Clinical Features and Prognostic Factors of Small Cell Lung Cancer:A Retrospective Study in 148 Patients

To better understand the outcomes of small cell lung cancer（SCLC）,we examined the clinical features and prognostic factors of SCLC in this study.A total of 148 patients who were diagnosed as having SCLC between January 2009 and December 2013 in Cancer Center of Union Hospital,Wuhan,China,were enrolled and their clinical features and prognostic factors were retrospectively analyzed.Log-rank test and Cox regression model were employed for analysis of prognostic factors.The 1-and 2-year overall survival（OS） rates were 59.7% and 25.7%,respectively,for limited disease（LD） patients whose median survival time（MST） was 16 months.The 1-and 2-year OS rates were 29.5% and 5.3%,respectively,for extensive disease（ED） patients whose MST was 10 months.The univariate analysis and multivariate analysis revealed that age,tumor stage,serum CEA and Ki-67 antigen were significantly correlated to the outcomes of SCLC,and they were significant prognostic factors for SCLC.

Dual-responsive supramolecular photodynamic nanomedicine with activatable immunomodulation for enhanced antitumor therapy

A major challenge facing photodynamic therapy(PDT) is that the activity of the immuneinduced infiltrating CD8^(+)T cells is subject to the regulatory T lymphocytes(Tregs), leaving the tumor at risk of recurrence and metastasis after the initial ablation. To augment the antitumor response and reprogram the immunosuppressive tumor microenvironment(TME), a supramolecular photodynamic nanoparticle(DACss) is constructed by the host-guest interaction between demethylcantharidin-conjugated β-cyclodextrin(DMC-CD) and amantadine-terminated disulfide-conjugated FFVLGGGC peptide with chlorin e6 decoration(Ad-ss-pep-Ce6) to achieve intelligent delivery of photosensitizer and immunomodulator for breast cancer treatment. The acid-labile β-carboxamide bond of DMC-CD is hydrolyzed in response to the acidic TME, resulting in the localized release of DMC and subsequent inhibition of Tregs.The guest molecule Ad-ss-pep-Ce6 can be cleaved by a high level of intracellular GSH, reducing photosensitizer toxicity and increasing photosensitizer retention in the tumor. With a significant increase in the CTL/Treg ratio, the combination of Ce6-based PDT and DMC-mediated immunomodulation adequately achieved spatiotemporal regulation and remodeling of the TME, as well as improved primary tumor and in situ lung metastasis suppression with the aid of PD-1 antibody.

First-line penpulimab(an anti-PD1 antibody)and anlotinib(an angiogenesis inhibitor)with nab-paclitaxel/gemcitabine(PAAG)in metastatic pancreatic cancer:a prospective,multicentre,biomolecular exploratory,phase II trial

Metastatic pancreatic cancer(mPC)has a dismal prognosis.Herein,we conducted a prospective,multicentre,single-arm,phase II trial evaluating the efficacy and safety of penpulimab and anlotinib in combination with nab-paclitaxel/gemcitabine(PAAG)in patients with first-line mPC(NCT05493995).The primary endpoints included the objective response rate(ORR)and disease control rate(DCR),while secondary endpoints encompassed progression-free survival(PFS),overall survival(OS),and safety.In 66 patients analysed for efficacy,the best response,indicated by the ORR,was recorded at 50.0%(33/66)(95%CI,37.4–62.6%),with 33 patients achieving partial response(PR).Notably,the DCR was 95.5%(63/66,95%CI,87.3–99.1%).The median PFS(mPFS)and OS(mOS)were 8.8(95%CI,8.1–11.6),and 13.7(95%CI,12.4 to not reached)months,respectively.Grade 3/4 treatment-related adverse events(TRAEs)were reported in 39.4%of patients(26/66).In prespecified exploratory analysis,patients with altered SWI/SNF complex had a poorer PFS.Additionally,low serum CA724 level,high T-cell recruitment,low Th17 cell recruitment,and high NK CD56dim cell scores at baseline were potential predicative biomarkers for more favourable efficacy.In conclusion,PAAG as a first-line therapy demonstrated tolerability with promising clinical efficacy for mPC.The biomolecular findings identified in this study possess the potential to guide the precise clinical application of the triple-combo regimen.

In situ tumor vaccine with optimized nanoadjuvants and lymph node targeting capacity to treat ovarian cancer and metastases

Tumor vaccine,a promising modality of tumor immunotherapy,needs to go through the process of tumor antigen generation and loading,antigen drainage to lymph nodes(LNs),antigen internalization by dendritic cells(DCs),DC maturation,and antigen cross-presentation to activate T-cells.However,tumor vaccines are often unable to satisfy all the steps,leading to the limitation of their application and efficacy.Herein,based on a smart nanogel system,an in situ nano-vaccine(CpG@Man-P/Tra/Gel)targeting LNs was constructed to induce potent anti-tumor immune effects and inhibit the recurrence and metastasis of ovarian cancer.The CpG@Man-P/Tra/Gel exhibited MMP-2-sensitive release of trametinib(Tra)and nano-adjuvant CPG@Man-P,which generated abundant in situ depot of whole-cell tumor antigens and formed in situ nano-vaccines with CpG@Man-P.Benefiting from mannose(Man)modification,the nano-vaccines targeted to LNs,promoted the uptake of antigens by DCs,further inducing the maturation of DCs and activation of T cells.Moreover,CpG@Man-P with different particle sizes were prepared and the effective size was selected to evaluate the antitumor effect and immune response in vivo.Notably,combined with PD-1 blocking,the vaccine effectively inhibited primary tumor growth and induced tumor-specific immune response against tumor recurrence and metastasis of ovarian cancer.

Combination losartan with hyaluronic acid modified diethyldithiocarbamate loaded hollow copper sulfide nanoparticles for the treatment of breast cancer and metastasis

The application of photothermal therapy(PTT)is greatly limited by the low accumulation of photothermal agents,uneven photothermal distribution,and heat endurance of cancer cells.Worse still,despite PTT enhances immunogenicity,the anti-tumor immune efficacy is still unsatisfactory due to the inefficient immunogenic cell death(ICD)induction and poor infiltration of immune cells.To solve the above problems of PTT,we developed hyaluronic acid(HA)modified hollow copper sulfide nanoparticles encapsulating diethyldithiocarbamate(DDTC)to construct a breast tumor targeting and near infrared(NIR)photo-responsive drug delivery system(D-HCuS@HA),which further combined with losartan to improve the accumulation and penetration in the tumor site.Upon irradiation,D-HCuS@HA realized enhanced PTT and released cytotoxic Cu(DDTC)_(2)to eliminate heat endurance tumor cells,thereby enhancing antitumor effect and inducing effective ICD.Moreover,the combination with losartan could remodel the tumor microenvironment,allowing more T cells to infiltrate into the tumor,and significantly inhibiting the occurrence and development of metastatic tumors.In vitro/vivo results revealed the great potential of D-HCuS@HA combined with losartan,which provides a new paradigm for anti-tumor and anti-metastases.

卒中预警综合征患者的静脉溶栓:与抗血小板治疗的比较

目的探讨静脉溶栓与抗血小板治疗在卒中预警综合征(stroke warning syndrome,SWS)患者中的有效性及安全性以及SWS患者转归的影响因素。方法回顾性纳入2018年6月1日至2023年12月31日兵器工业五二一医院收治的SWS患者。部分患者给予阿替普酶静脉溶栓,然后进行口服抗血小板治疗;部分患者仅接受抗血小板治疗。主要观察指标为发病后90 d时改良Rankin量表评分,0~2分定义为转归良好。结果共纳入35例SWS患者,男性26例(74.3%),年龄(58.29±11.06)岁。19例(54.3%)接受静脉溶栓,27例(77.1%)90 d时转归良好。静脉溶栓组与仅抗血小板治疗组人口统计学、基线资料以及转归良好均差异无统计学意义。静脉溶栓组有1例出现新发卒中,1例出现短暂性脑缺血发作。转归良好组与转归不良组ABCD2评分、收缩压、低密度脂蛋白胆固醇、空腹血糖、发作时最高美国国立卫生研究院卒中量表(National Institutes of Health Stroke Scale,NIHSS)评分以及症状持续时间差异有统计学意义(P均<0.05)。结论静脉溶栓与仅抗血小板药治疗SWS的效果相近。ABCD2评分、收缩压、低密度脂蛋白胆固醇、空腹血糖、发作时最高NIHSS评分以及症状持续时间可能是SWS患者转归的影响因素。

长江口芦苇和互花米草叶面积生长对立地增温的响应

采用开顶式生长室(Open top chambers,OTCs)模拟立地增温的方法(4个OTC,4个对照),研究芦苇(Phragmites australis)和互花米草(Spartina alterniflora)实生苗顶叶面积、单株总叶面积和叶面积指数(LAI)对增温(OTC内空气年平均气温增加了2.00±0.17℃)的响应.结果显示:(1)与对照相比,一年生长后芦苇和互花米草LAI分别显著增加.芦苇LAI于9月份达到峰值,增加了5.40%;而互花米草呈现持续增加趋势,于10月份达到峰值,增加了7.00%(P <0.05).(2)芦苇顶叶面积于8月份达到峰值,增加了12.94%;互花米草于9月份达到峰值,增加了23.96%.同时增温使互花米草顶叶面积伸展延后3 d.(3)芦苇单株总叶面积于9月份达到峰值,增加了9.36%;而互花米草于10月份达到峰值,与对照相比,增加了20.26%.上述结果表明在未来大气增温条件下,互花米草叶生长对大气增温的响应比芦苇更加敏感.

开放腹膜前修补术与经腹腹膜前修补术治疗腹股沟疝的疗效比较

目的比较开放腹膜前修补术与经腹腹膜前修补术治疗腹股沟疝的效果。方法回顾性分析2019年10月至2021年11月北京市垂杨柳医院收治的202例腹股沟疝患者临床资料,分为开放组122例,腔镜组80例,比较2组病例一般资料、手术时间、术中出血量、住院时间、住院费用、疼痛程度及术后并发症情况。结果2组患者的手术时间、术中出血量、住院时间、术后1个月疼痛程度及术后并发症差异均无统计学意义(P>0.05);腔镜组术后第1天、第7天疼痛程度明显轻于开放组(P<0.001),腔镜组住院费用明显高于开放组(P<0.001)。结论开放腹膜前修补术与经腹腹膜前修补术均可有效治疗腹股沟疝,后者疼痛更轻、恢复更快。

A nanocleaner specifically penetrates the blood-brain barrier at lesions to clean toxic proteins and regulate inflammation in Alzheimer's disease

Insurmountable blood-brain barrier(BBB) and complex pathological features are the key factors affecting the treatment of Alzheimer's disease(AD).Poor accumulation of drugs in lesion sites and undesired effectiveness of simply reducing Aβ deposition or TAU protein need to be resolved urgently.Herein,a nanocleaner is designed with a rapamycin-loaded ROS-responsive PLGA core and surface modification with KLVFF peptide and acid-cleavable DAG peptide [R@(ox-PLGA)-KcD].DAG can enhance the targeting and internalization effect of nanocleaner towards neurovascular unit endothelial cells in AD lesions,and subsequently detach from nanocleaner in response to acidic microenvironment of endosomes to promote the transcytosis of nanocleaner from endothelial cells into brain parenchyma.Then exposed KLVFF can capture and carry Aβ to microglia,attenuating Aβ-induced neurotoxicity.Strikingly,rapamycin,an autophagy promoter,is rapidly liberated from nanocleaner in the high ROS level of lesions to improve Aβ degradation and normalize inflammatory condition.This design altogether accelerates Aβ degradation and alleviates oxidative stress and excessive inflammatory response.Collectively,our finding offers a strategy to target the AD lesions precisely and multi-pronged therapies for clearing the toxic proteins and modulating lesion microenvironment,to achieve efficient AD therapy.

Numerical analysis of broadband noise reduction with wavy leading edge

Large Eddy Simulation（LES） is performed to investigate the airfoil broadband noise reduction with wavy leading edge under anisotropic incoming turbulence. The anisotropic incoming turbulence is generated by a rod with a diameter of 10 mm. The incoming flow velocity is 40 m/s and the corresponding Reynolds numbers based on airfoil chord and rod diameter are about 397000 and 26000, respectively. The far-field acoustic field is predicted using an acoustic analogy method which has been validated by the experiment. A straight leading edge airfoil and a wavy leading edge airfoil are simulated. The results show that wavy leading edge increases the airfoil lift and drag whereas the lift and drag fluctuations are substantially reduced. In addition, wavy leading edge can significantly change the flow pattern around the leading edge and a pair of counter-rotating streamwise vortices stemming from each wavy leading edge peak are observed.An averaged noise reduction of 9.5 dB is observed with the wavy leading edge at the azimuthal angle of 90°. Moreover, the wavy leading edge can mitigate noise radiation at all the azimuthal angles without significantly changing the noise directivity. The underlying noise reduction mechanisms are then analyzed in detail.

Co-delivery of photosensitizer and diclofenac through sequentially responsive bilirubin nanocarriers for combating hypoxic tumors

Considering that photodynamic therapy(PDT)-induced oxygen consumption and microvascular damage could exacerbate hypoxia to drive more glycolysis and angiogenesis, a novel approach to potentiate PDT and overcome the resistances of hypoxia is avidly needed. Herein, morpholine-modified PEGylated bilirubin was proposed to co-deliver chlorin e6, a photosensitizer, and diclofenac(Dc). In acidic milieu, the presence of morpholine could enable the nanocarriers to selectively accumulate in tumor cells, while PDT-generated reactive oxidative species(ROS) resulted in the collapse of bilirubin nanoparticles and rapid release of Dc. Combining with Dc showed a higher rate of apoptosis over PDT alone and simultaneously triggered a domino effect, including blocking the activity and expression of lactate dehydrogenase A(LDHA), interfering with lactate secretion, suppressing the activation of various angiogenic factors and thus obviating hypoxia-induced resistance-glycolysis and angiogenesis. In addition, inhibition of hypoxia-inducible factor-1a(HIF-1a) by Dc alleviated hypoxia-induced resistance. This study offered a sequentially responsive platform to achieve sufficient tumor enrichment, on-demand drug release and superior anti-tumor outcomes in vitro and in vivo.

GSH-responsive SN38 dimer-loaded shape-transformable nanoparticles with iRGD for enhancing chemo-photodynamic therapy

Accurate tumor targeting,deep penetration and superb retention are still the main pursuit of developing excellent nanomedicine.To achieve these requirements,a stepwise stimuli-responsive strategy was developed through co-administration tumor penetration peptide iRGD with shape-transformable and GSH-responsive SN38-dimer(d-SN38)-loaded nanoparticles(d-SN38@NPs/iRGD).Upon intravenous injection,d-SN38@NPs with high drug loading efficiency(33.92±1.33%)could effectively accumulate and penetrate into the deep region of tumor sites with the assistance of iRGD.The gathered nanoparticles simultaneously transformed into nanofibers upon 650 nm laser irradiation at tumor sites so as to promote their retention in the tumor and burst release of reactive oxygen species for photodynamic therapy.The loaded d-SN38 with disulfide bond responded to the high level of GSH in tumor cytoplasm,which consequently resulted in SN38 release and excellent chemo-photodynamic effect on tumor.In vitro,coadministering iRGD with d-SN38@NPs+laser showed higher cellular uptake,apoptosis ratio and multicellular spheroid penetration.In vivo,d-SN38@NPs/iRGD+laser displayed advanced penetration and accumulation in tumor,leading to 60.89%of tumor suppression in 4 T1 tumor-bearing mouse model with a favorable toxicity profile.Our new strategy combining iRGD with structural transformable nanoparticles greatly improves tumor targeting,penetrating and retention,and empowers anticancer efficacy.

Application of next generation sequencing in the screening of monogenic diseases in China,2021:a consensus among Chinese newborn screening experts

Newborn screening(NBS)refers to a maternal and newborn healthcare technology,in which special examinations of congenital and genetic diseases that could seriously impact the health of newborns,are implemented during the neonatal period to provide early diagnosis and treatment[1].With a history of more than 60 years,NBS has advanced greatly due to technological progress resulting in significant improvement in the number of diseases covered by NBS and in screening efficiency[2-7].

Pressure field measurements on large-scale propeller blades using pressure-sensitive paint

Pressure-sensitive paint(PSP)is a global pressure measurement technique.Compared with pressure transducers,PSP has significant advantages such as high spatial resolution and a lack of contact when applied to fast-rotating blades.However,due to the limitations of other pressure measurement techniques,the validation of PSP measurements on fast-rotating blades is generally difficult.In this work,a comprehensive study including PSP measurement,force balance measurement,and simulation was conducted on a 1 m-diameter propeller at the China Aerodynamic Research and Development Center.First,our computational fluid dynamics(CFD)code was validated by comparing the calculated aerodynamic thrust with the results from force balance measurements.Then,the pressure distributions on the propeller blade obtained by PSP were carefully compared with the CFD results under different working conditions.The results of PSP measurements,force balance measurements,and CFD showed good agreement,and the PSP measurement errors were estimated to be less than 5% of the dynamic pressure at the blade tip.Finally,the variations in pressure distribution under different rotating speeds and free-stream velocities were discussed.

Hollow copper sulfide nanoparticles carrying ISRIB for the sensitized photothermal therapy of breast cancer and brain metastases through inhibiting stress granule formation and reprogramming tumor-associated macrophages

As known,the benefits of photothermal therapy(PTT)are greatly limited by the heat tolerance of cancer cells resulting from overexpressed heat shock proteins(HSPs).Then HSPs further trigger the formation of stress granules(SGs)that regulate protein expression and cell viability under various stress conditions.Inhibition of SG formation can sensitize tumor cells to PTT.Herein,we developed PEGylated pH(low)insertion peptide(PEG-pHLIP)-modified hollow copper sulfide nanoparticles(HCuS NPs)encapsulating the SG inhibitor ISRIB,with the phase-change material lauric acid(LA)as a gatekeeper,to construct a pH-driven and NIR photo-responsive controlled smart drug delivery system(IL@H-PP).The nano medicine could specifically target slightly acidic tumor sites.Upon irradiation,IL@H-PP realized PTT,and the light-controlled release of ISRIB could effectively inhibit the formation of PTT-induced SG to sensitize tumor cells to PTT,thereby increasing the antitumor effect and inducing potent immunogenic cell death(ICD).Moreover,IL@H-PP could promote the production of reactive oxygen species(ROS)by tumor-associated macrophages(TAMs),repolarizing them towards the M1 phenotype and remodeling the immunosuppressive microenvironment.In vitro/vivo results revealed the potential of PTT combined with SG inhibitors,which provides a new paradigm for antitumor and antimetastases.

FMR1 allele frequencies in 51,000 newborns:a large-scale population study in China

Background Fragile X syndrome(FXS).caused by CGG-repeat expansion in FMR1 promoter,is one of the most common causes of mental retardation.Individuals with full mutation and premutation alleles have a high risk of psychophysiological disorder and of having affected offspring.Frequencies of FMR1 alleles in general newborns have been reported in Caucasians but have not been investigated in the large-scale population in the mainland of China.Methods The sizes of FMRI CGG-repeats were analyzed in 51,661 newborns(28,114 males and 23,547 females)and also in a cohort of 33 children diagnosed with developmental delay using GC-rich polymerase chain reaction(PCR)and triple repeat primed PCR.Results The frequency of CGG repeats>100 was 1/9371 in males and 1/5887 in females,and the frequency of CGG repeats>54 was 1/1561 in males and 1/1624 in females.FMRJ full mutation and premutation were identified in 27.27%of children who had Ages and Stages Questionnaire scores less than two standard deviations from the cutoff value.Conclusions Our study revealed the prevalence of FXS in China and improved the sample databases of FXS,suggesting that the prevalence of FXS in Chinese is higher than estimated previously and that FXS screening can be advised to high-risk families.

Novel ACADVL variants resulting in mitochondrial defects in long-chain acyl-CoA dehydrogenase deficiency

The pathogenesis of very-long-chain acyl-CoA dehydrogenase(VLCAD)deficiency is highly heterogeneous and still unclear.Additional novel variants have been recently detected in the population.The molecular and cellular effects of these previously unreported variants are still poorly understood and require further characterization.To address this problem,we have evaluated the various functions and biochemical consequences of six novel missense variants that lead to mild VLCAD deficiency.Marked deficiencies in fatty acid oxidation(FAO)and other mitochondrial defects were observed in cells carrying one of these six variants(c.541 C>T,c.863 T>G,c.895 A>G,c.1238 T>C,c.1276 G>A,and c.1505 T>A),including reductions in mitochondrial respiratory-chain function and adenosine teriphosphate(ATP)production,and increased levels of mitochondrial reactive oxygen species(ROS).Intriguingly,higher apoptosis levels were found in cells carrying the mutant VLCAD under glucose-limited stress.Moreover,the stability of the mutant homodimer was disturbed,and major conformational changes in each mutant VLCAD structure were predicted by molecular dynamics(MD)simulation.The data presented here may provide valuable information for improving management of diagnosis and treatment of VLCAD deficiency and for a better understanding of the general molecular bases of disease variability.

Recurrent rhabdomyolysis and glutaric aciduria type I: a case report and literature review

Background:Glutaric acidemia type I(GA-I)is a rare metabolic disorder caused by mutation of the glutaryl-CoA dehydrogenase(GCDH)gene.The occurrence of rhabdomyolysis with GA-I is extremely rare.Methods:We reported a child with recurrent rhabdomyolysis and undiagnosed glutaric acidemia type I(GA-I).And a literature review was performed.Results:A 4.5-year-old girl was admitted to our hospital due to recurrent rhabdomyolysis for 3 times within three years.At the third admission,she was diagnosed with GA-I by biochemical testing and mutation analysis.The girl was found to have a serine to leucine replacement mutation of the GCDH gene in exon 8 at position 764.Other three patients with rhabdomyolysis and GA-I were discovered by literature searching.Conclusion:This report highlights that patients with GA-I may have an increased risk of rhabdomyolysis.

Author correction to “A nanocleaner specifically penetrates the blood‒brain barrier at lesions to clean toxic proteins and regulate inflammation in Alzheimer’s disease” [Acta Pharmaceutica Sinica B 12, (2021) 4032e4044]

The authors regret that there were some picture errors in Fig.4A and data errors Fig.7A owing to the mistakes of copying and pasting in the process of assembling figures and making a dia-gram.The raw data of correct images of group b in Fig.4A and values of high dose in Fig.7A are provided in the supporting information,and the authors revise Figs.4 and 7 as below.The revisions do not affect any results and conclusions of the current work.The authors apologize for any inconvenience caused to the journal and readers.

Composite structure of ZnO films coated with reduced graphene oxide: structural,electrical and electrochemical properties

ZnO films coated with reduced graphene oxide（RGO-ZnO） were prepared by a simple chemical approach. The graphene oxide（GO） films transferred onto ZnO films by spin coating were reduced to RGO films by two steps（exposed to hydrazine vapor for 12 h and annealed at 600 °C）. The crystal structures, electrical and photoluminescence properties of RGO-ZnO films on quartz substrates were systematically studied. The SEM images illustrated that RGO layers have successfully been coated on the ZnO films very tightly. The PL properties of RGO-ZnO were studied. PL spectra show two sharp peaks at 390 nm and a broad visible emission around 490 nm.The resistivity of RGO-ZnO films was measured by a Hall measurement system, RGO as nanofiller considerably decrease the resistivity of ZnO films. An electrode was fabricated, using RGO-ZnO films deposited on Si substrate as active materials, for super capacitor application. By comparison of different results, we conclude that the RGOZnO composite material couples possess the properties of super capacitor.