Acidic/hypoxia dual-alleviated nanoregulators for enhanced treatment of tumor chemo-immunotherapy

Chemotherapy plays a crucial role in triple-negative breast cancer (TNBC) treatment as it not only directly kills cancer cells but also induces immunogenic cell death. However, the chemotherapeutic efficacy was strongly restricted by the acidic and hypoxic tumor environment. Herein, we have successfully formulated PLGA-based nanoparticles concurrently loaded with doxorubicin (DOX), hemoglobin (Hb) and CaCO3 by a CaCO3-assisted emulsion method, aiming at the effective treatment of TNBC. We found that the obtained nanomedicine (DHCaNPs) exhibited effective drug encapsulation and pH-responsive drug release behavior. Moreover, DHCaNPs demonstrated robust capabilities in neutralizing protons and oxygen transport. Consequently, DHCaNPs could not only serve as oxygen nanoshuttles to attenuate tumor hypoxia but also neutralize the acidic tumor microenvironment (TME) by depleting lactic acid, thereby effectively overcoming the resistance to chemotherapy. Furthermore, DHCaNPs demonstrated a notable ability to enhance antitumor immune responses by increasing the frequency of tumor-infiltrating effector lymphocytes and reducing the frequency of various immune-suppressive cells, therefore exhibiting a superior efficacy in suppressing tumor growth and metastasis when combined with anti-PD-L1 (αPD-L1) immunotherapy. In summary, this study highlights that DHCaNPs could effectively attenuate the acidic and hypoxic TME, offering a promising strategy to figure out an enhanced chemo-immunotherapy to benefit TNBC patients.

中国云南新草露尾甲属一新种和二新记录种记述(鞘翅目:露尾甲科)

记述采自中国云南的新草露尾甲属1新种双点新草露尾甲Neopallodes bipunctatus sp. nov.和2中国新记录种,太阳新草露尾甲NeopallodessolarisKirejtshuk,1987rec.nov.和近齿新草露尾甲Neopallodes subdentatus Kirejtshuk, 1994 rec. nov.,提供3个种的整体图和特征图。并提供了该属的中国名录。

Photosynthetic Toxicity and Oxidative Damage Induced by nano-Fe3O4 on <i>Chlorella vulgaris</i>in Aquatic Environment

With the rapid development of nanotechnology and widespread use of nanoproducts, concerns have arisen regarding the ecotoxicity of these materials. In this paper, the photosynthetic toxicity and oxidative damage induced by nano Fe3O4 on a model organism, Chlorella vulgaris (C. vulgaris) in aquatic environment, were studied. The results showed that Nano-Fe3O4 was toxic to C. vulgaris and affected its content of chlorophyll a, malonaldehyde and glutathione, CO2 absorption, net photosynthetic rate, superoxide dismutase activity and inhibition of hydroxyl radical generation. At higher concentrations, compared with the control group, the toxicity of nano-Fe3O4 was significantly different. It suggested that nano-Fe3O4 is ecotoxic to C. vulgaris in aquatic environment.

Generation of Hepatitis B virus PreS2-S antigen in Hansenula polymorpha

Despite the long availability of a traditional prophylactic vaccine containing the HBV surface antigen(HBsA g) and aluminum adjuvant, nearly 10% of the population remains unable to generate an effective immune response. Previous studies have indicated that hepatitis B virus(HBV) PreS 2-S is abundant in T/B cell epitopes, which induces a stronger immune response than HBsA g, particularly in terms of cytotoxic T lymphocyte(CTL) reaction. In the current study, the HBV PreS 2-S gene encoding an extra26 amino acids(PreS 2 C-terminus) located at the N-terminus of HBsA g was cloned into the pV CH1300 expression vector. Pre S2-S expressed in the methylotrophic yeast, Hansenula polymorpha, was produced at a yield of up to 250 mg/L. Subsequent purification steps involved hydrophobic adsorption to colloidal silica, ion-exchange chromatography and density ultracentrifugation. The final product was obtained with a total yield of ~15% and purity of ~99%. In keeping with previous studies, ~22 nm viruslike particles were detected using electron microscopy. The generated PreS 2-S antigen will be further studied for efficacy and safty in animals.

Fucoidan-based dual-targeting mesoporous polydopamine for enhanced MRI-guided chemo-photothermal therapy of HCC via P-selectin-mediated drug delivery

The development of novel theranostic agents with outstanding diagnostic and therapeutic performances is still strongly desired in the treatment of hepatocellular carcinoma(HCC).Here,a fucoidan-modified mesoporous polydopamine nanoparticle dual-loaded with gadolinium iron and doxorubicin(FMPDA/Gd^(3+)/DOX)was prepared as an effective theranostic agent for magnetic resonance imaging(MRI)-guided chemo-photothermal therapy of HCC.It was found that FMPDA/Gd^(3+)/DOX had a high photothermal conversion efficiency of 33.4%and excellent T1-MRI performance with a longitudinal relaxivity(r1)value of 14.966 m M^(-1)·s^(-1).Moreover,the results suggested that FMPDA/Gd^(3+)/DOX could effectively accumulate into the tumor foci by dual-targeting the tumor-infiltrated platelets and HCC cells,which resulted from the specific interaction between fucoidan and overexpressed p-selectin receptors.The excellent tumor-homing ability and MRI-guided chemo-photothermal therapy therefore endowed FMPDA/Gd^(3+)/DOX with a strongest ability to inhibit tumor growth than the respective single treatment modality.Overall,our study demonstrated that FMPDA/Gd^(3+)/DOX could be applied as a potential nanoplatform for safe and effective cancer theranostics.

ACBP4-WRKY70-RAP2.12 module positively regulates submergence-induced hypoxia response in Arabidopsis thaliana

ACYL-CoA-BINDING PROTEINs(ACBPs)play crucial regulatory roles during plant response to hypoxia,but their molecular mechanisms remain poorly understood.Our study reveals that ACBP4 serves as a positive regulator of the plant hypoxia response by interacting with WRKY70,influencing its nucleocytoplasmic shuttling in Arabidopsis thaliana.Furthermore,we demonstrate the direct binding of WRKY70 to the ACBP4 promoter,resulting in its upregulation and suggesting a positive feedback loop.Additionally,we pinpointed a phosphorylation site at Ser638 of ACBP4,which enhances submergence tolerance,potentially by facilitating WRKY70's nuclear shuttling.Surprisingly,a natural variation in this phosphorylation site of ACBP4 allowed A.thaliana to adapt to humid conditions during its historical demographic expansion.We further observed that both phosphorylated ACBP4 and oleoyl-Co A can impede the interaction between ACBP4 and WRKY70,thus promoting WRKY70's nuclear translocation.Finally,we found that the overexpression of orthologous Bna C5.ACBP4and Bna A7.WRKY70 in Brassica napus increases submergence tolerance,indicating their functional similarity across genera.In summary,our research not only sheds light on the functional significance of the ACBP4 gene in hypoxia response,but also underscores its potential utility in breeding flooding-tolerant oilseed rape varieties.

Chronomodulated chemotherapy for locoregionally advanced nasopharyngeal carcinoma:A phase Ⅱ randomized controlled trial

Objective:To validate the safety and efficacy of chronochemotherapy for locoregionally advanced nasopharyngeal carcinoma(NPC).Methods:Participants for this phase II randomized controlled trial were recruited from the Department of Head and Neck Oncology at the Affiliated Cancer Hospital of Guizhou Medical University.Patients enrolled(128 in total,112 in the final analysis)between April 1,2017,and February 28,2018,were randomly divided into the chronochemotherapy and conventional chemotherapy groups.In the chronochemotherapy group,docetaxel was intravenously administered between 3:30 a.m.and 4:30 a.m.on day 1,followed by intravenous administration of cisplatin between 10:00 a.m.and 10:00 p.m.from day 1to day 5.In addition,5-fluorouracil was administered through a continuous intravenous pump between 10:00 p.m.and 10:00 a.m.(2nd day)from day 1 to day 5.In the conventional chemotherapy group,docetaxel(on day 1),cisplatin(on day 2),and 5-fluorouracil(from day 1 to day 5,120 h in total)were administered without time-specific constraints.Both groups underwent intensitymodulated radiation therapy with 6-MV X-rays.The gross target volume(GTV)comprised the nasopharyngeal GTV and cervical lymph node GTV.The primary endpoint was immune function,quantified by measuring dendritic cell and lymphocyte subsets,whereas the secondary endpoints were therapeutic efficacy and incidence of adverse events.Pearson Chi-square test was applied to compare total events between the groups,Mann-Whitney U test was used to compare the DC subsets and toxicities,and Wilcoxon signed-rank test was used to compare the continuous variables between the two groups.Results:Chronochemotherapy preserved immune function,as evidenced by elevated levels of myeloid dendritic cells(P=0.394)and higher CD4/CD8 ratio(P?0.781).No significant difference in overall response rate,measured as the sum of complete and partial response rates,was observed between the groups(P=0.711).A reduction in the incidence of vomiting(P=0.002),stomatitis(P=0.028),and mucositis(P=0.028)was observed in the chronochemotherapy group.Leukopenia incidence rate was 83.3% and 92.3% in the chronochemotherapy and conventional chemotherapy groups,respectively(P=0.232).Conclusions:In patients with locoregionally advanced NPC,the overall response rate of chronochemotherapy is comparable to that of conventional chemotherapy;however,chronochemotherapy shows fewer adverse events.

基于局部泰勒展开的高精度无网格算法

光滑粒子动力学方法(Smoothed Particle Hydrodynamics,SPH)所具备的无网格特性使其摆脱了网格划分过程,在处理复杂几何边界上具有潜在优势。然而,传统SPH受限于空间微分高阶一致性缺失,无法实现高精度求解。本文基于SPH粒子的局部泰勒展开,通过邻域粒子空间矩阵求解,实现了满足高阶一致性的SPH微分算子算法。通过一、二维函数证明了该算法在任意粒子分布中微分2、3、4阶一致性。随后,基于热传导方程、Burgers方程、纳维–斯托克斯方程等偏微分方程证明了该算法求解空间算子的精确性与稳定性。基于局部泰勒展开的SPH算法为无网格方法在复杂几何域的高精度数值求解提供了一种可行方法。

LncRNA与肝脏糖脂代谢的研究进展

长链非编码RNA(Long non-coding RNA,lncRNA)因参与多个层级上的生物进程而成为当下生命科学领域的研究热点。LncRNA可以与DNA、RNA和蛋白质等生物分子结合,并进一步影响靶基因的转录、翻译以及翻译后修饰等过程,从而发挥在细胞生理代谢过程中的调控作用。目前研究显示,lncRNA通过多种途径在肝脏代谢中发挥重要作用。文中以lncRNA的功能及其与肝脏能量代谢和相关疾病的关系为着眼点,阐述了lncRNA发挥作用的机制以及未来的研究前景。

Homoharringtonine is a safe and effective substitute for anthracyclines in children younger than 2 years old with acute myeloid leukemia

Homoharringtonine (HHT),a plant alkaloid from Cephalotaxus harringtonia,exhibits a unique anticancer mechanism and has been widely used in China to treat patients with acute myeloid leukemia (AML) since the 1970s.Trial SCMC-AML-2009 presented herein was a randomized clinical study designed based on our previous findings that pediatric AML patients younger than two years old may benefit from HHT-containing chemotherapy regimens.Patients randomized to arm A were treated with a standard chemotherapy regimen comprising mainly of anthracyclines and cytarabine (Ara-C),whereas patients in arm B were treated with HHTcontaining regimens in which anthracyclines in all but the initial induction therapy were replaced by HHT.From February 2009 to November 2015,59 patients less than 2 years old with de novo AML (other than acute promyelocytic leukemia) were recruited.A total of 42 patients achieved a morphologic complete remission (CR) after the first course,with similar rates in both arms (70.6% vs.72.0%).At the end of the follow-up period,40 patients remained in CR and 5 patients underwent hematopoietic stem cell transplantation in CR,which could not be considered as events but censors.The 5-year event-free survival (EFS) was 60.2%± 9.6% for arm A and 88.0%± 6.5% for arm B (P=0.024).Patients in arm B experienced shorter durations of leukopenia,neutropenia,and thrombocytopenia and had a lower risk of infection during consolidation chemotherapy with high-dosage Ara-C.Consequently,the homoharringtonine-based regimen achieved excellent EFS and alleviated hematologic toxicity for children aged younger than 2 years with de novo AML compared with the anthracycline-based regimen.

Fiber-Optic Fabry-Perot Hydrogen Sensor Coated With Pd-Y Film

A fiber-optic Fabry-Perot hydrogen sensor was developed by measuring the fringe contrast changes at different hydrogen concentrations. The experimental results indicated that the sensing performance with the Pd-Y film was better than that with the Pd film. A fringe contrast with a decrease of 0.5 dB was detected with a hydrogen concentration change from 0% to 5.5%. The temperature response of the sensor was also measured.

The innovations in China’s primary health care reform: Development and characteristics of the community health services in Hangzhou

Objective:This study focuses on Hangzhou,a Chinese city with a population of nine million urban and rural residents,to examine the successful development and innovation experience of its primary health care service system during the new health reform in China since 2009 and then dis-seminate the findings through international third parties.Methods:Measures such as data analysis,study of documents and regulations,fieldwork,and expert discussions were used to systematically investigate primary health care in Hangzhou.The findings will have a profound practical impact on the health reform for nine million rural and urban residents throughout Hangzhou’s municipal boroughs.Results:Community health services in Hangzhou are characterized as follows:They are gov-ernment led;they are guaranteed with enough financing,personnel,facilities,and regulation;sup-ported by the unified information platform;general practitioners have been assigned the key role of health‘gatekeepers’;they provide primary care combined with basic public health services;there are integrated urban and rural health services and insurance coverage;and there is health care-pen-sion-nursing integration and general practitioner-contracted‘smart’services.Preliminary data collection and analysis indicate that the basic health status of Hangzhou residents is superior to that of residents of China as a whole,and some health indicators in Hangzhou are comparable to those in Western developed countries.Conclusion:It is reasonable to believe that the primary health care level in China,including Hangzhou,will be further developed and promoted with indexed performance evaluations and more effective implementation of additional measures.

Simultaneous Force and Temperature Measurement Using Optical Microfiber Asymmetrical Interferometer

A novel optical microfiber asymmetric Fabry-Perot interferometric （MAFPI） sensor is developed for simultaneous measurement of force and temperature. The MAFPI structure is formed by a weak fiber Bragg grating （FBG）, a section of the microfiber, and a cleaved fiber end surface. The narrowband beam reflected from the low-reflectivity FBG and the broadband beam from the Fresnel reflection interfere lead to its unique sensing performance. The force sensing is performed by detecting the bending-loss induced fringe contrast changes, while the Bragg wavelength shift is employed for temperature measurement. Sensitivities of 9.8pm/℃ and 0.025dB/μN were obtained experimentally for temperature and force measurements, respectively.