholesterol (TC):HDL-cholesterol (HDL-C) ratio and apolipoprotein B (ApoB) in these two groups were also significantly elevated compared to the group with persistently low dietary cholesterol intake (all P < 0.05). An association between trajectories of cholesterol and the incidence of diabetes was also observed; however, such an association became non significant after additional adjustment for other nutrients, food consumption and social environment. CONCLUSIONS: Gradually increasing or persistently high cholesterol consumption throughout adulthood was significantly associated with an increased risk of hypertension and all-cause mortality with elevated serum lipids.

Predicting county-scale maize yields with publicly available data.

Maize (corn) is the dominant grain grown in the world. Total maize production in 2018 equaled 1.12 billion tons. Maize is used primarily as an animal feed in the production of eggs, dairy, pork and chicken. The US produces 32% of the world's maize followed by China at 22% and Brazil at 9% ( https://apps.fas.usda.gov/psdonline/app/index.html#/app/home ). Accurate national-scale corn yield prediction critically impacts mercantile markets through providing essential information about expected production prior to harvest. Publicly available high-quality corn yield prediction can help address emergent information asymmetry problems and in doing so improve price efficiency in futures markets. We build a deep learning model to predict corn yields, specifically focusing on county-level prediction across 10 states of the Corn-Belt in the United States, and pre-harvest prediction with monthly updates from August. The results show promising predictive power relative to existing survey-based methods and set the foundation for a publicly available county yield prediction effort that complements existing public forecasts.