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.

A three-dimensional (3D) liver-kidney on a chip with a biomimicking circulating system for drug safety evaluation.

The liver and kidney are the major detoxifying organs in the human body and play an important role in pharmacokinetics. Drug-induced hepatotoxicity and nephrotoxicity can cause irreversible damage to the liver and kidney and are a major cause of drug failure in later stages. Both animal models and conventional cell culture have a number of limitations, such as animal ethics and gene mismatching and there is an urgent need to develop a new drug toxicity evaluation approach. In this paper, a 3D liver-kidney on a chip with a biomimicking circulating system (LKOCBCS) was constructed to obtain kidney and liver models in vitro for drug safety evaluation. LKOCBCS, which has a parallel circulating system mimicking biological circulation, consists of 3D biomimetic tissue of liver lobules similar to that of the human liver constructed by 3D bioprinting and renal proximal tubule barriers fabricated by ultrafast laser assisted etching. The proposed LKOCBCS facilitates the communication between the liver and the kidney, including the exchange of nutrients, compounds, and metabolites. The results revealed that the glucose concentration and cell metabolism stabilized after 7 days. A dynamically repeated low-dose administration of cyclosporine A (CsA) was fed to the system, and hepatotoxicity and nephrotoxicity were observed on day 3 according to the changes in toxicity markers. The high levels of drug induced biomarkers expressed in LKOCBCS indicate that this system is more sensitive than the monoculture liver chip and it is highly potential in replacing animal models for effective drug toxicity screening.

Systematical Investigation of Flicker Noise in 14 nm FinFET Devices towards Stochastic Computing Application.

Stochastic computing (SC) is widely known for its high error tolerance and efficient computing ability of complex functions with remarkably simple logic gates. The noise of electronic devices is widely used to be the entropy source due to its randomness. Compared with thermal noise and random telegraph noise (RTN), flicker noise is favored by researchers because of its high noise density. Meanwhile, unlike using RRAM, PCRAM and other emerging memory devices as the entropy source, using logic devices does not require any additional process steps, which is significant for industrialization. In this work, we systematically and statistically studied the 1/f noise characteristics of 14 nm FinFET, and found that miniaturizing the channel area of the device or lowering the ambient temperature can effectively increase the 1/f noise density of the device. This is of great importance to improve the accuracy of the SC system and simplify the complexity of the stochastic number generator (SNG) circuit. At the same time, these rules of 1/f noise characteristics in FinFET devices can provide good guidance for our device selection in circuit design.

Digital twin-driven dynamic monitoring system of the upper limb force.

Digital twin represents the core technology to realize the dynamic monitoring of complex industrial systems. However, the human body, as the most complex system in the physical world, digital twin is rarely applied in it. In this study, we successfully demonstrated a digital twin in the human biomedical application by proposing a dynamic monitoring system of the upper limb force. In this system, the real upper limb drives the motion of the virtual one in real-time and dynamically updates the force. Meanwhile, the virtual upper limb feeds back the monitoring-results of the force to the controller of the real upper limb via immersive virtual reality interaction. Experimental results of the typical motions of the upper limb revealed that the proposed system functioned interactively in real-time in a non-invasive manner, while ensuring the accurate solving of the muscle force. In conclusion, our digital twin-driven system is of great importance for rehabilitation medicine, biomechanical scientific research and physical training, promoting the application of the digital twin in the human biomedical field.

Chronic lead exposure prolongs the immature stages of brown-legged grain mite, Aleuroglyphus ovatus, in a long-term population study.

An important aspect of environmental pollution, lead contamination is a widespread problem in several ecosystems. The present study aimed to evaluate the potential effects of low concentration lead stress on the development and reproduction of Aleuroglyphus ovatus. They were fed with artificial diet containing four different concentrations of lead (12.5, 25, 50, and 100 mg/kg). The results showed that there were both accelerating effect of lead (at low concentrations), as well as retarding effects (at high concentrations) on the development of the mite, and lead stress significantly prolonged the immature stages of A. ovatus and this inhibitory effect was greater with greater lead concentrations. The immature stages in the L group were shorter than those in the S group. In the S and L groups, the oviposition periods were significantly longer in the treatments with lower lead concentrations than in the control, while they were significantly shorter in those treatments of higher lead concentrations. Age-specific survival rate (lx) started to decline earlier in the S group, whereas there were no differences between the L group and CK. Age-specific fecundity rate (mx) peaked earlier in the S group than in CK, while mx peaked later in L1 and L2 than in CK. The rm value and net reproduction rate (R0) of treated A. ovatus decreased with increasing lead concentrations. Lower lead concentrations could promote population expansion while higher concentrations could inhibit population size. These results confirmed the developmental effect of lead stress on A. ovatus, highlighting that heavy metal contamination has negative effects on organisms in their natural environment.

The metabolism and detoxification effects of lead exposure on Aleurolyphus ovatus (Acari: Acaridae) via transcriptome analysis.

Aleurolyphus ovatus Troupeau is one of the most predominant species of the Acaridae family worldwide. Recent reports have demonstrated that the accumulation of lead in stored grains and dietary items exceeds the required standards. However, the molecular mechanism of heavy metal stress on mites has not been reported. To understand the mechanism underlying the heavy metal response of A. ovatus, comparative transcriptome analysis was performed in this study using an Illumina high throughput mRNA sequencing (RNA-seq) platform. A. ovatus was fed on artificial diets containing two different concentrations of lead, namely, a low concentration of 12.5 mg/kg (LAO) and a high concentration of 100 mg/kg (HAO), while the mites in the control (NAO) group were not exposed to lead. A total of 44,362 unigenes, with an average length of 1547 bp, were identified. Of these, 996 unigenes were successfully annotated in seven functional databases. The number of differentially expressed genes (DEGs) in A. ovatus under different lead concentrations was compared. In NAO versus LAO group, including 310 up-regulated and 1580 down-regulated DEGs. In NAO versus HAO group, including 3928 up-regulated and 1761 down-regulated DEGs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment indicated that detoxification enzyme genes were significantly expressed in pathways, such as cytochrome P450 foreign body metabolism, glutathione metabolism and drug metabolism-cytochrome pathway. The results of gene annotation and quantitative real-time PCR showed that high concentration of lead significantly stimulated the expression of metabolic detoxification enzyme genes such as glutathione S transferase (GST) and superoxide dismutase (SOD), while low concentration inhibited their expression. This study will provide a basis for the molecular mechanism of A. ovatus in response to heavy metal lead stimulation in stored grain.

Sizable spin-to-charge conversion in PLD-grown amorphous (Mo, W)Te2-xfilms.

We report on the spin-to-charge conversion (SCC) in Mo0.25W0.75Te2-x(MWT)/Y3Fe5O12(YIG) heterostructures at room temperature. The centimeter-scale amorphous MWT films are deposited on liquid-phase-epitaxial YIG by pulsed laser deposition technique. The significant SCC voltage is measured in the MWT layer with a sizable spin Hall angle of ∼0.021 by spin pumping experiments. The control experiments by inserting MgO or Ag layer between MWT and YIG show that the SCC is mainly attributed to the inverse spin Hall effect rather than the thermal or interfacial Rashba effect. Our work provides a novel spin-source material for energy-efficient topological spintronic devices.

Metabolic Mechanism and Physiological Role of Glycerol 3-Phosphate in Pseudomonas aeruginosa PAO1.

Pseudomonas aeruginosa is an important opportunistic pathogen that is lethal to cystic fibrosis (CF) patients. Glycerol generated during the degradation of phosphatidylcholine, the major lung surfactant in CF patients, could be utilized by P. aeruginosa. Previous studies have indicated that metabolism of glycerol by this bacterium contributes to its adaptation to and persistence in the CF lung environment. Here, we investigated the metabolic mechanisms of glycerol and its important metabolic intermediate glycerol 3-phosphate (G3P) in P. aeruginosa PAO1. We found that G3P homeostasis plays an important role in the growth and virulence factor production of P. aeruginosa PAO1. The G3P accumulation caused by the mutation of G3P dehydrogenase (GlpD) and exogenous glycerol led to impaired growth and reductions in pyocyanin synthesis, motilities, tolerance to oxidative stress, and resistance to kanamycin. Transcriptomic analysis indicates that the growth retardation caused by G3P stress is associated with reduced glycolysis and adenosine triphosphate (ATP) generation. Furthermore, two haloacid dehalogenase-like phosphatases (PA0562 and PA3172) that play roles in the dephosphorylation of G3P in strain PAO1 were identified, and their enzymatic properties were characterized. Our findings reveal the importance of G3P homeostasis and indicate that GlpD, the key enzyme for G3P catabolism, is a potential therapeutic target for the prevention and treatment of infections by this pathogen. IMPORTANCE In view of the intrinsic resistance of Pseudomonas aeruginosa to antibiotics and its potential to acquire resistance to current antibiotics, there is an urgent need to develop novel therapeutic options for the treatment of infections caused by this bacterium. Bacterial metabolic pathways have recently become a focus of interest as potential targets for the development of new antibiotics. In this study, we describe the mechanism of glycerol utilization in P. aeruginosa PAO1, which is an available carbon source in the lung environment. Our results reveal that the homeostasis of glycerol 3-phosphate (G3P), a pivotal intermediate in glycerol catabolism, is important for the growth and virulence factor production of P. aeruginosa PAO1. The mutation of G3P dehydrogenase (GlpD) and the addition of glycerol were found to reduce the tolerance of P. aeruginosa PAO1 to oxidative stress and to kanamycin. The findings highlight the importance of G3P homeostasis and suggest that GlpD is a potential drug target for the treatment of P. aeruginosa infections.

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.

Long-Term Accuracy Enhancement of Binary Neural Networks Based on Optimized Three-Dimensional Memristor Array.

In embedded neuromorphic Internet of Things (IoT) systems, it is critical to improve the efficiency of neural network (NN) edge devices in inferring a pretrained NN. Meanwhile, in the paradigm of edge computing, device integration, data retention characteristics and power consumption are particularly important. In this paper, the self-selected device (SSD), which is the base cell for building the densest three-dimensional (3D) architecture, is used to store non-volatile weights in binary neural networks (BNN) for embedded NN applications. Considering that the prevailing issues in written data retention on the device can affect the energy efficiency of the system's operation, the data loss mechanism of the self-selected cell is elucidated. On this basis, we introduce an optimized method to retain oxygen ions and prevent their diffusion toward the switching layer by introducing a titanium interfacial layer. By using this optimization, the recombination probability of Vo and oxygen ions is reduced, effectively improving the retention characteristics of the device. The optimization effect is verified using a simulation after mapping the BNN weights to the 3D VRRAM array constructed by the SSD before and after optimization. The simulation results showed that the long-term recognition accuracy (greater than 105 s) of the pre-trained BNN was improved by 24% and that the energy consumption of the system during training can be reduced 25,000-fold while ensuring the same accuracy. This work provides high storage density and a non-volatile solution to meet the low power consumption and miniaturization requirements of embedded neuromorphic applications.

The Transcriptome Characteristics of Severe Asthma From the Prospect of Co-Expressed Gene Modules.

Rationale: Severe asthma is a heterogeneous disease with multiple molecular mechanisms. Gene expression studies of asthmatic bronchial epithelial cells have provided biological insights and underscored possible pathological mechanisms; however, the molecular basis in severe asthma is still poorly understood. Objective: The objective of this study was to identify the features of asthma and uncover the molecular basis of severe asthma in distinct molecular phenotype. Methods: The k-means clustering and differentially expressed genes (DEGs) were performed in 129 asthma individuals in the Severe Asthma Research Program. The DEG profiles were analyzed by weighted gene co-expression network analysis (WGCNA), and the expression value of each gene module in each individual was annotated by gene set variation analysis (GSVA). Results: Expression analysis defined five stable asthma subtype (AS): 1) Phagocytosis-Th2, 2) Normal-like, 3) Neutrophils, 4) Mucin-Th2, and 5) Interferon-Th1 and 15 co-expressed gene modules. "Phagocytosis-Th2" enriched for receptor-mediated endocytosis, upregulation of Toll-like receptor signal, and myeloid leukocyte activation. "Normal-like" is most similar to normal samples. "Mucin-Th2" preferentially expressed genes involved in O-glycan biosynthesis and unfolded protein response. "Interferon-Th1" displayed upregulation of genes that regulate networks involved in cell cycle, IFN gamma response, and CD8 TCR. The dysregulation of neural signal, REDOX, apoptosis, and O-glycan process were related to the severity of asthma. In non-TH2 subtype (Neutrophils and Interferon-Th1) with severe asthma individuals, the neural signals and IL26-related co-expression module were dysregulated more significantly compared to that in non-severe asthma. These data infer differences in the molecular evolution of asthma subtypes and identify opportunities for therapeutic development. Conclusions: Asthma is a heterogeneous disease. The co-expression analysis provides new insights into the biological mechanisms related to its phenotypes and the severity.

Assessing the impacts of differential depositional settings and/or anthropogenic perturbations on sulfur and iron diagenesis in sediments of the Bohai Sea and North Yellow Sea.

Natural processes and human activities exert important impacts on elemental cycling in coastal sediments, which has not been well documented. Sediments in the Bohai Sea and North Yellow Sea were investigated to assess the impacts of the Yellow River inputs and/or anthropogenic perturbations on diagenesis of iron and sulfur. Labile iron (0.5 M HCl-extractable iron) in the sediments is low due to iron-poor nature of source materials. Dynamic regimes and low availability of labile organic carbon (OC) result in relatively low sulfide contents in deltaic sediments. However, low but continuous supply of labile OC exported from an anthropogenically impacted bay could substantially elevate sulfide burial in sediments near the bay. Neither offshore oil exploitations nor frequent algal blooms in the seas have detectable influences on iron and sulfur diagenesis in the sediments. The sediments are capable of quickly consuming porewater sulfide by reaction with reactive iron under the current conditions.

Electrochemically Enabled, Nickel-Catalyzed Dehydroxylative Cross-Coupling of Alcohols with Aryl Halides.

As alcohols are ubiquitous throughout chemical science, this functional group represents a highly attractive starting material for forging new C-C bonds. Here, we demonstrate that the combination of anodic preparation of the alkoxy triphenylphosphonium ion and nickel-catalyzed cathodic reductive cross-coupling provides an efficient method to construct C(sp2)-C(sp3) bonds, in which free alcohols and aryl bromides-both readily available chemicals-can be directly used as coupling partners. This nickel-catalyzed paired electrolysis reaction features a broad substrate scope bearing a wide gamut of functionalities, which was illustrated by the late-stage arylation of several structurally complex natural products and pharmaceuticals.

[A Thyroid Ultrasound Image-based Artificial Intelligence Model for Diagnosis of Central Compartment Lymph Node Metastasis in Papillary Thyroid Carcinoma].

Objective To establish an artificial intelligence model based on B-mode thyroid ultrasound images to predict central compartment lymph node metastasis(CLNM)in patients with papillary thyroid carcinoma(PTC). Methods We retrieved the clinical manifestations and ultrasound images of the tumors in 309 patients with surgical histologically confirmed PTC and treated in the First Medical Center of PLA General Hospital from January to December in 2018.The datasets were split into the training set and the test set.We established a deep learning-based computer-aided model for the diagnosis of CLNM in patients with PTC and then evaluated the diagnosis performance of this model with the test set. Result The accuracy,sensitivity,specificity,and area under receiver operating characteristic curve of our model for predicting CLNM were 80%,76%,83%,and 0.794,respectively. Conclusion Deep learning-based radiomics can be applied in predicting CLNM in patients with PTC and provide a basis for therapeutic regimen selection in clinical practice.

Study on the Methods of Separation and Detection of Chelates.

The separation and purification techniques of chelates can improve the accuracy of detecting results of the chelation rate. As a quantitative indicator of metal ion chelates, the chelation rate can not only reflect the completion of chelation but also determine the amount of metal ions in different forms. The determination of chelation rate can help to determine the suitable chelating reaction conditions, make theoretical basis for the fertilizer efficiency, analyze the stability of chelating fertilizers and study the action mechanism of trace elements. In our study, the methods of separation free metal ions from mixture were reviewed first, including gel filtration chromatography, organic solvent precipitation, ion exchange chromatography, membrane separation and high performance liquid chromatography. Then, the qualitative analysis methods of chelates were introduced briefly, including chemical identification, infrared spectroscopy, ultraviolet spectroscopy. A detailed overview of the quantitative determination methods of chelates were also shown, such as ethylenediaminetetraacetic acid titration, chemical titration, atomic absorption spectrometry, inductively coupled plasma atomic emission spectrometry, inductively coupled plasma mass spectrometry, spectrophotometric, chemical modified electrode. In addition, the merits and demerits of chelated rate determination methods of various determination methods were analyzed, and summarized the applicability of various methods, which provided a theoretical basis for optimizing chelating process, characterizing the structure of chelates and analyzing the mechanism of chelating fertilizer. The current methods of measuring chelation rate were also summarized and prospected.

[Research Advances on Combination Strategies of Demethylating Agents for Elderly Acute Myeloid Leukemia--Review].

Abstract　　 Demethylating agents (HMAs) hold an important status in therapy for elderly acute myeloid leukemia, who are not eligible for intensive chemotherapy (ICT). Beyond the edge of monotherapy, domestic and foreign scholars have carried out a lot of studies on combination strategies, such as HMAs with low-intensity therapy (G-CSF, low-dose cytarabine and aclarubicin, CAG), with targeted therapy (BCL-2 inhibitor), with immunotherapy (immune checkpoint inhibitors, ICI), and with other epigenetic therapys (isocitrate dehydrogenase or histonedeacetylase inhibitor）. Some of these researches have obtained positive results and discussed the mechanisms of combination strategies besides. In this review, the combination of HMAs with other drugs are summraized briefly.

[Expression of survivin in patients with acute myeloid leukemia].

Objective of this study was to detect the expression of Survivin in acute myeloid leukemia (AML) and investigate the relationship of its expression levels with clinical variates and its correlations with BCL-2 ,Bcl-xL and MCL-1. The expression of Survivin, BCL-2, Bcl-xL and MCL-1 were measured by immunohistochemistry in bone marrow biopsy of 63 newly diagnosed AML patients, and the relationship between its expression level and clinical parameters (age, sex, WBC count, diagnosis, prognosis), especially fusion protein AML1/ETO was investigated. The results showed that the expression level of Survivin in newly diagnosed AML patients was higher than that of normal controls (P < 0.01), the expression levels of Survivin did not correlate with age, sex, and WBC counts of patients and so on. There was no significant difference of Survivin expression between different NCCN prognosis groups, either between patients with AML1/ETO or FLT3-ITD mutation and the other patients. Survivin positive patients were got to have lower CR rate but higher relapse rate, however that was not significant in statistics. Indeed, the cumulative survivin rate of Survivin positive patients were lower than that of Survivin negative patients (P = 0.04). Finally, positive correlation between Survivin and MCL-1 was also observed (r = 0.639, P = 0.000). It is concluded that overexpression of Survivin are closely related with occurrence and development of acute leukemia, and may be used as an indicator of prognosis evaluation. In addition, Survivin and MCL-1 may have a relationship of cooperation or interaction.

[Effect of cyclophosphamide on murine bone marrow hematopoietic cells and its possible mechanism].

This study was purposed to investigate the effect of chemotherapeutic drug cyclophosphamide (CTX) on normal murine bone marrow hematopoietic cells, especially on the self-renewal, proliferation and differentiation of bone marrow hematopoietic cells, and possible mechanisms. The CTX-treated mouse model was established by CTX 200 mg/kg, ip. The exact time of complete recovery of hematopoiesis was determined by monitoring the recovery level of differential blood counts and the proportion of LKS(+) cells in bone marrow cells. The function of bone marrow hematopoietic cells such as self-renewal, proliferation and differentiation were assessed by non-competitive and competitive bone marrow transplantation. The potential effect of CTX on senescence of bone marrow hematopoietic cells was analyzed by detecting p16(Ink4a) mRNA relative expression and SA-ß-galactosidase (gal) staining. The results showed that the CTX could induce long-term but latent damage to bone marrow hematopoietic cell function and lead to the decrease in competency of bone marrow hematopoietic cells to reconstitute while seemingly permitting a complete recovery. Furthermore, the serial-transplantation model showed that these mice received transplantation of bone marrow hematopoietic cells from CTX-treated mice exhibited a high expression of p16(Ink4a) mRNA and SA-ß-gal staining. It is concluded that CTX-induced bone marrow cellular senescence may play an important role in CTX-induced long-term injury to bone marrow hematopoietic cells.