Efficacy and safety of low-dose cyclophosphamide combined with lenvatinib, pembrolizumab and TACE for unresectable hepatocellular carcinoma:A single-center, prospective,single-arm clinical trial

Objective: Unresectable hepatocellular carcinoma(uHCC) continues to pose effective treatment options. The objective of this study was to assess the efficacy and safety of combining low-dose cyclophosphamide with lenvatinib, pembrolizumab and transarterial chemoembolization(TACE) for the treatment of uHCC.Methods: From February 2022 to November 2023, a total of 40 patients diagnosed with uHCC were enrolled in this small-dose, single-center, single-arm, prospective study. They received a combined treatment of low-dose cyclophosphamide with lenvatinib, pembrolizumab, and TACE. Study endpoints included progression-free survival(PFS), objective response rate(ORR), and safety assessment. Tumor response was assessed using the modified Response Evaluation Criteria in Solid Tumors(mRECIST), while survival analysis was conducted through KaplanMeier curve analysis for overall survival(OS) and PFS. Adverse events(AEs) were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events(version 5.0).Results: A total of 34 patients were included in the study. The median follow-up duration was 11.2 [95% confidence interval(95% CI), 5.3-14.6] months, and the median PFS(mPFS) was 15.5(95% CI, 5.4-NA) months.Median OS(mOS) was not attained during the study period. The ORR was 55.9%, and the disease control rate(DCR) was 70.6%. AEs were reported in 27(79.4%) patients. The most frequently reported AEs(with an incidence rate >10%) included abnormal liver function(52.9%), abdominal pain(44.1%), abdominal distension and constipation(29.4%), hypertension(20.6%), leukopenia(17.6%), constipation(17.6%), ascites(14.7%), and insomnia(14.7%). Abnormal liver function(14.7%) had the most common grade 3 or higher AEs.Conclusions: A combination of low-dose cyclophosphamide with lenvatinib, pembrolizumab, and TACE is safe and effective for u HCC, showcasing a promising therapeutic strategy for managing uHCC.

Synaptic Transmission of Primary Hippocampal Neurons was Enhanced after Terahertz Waves Exposure

Terahertz(THz)waves,also known as T-rays,encompass frequencies ranging from 0.1 to 10 THz and possess unique properties that render them applicable in various biomedical domains,particularly in neurobiology[1].Synaptic transmission,the process through which signals propagate between neurons at synapses,is pivotal for brain function and information processing.

Advancements in understanding mechanisms of hepatocellular carcinoma radiosensitivity:A comprehensive review

Primary liver cancer is a significant health problem worldwide.Hepatocellular carcinoma(HCC)is the main pathological type of primary liver cancer,accounting for 75%-85%of cases.In recent years,radiotherapy has become an emerging treatment for HCC and is effective for various stages of HCC.However,radiosensitivity of liver cancer cells has a significant effect on the efficacy of radiotherapy and is regulated by various factors.How to increase radiosensitivity and improve the therapeutic effects of radiotherapy require further exploration.This review summarizes the recent research progress on the mechanisms affecting sensitivity to radiotherapy,including epigenetics,transportation and metabolism,regulated cell death pathways,the microenvironment,and redox status,as well as the effect of nanoparticles on the radiosensitivity of liver cancer.It is expected to provide more effective strategies and methods for clinical treatment of liver cancer by radiotherapy.

Enhanced vibrational resonance in a single neuron with chemical autapse for signal detection

Many animals can detect the multi-frequency signals from their external surroundings.The understanding for underlying mechanism of signal detection can apply the theory of vibrational resonance,in which the moderate high frequency driving can maximize the nonlinear system's response to the low frequency subthreshold signal.In this work,we study the roles of chemical autapse on the vibrational resonance in a single neuron for signal detection.We reveal that the vibrational resonance is strengthened significantly by the inhibitory autapse in the neuron,while it is weakened typically by the excitatory autapse.It is generally believed that the inhibitory synapse has a suppressive effect in neuronal dynamics.However,we find that the detection of the neuron to the low frequency subthreshold signal can be improved greatly by the inhibitory autapse.Our finding indicates that the inhibitory synapse may act constructively on the detection of weak signal in the brain and neuronal system.

The Contribution of Mesoscale Convective Systems to Intense Hourly Precipitation Events during the Warm Seasons over Central East China

Central East China is an area where both intense hourly precipitation（IHP） events and mesoscale convection systems（MCSs） occur frequently in the warm seasons. Based on mosaics of composite Doppler radar reflectivity and hourly precipitation data during the warm seasons（May to September） from 1 July 2007 to 30 June 2011, the contribution of MCSs to IHP events exceeding 20 mm h^-1 over central East China was evaluated. An MCS was defined as a continuous or quasicontinuous band of 40d BZ reflectivity that extended for at least 100 km in at least one direction and lasted for at least 3h. It was found that the contribution of MCSs to IHP events was 45% on average over central East China. The largest contribution,more than 80%, was observed along the lower reaches of the Yellow River and in the Yangtze River–Huaihe River valleys.These regions were the source regions of MCSs, or along the frequent tracks of MCSs. There were two daily peaks in the numbers of IHP events： one in the late afternoon and one in the early morning. These peaks were more pronounced in July than in other months. MCSs contributed more to the early-morning IHP event peaks than to the late-afternoon peaks. The contributions of MCSs to IHP events with different intensities exhibited no significant difference, which fluctuated around 50% on average over central East China.

Hsa-miR-214-3p inhibits breast cancer cell growth and improves the tumor immune microenvironment by downregulating B7H3

Background:Immune checkpoint inhibitors play an important role in the treatment of solid tumors,but the currently used immune checkpoint inhibitors targeting programmed cell death-1(PD-1),programmed cell death ligand-1(PD-L1),and cytotoxic T-lymphocyte antigen-4(CTLA-4)show limited clinical efficacy in many breast cancers.B7H3 has been widely reported as an immunosuppressive molecule,but its immunological function in breast cancer patients remains unclear.Methods:We analyzed the expression of B7H3 in breast cancer samples using data from the Cancer Genome Atlas Program(TCGA)and the Gene Expression Omnibus(GEO)databases.MicroRNAs were selected using the TarBase,miRTarBase,and miRBase databases.The regulatory role of the microRNA hsa-miR-214-3p on B7H3 was investigated through dual-luciferase reporter assays,which identified the specific action sites of interaction.The expression levels of B7H3 and hsa-miR-214-3p in human breast cancer tissues and adjacent normal tissues were quantified using Western blotting and quantitative PCR(qPCR).In vitro experiments were performed to observe the effects of modulating the expression of B7H3 or hsa-miR-214-3p on breast cancer cell proliferation and apoptosis.Additionally,the regulatory impact of hsa-miR-214-3p on B7H3 was examined.Enzyme-linked immunosorbent assays(ELISA)and flow cytometry were employed to assess the effects of co-cultured breast cancer cells and normal human peripheral blood mononuclear cells(PBMCs)on immune cells and associated cytokines.Results:In breast cancer tissues,the expression level of B7H3 is inversely correlated with that of hsa-miR-214-3p,as well as with the regulatory effects on breast cancercell behavior.Hsa-miR-214-3p was found to inhibit breast cancer cell growth by downregulating B7H3.Importantly,our research identified,for the first time,two binding sites for hsa-miR-214-3p on the 3’UTR of B7H3,both of which exert similar effects independently.Co-culture experiments revealed that hsamiR-214-3p obstructs the suppressive function of B7H3 on CD8^(+)T cells and natural killer cells.Conclusions:This study confirms the existence of two hsa-miR-214-3p binding sites on the 3’UTR of B7H3,reinforcing the role of hsamiR-214-3p as a regulatory factor for B7H3.In breast cancer,hsa-miR-214-3p reduces tumor cell proliferation and enhances the tumor immune microenvironment by downregulating B7H3.These findings suggest new potential targets for the clinical treatment of breast cancer.

叶片多尺度表面对压气机气动性能影响及其高性能制造研究进展

叶片几何形状误差精细化控制、表面波纹度控制和布置合理的介微观仿生减阻结构是提升压气机叶片气动性能的有效手段,也是目前新一代航空发动机重点关注的方向之一。这类结构通常几何形状复杂,制造难度较大。首先,综述了叶片几何形状误差、表面波纹度和介微观仿生减阻结构等不同尺度的表面特征对流场特性的改变以及不同尺度的表面结构特征对压气机气动性能的影响规律,分析了多尺度表面的制造工艺及其最新进展。其次,引出了气动性能约束下的压气机叶片高性能制造中对几何形状公差范围、表面波纹度以及介微观仿生结构制造技术的要求。最后,结合多尺度表面高性能制造发展现状,对进一步提升压气机叶片气动性能的研究内容与发展方向进行了展望。

Hyaluronidase-triggered anticancer drug and siRNA delivery from cascaded targeting nanoparticles for drug- resistant breast cancer therapy

Drug resistance renders standard chemotherapy ineffective in the treatment of connective tissue growth factor （CTGF）-overexpressing breast cancer. By co-embedding the breast tumor cell-penetrating peptide （PEGA-pVEC） and hyaluronic acid （HA） as a targeting media, novel cascaded targeting nanoparficles （HACT NPs） were created on a rattle mesoporous silica （rmSiO2） scaffold for the pinpoint delivery of siRNAs along with an anticancer drug, aiming at overcoming the drug resistance of CTGF-overexpressing breast cancer in vivo. The targeting nanoparticles selectively accumulated in the vasculature under the guidance of the PEGA-pVEC peptide, cascaded by receptor-mediated endocytosis with the aid of another targeting agent, HA, presenting a greater in vivo tumor targeting ability than single targeting ligand vectors. In addition, an HA shell prevented the leakage of therapeutic drugs during the cargo transport process, until the hyaluronidase （HAase）-triggered degradation upon lysosomes entering, guaranteeing a controllable drug release inside the target cells. When the protective shell disintegrates, the released siRNA took charge to silence the gene associated with drug resistance, CTGF, thus facilitating doxorubicin-induced apoptosis. The cascaded targeting media （PEGA-pVEC and HA） advances precision-guided therapy in vivo, while the encapsulation of siRNAs into a chemotherapy drug delivery system provides an efficient strategy for the treatment of drug resistance cancers.

Optimal configuration for vibration frequencies in a ring of harmonic oscillators： The nonidentical mass effect

The parameter diversity effect in coupled nonidentical elements has attracted persistent interest in nonlinear dynamics. Of fundamental importance is the so-called optimal configuration problem for how the spatial position of elements with different parameters precisely determines the dynamics of the whole system. In this work, we study the optimal configuration problem for the vibration spectra in the classical mass-spring model with a ring configuration, paying particular attention to how the configuration of different masses affects the second smallest vibration frequency （ω2） and the largest one （ωN）. For the extreme values of ω2 and ωN, namely, （ω2）min, （ω2）max, （ωN）min, and （ωN）max, we find some explicit organization rules for the optimal configurations and some approximation rules when the explicit organization rules are not available. The different distributions of ω2 and ωN are compared. These findings are interesting and valuable for uncovering the underlying mechanism of the parameter diversity effect in more general cases.

Time-series variation and attribution analysis of downward shortwave radiation over the Yunnan-Kweichow plateau from 1984 to 2018

The downward shortwave radiation(DSR)is a key input parameter for land surface models and climate models.Based on the daily averaged Global Land Surface Satellite downward shortwave radiation(GLASS-DSR)dataset over the Yunnan-Kweichow Plateau(YKP)from 1984 to 2018,this paper analyzes variation trend and breakpoints of DSR.The results show that:annual averaged DSR decreases at a decreasing rate of-1.84 W·m^(-2)·decade^(-1) over the YKP from 1984 to 2018;the overall distribution of interannual averaged DSR shows higher in the mid-west,and gradually decreasing from west to northeast over the YKP;the estimated averaged DSR is larger in spring than in summer due to the influence of the monsoon;monthly averaged DSR reaches its maximum in May and its minimum in December;breakpoints are found in the seasonal and trend components of daily averaged DSR.Eleven driving factors are examined for their effects on DSR variation,including annual average temperature,precipitation,10 m wind speed,aerosol optical thickness(AOT),total cloud cover,elevation,slope,aspect,longitude,latitude,and climate zones.According to thefindings,AOT predominates in the spatio-temporal distribution of DSR over the YKP.This study will contribute to studies related to climate change and highland radiation.

Retrieval of high spatial resolution mountainous land surface temperature considering topographic and adjacency effects

Land surface temperature(LST) is a key parameter reflecting the interaction between land and atmosphere. Currently,thermal infrared(TIR) quantitative remote sensing technology is the only means to obtain large-scale, high spatial resolution LST. Accurately retrieving high spatial resolution mountainous LST(MLST) plays an important role in the study of mountain climate change. The complex terrain and strong spatial heterogeneity in mountainous areas change the geometric relationship between the surface and satellite sensors, affecting the radiation received by the sensors, and rendering the assumption of planar parallelism invalid. In this study, considering the influence of complex terrain in mountainous areas on atmospheric downward radiation and the thermal radiation contribution of adjacent pixels, a mountainous TIR radiative transfer model based on the sky view factor was developed. Combining with the atmospheric radiative transfer model MODTRAN 5.2, a nonlinear generalized split-window algorithm suitable for high spatial resolution MLST retrieval was constructed and applied to Landsat-9 TIRS-2satellite TIR remote sensing data. The analysis results indicate that neglecting the topographic and adjacency effects would lead to significant discrepancies in LST retrieval, with simulated data showing LST differences of up to 2.5 K. Furthermore, due to the lack of measured MLST in the field, the MLST accuracy obtained by this retrieval method was indirectly validated using the currently recognized highest-accuracy forward 3D radiative transfer model DART. The MLST and emissivity were input into the DART model to simulate the brightness temperature at the top of the atmosphere(TOA) of Landsat-9 band 10, and compared with the brightness temperature at TOA of Landsat-9 band 10. The RMSE(Root Mean Square Error) for the two subregions was0.50 and 0.61 K, respectively, indicating that the method proposed can retrieve high-precision MLST.

Acidity-triggered TAT-presenting nanocarriers augment tumor retention and nuclear translocation of drugs

Hierarchical targeting strategy can combat the sequential drug delivery barriers by changing their properties with response to tumor stimuli. Among these strategies, much less attention has been paid to address the issues of rapid tumor clearance and insufficient cellular translocation. In this work, we demonstrate that a transactivator of transcription （TAT）-presenting nanomedicine （DATAT-NP/Pt）, apart from improving tumor accumulation and cellular uptake, can simultaneously enhance tumor retention and promote nuclear translocation of encapsulated platinum prodrugs, and thus improve therapeutic efficacy. Specifically, a protecting 2,3-dimethylmaleic anhydride （DA） corona on the nanomedicine prevented the TAT peptide from serum. DATAT-NP/Pt efficiently accumulated at the tumor site through the enhanced permeability and retention （EPR） effect, followed by acid-triggered TAT presenting within the tumor acidic microenvironment （pH ~ 6.8）. The exposed TAT peptide augmented tumor retention and nuclear translocation of DATAT-NP/Pt. We used a tumor-on-a-chip microfluidic system to real-time mimic and analyze tumor accumulation and retention at physiological flow conditions and revealed that surface absorption of nanomedicines on tumors was critical in determining their tumor retention and clearance. Furthermore, the TAT peptide rapidly translocated the DATAT-NP/Pt into the perinuclear region, allowing for higher nuclear platinum concentrations and increased Pt-DNA adduct formation in nuclei, which consequently reversed cisplatin resistance. Our work presents a new strategy to overcome path- ophysiological barriers of tumor clearance and insufficient cellular translocation and provides new insights for the design of cancer nanomedicines.

Cloning of a novel gene associated with human nasopharyngeal carcinoma

One EST N27741 with high expression in normal adult nasopharynx tissues but low expression in adult poorly differentiated squamous nasopharyngeal carcinoma has been selected out by the high-density cDNA array expression profiling technique. The differential expression has been confirmed by RT-PCR. One novel gene of 1096 bp has been cloned based on this EST. Bioinformatics analysis found that the new gene sequence contains a whole reading frame encoding 256 amino acids. There is a stop codon TAA in front of the 5’ end start codon, and a tailing signal AATAAA and poly A tail at the 3’ end. There is no homologous known gene found after searching by blasting this sequence to non-redundancy nucleotide database. Therefore it is considered a novel gene related to nasopharyngeal carcinoma.

Profiling gene expression patterns of nasopharyngeal carcinoma and normal nasopharynx tissues with cDNA microarray

5 μg of total RNAs from normal nasopharynx and nasopharyngeal carcinoma tissue have been labeled with α-32P-dCTP during reverse transcription. The synthesized cDNA probes have been hybridized to high-density cDNA microarray containing 5184 genes or expression sequence tags (ESTs). Then image analysis software has been applied to comparing their expression profiles. Results show that 187 ESTs were of density value above 200 in nasopharyngeal carcinoma tissue while there were 307 such ESTs in normal nasopharynx tissue; 38 ESTs were strongly expressed in nasopharynx, but weakly expressed in nasopharyngeal carcinoma; 48 ESTs were strongly expressed in nasopharyngeal carcinoma, but weakly expressed in normal nasopharynx. These results suggest that there may exist some new differentially expressed genes involved in nasopharyngeal carcinoma development. Furthermore, the results strongly indicate that high-density cDNA microarray is a powerful and efficient tool for large-scale screening differentially

Full-color quantum dots active matrix display fabricated by ink-jet printing

Making full-color active matrix display based on quantum dot light emitting diodes(AM-QLEDs) via ink-jet printing is attractive in display industry due to QLEDs' wide color gamut and their potential manufacturing advantages of large screen size and low cost. The challenges for realizing AM-QLED display are how to achieve high quality films through ink-jet printing, multi-color patterning, electroluminescence(EL) color purity, and high efficiency. Herein, a 2-inch diagonal full-color AM-QLEDs display with pixel density of 120 pixels per inch(PPI) fabricated by ink-jet printing technique is presented. Driven by a metal oxide TFT(MOTFT) back-panel, the display exhibits a maximum brightness of 400 cd m.2, and a color gamut of 109%(NTSC 1931). The red, green, and blue(RGB) monochrome QLEDs passive matrix panels fabricated by ink-jet printing technique have a current efficiency(CE) of 2.5, 13.9, and 0.30 cd A.1, respectively. To the best of our knowledge, the efficiencies are the highest among passive matrix QLEDs panels made by ink-jet printing technique. The ink-jet printed QDs films show good thickness uniformity due to high viscosity and low volatility of the printable inks, and no cross-contamination between adjacent pixels resulting from the hydrophobic pixel defining layer.

Constructing backbone network by using tinker algorithm

Revealing how a biological network is organized to realize its function is one of the main topics in systems biology. Tile functional backbone network, defined as the primary structure of the biological network, is of great importance in maintaining the main function of the biological network. We propose a new algorithm, the tinker algorithm, to determine this core structure and apply it in the cell-cycle system. With this algorithm, the backbone network of the cell-cycle network can be determined accurately and efficiently in various models such as the Boolean model, stochastic model, and ordinary differential equation model. Results show that our algorithm is more efficient than that used in the previous research. We hope this method can be put into practical use in relevant future studies.