Challenges of evaluating immunotherapy efficacy in solid tumors

Immunotherapy is one of the most promising treatments for multiple tumor types.The significant clinical benefits and durable responses of immunotherapy have led to the emergence of various immune-related clinical response patterns that extend beyond those achieved with cytotoxic agents.Various studies investigated the efficacy of immunotherapy,including the effect on tumor size,long-term survival benefits,and the ability to overcome the particularly challenging survival curves tailing phenomenon.The current immune-related methods guidelines,such as immune-related Response Criteria(irRC),immune-related Response Evaluation Criteria in Solid Tumors(irRECIST),immune Response Evaluation Criteria in Solid Tumors(iRECIST),and immune-modified Response Evaluation Criteria in Solid Tumors(imRECIST),could be well-adapted to identify the heterogeneity of responses that appear in patients receiving immunotherapy,such as pseudoprogression(PsPD)and hyperprogressive disease(HPD),and to some extent to overcome the limitation of evaluating the efficacy of immunotherapy on tumor size by imaging.Additionally,a second type of evaluation method was proposed based on survival,which includes milestone analysis and restricted mean survival time.Currently,milestone analysis is a complementary tool to summarize and interpret trial results along with more conventional measures of survival and other less established metrics.A golden standard evaluation method to distinguish the efficacy of immunotherapy may improve the process of imaging and aid survival-based efficacy evaluation in patients with solid tumors.

Clinical challenges in neoadjuvant immunotherapy for non-small cell lung cancer

Immune checkpoint inhibitors(ICIs),a type of immunotherapy,have become one of the most important therapeutic options for first-and second-line treatment of advanced non-small cell lung cancer(NSCLC).Recent clinical studies have shown that immunotherapy can offer substantial survival benefits to patients with early-stage or resectable advanced NSCLC.However,considering the importance of timing when using ICIs and their associated adverse events(AEs),the advantages and disadvantages of using these agents need to be weighed carefully when deciding the use of a combined treatment.In addition,the inconsistency between imaging assessment and pathological results poses further challenges to the evaluation of efficacy of neoadjuvant immunotherapy.It is also important to develop new methodologies and discover suitable biomarkers that can be used to evaluate survival outcomes of immunotherapy and identify patients who would benefit the most from this treatment.In this review,we aimed to summarize previous results of ongoing clinical trials on neoadjuvant immunotherapy for lung cancer and discuss the challenges and future perspectives of this therapeutic approach in the treatment of resectable NSCLC.

Deep Learning Applications for COVID-19 Analysis:A State-of-the-Art Survey

The COVID-19 has resulted in catastrophic situation and the deaths of millions of people all over the world.In this paper,the predictions of epidemiological propagation models,such as SIR and SEIR,are introduced to analyze the earlier COVID-19 propagation.The deep learning methods combined with transfer learning are familiar with classification-detection approaches based on chest X-ray and CT images are presented in detail.Besides,deep learning approaches have also been applied to lung ultrasound(LUS),which has been shown to be more sensitive than chest X-ray and CT images in detecting COVID-19.In the absence of a vaccine,the machine learning-related approaches are applied to analyze vaccine candidates in the realm of biology and medicine.The telehealth system played a major role in combating the pandemic from all aspects and reducing contact with patients during this period.Natural language processing-related methods are utilized to analyze tweets related to the COVID-19 epidemic on social media,and further analyze public sentiment and subject modeling,so as to arrange corresponding measures to appease public sentiment.In particular,this survey is to summarize and analyze the contributions made in various fields during the COVID-19 pandemic by considering both the contribution of deep learning in chest X-ray and CT images,as well as the application of the latest LUS during the COVID-19 pandemic.Telehealth and the importance of public sentiment analysis during a pandemic were also described in detail.

Potential new applications of immunotherapy for neuroendocrine neoplasms:immune landscape,current status and future perspectives

Neuroendocrine neoplasms(NENs)are a highly heterogeneous class of tumors arising from neuroendocrine cells and peptidergic neurons.After failure of first-line treatment,patients have poor prognosis and limited treatment options.Immune checkpoint inhibitors(ICIs)may be a powerful means of increasing therapeutic efficacy for such patients,but ICIs alone have low response rates and short disease control durations in most NENs and may be effective for only a portion of the population.ICIs combined with other immunotherapies,targeted therapies,or cytotoxic drugs have achieved some efficacy in patients with NENs and are worthy of further exploration to assess their benefits to the population.In addition,accumulating experimental and clinical evidence supports that the interaction between neuroendocrine and immune systems is essential to maintain homeostasis,and assessment of this broad neuroendocrine-immune correlation is essential for NEN treatment.In this review,we summarize the immune microenvironment characteristics,advances in immunotherapy,predictive biomarkers of ICI efficacy for NENs,and the effects of common endocrine hormones on the immune system,highlighting possible new application areas for this promising treatment in neglected NENs.

Molecular classification of small cell lung cancer subtypes:Characteristics,prognostic factors,and clinical translation

Small cell lung cancer(SCLC)is a highly malignant tumor with a very poor prognosis;therefore,more effective treatments are urgently needed for patients afflicted with the disease.In recent years,emerging molecular classifications based on key transcription factors of SCLC have provided more information on the tumor pathophysiology,metastasis,immune microenvironment,and acquired therapeutic resistance and reflected the intertumoral heterogeneity of the various SCLC phenotypes.Additionally,advances in genomics and single-cell sequencing analysis have further revealed the high intratumoral heterogeneity and plasticity of the disease.Herein,we review and summarize these recent lines of evidence and discuss the possible pathogenesis of SCLC.

Tb(Ⅲ)functionalized MOF based self-calibrating sensor integrated with logic gate operation for efficient epinephrine detection in serum

By anchoring Tb^(3+)ions on its free carboxyl groups of the nanocaged NiMOF,a dual-emission self-calibrating sensor of Tb^(3+)@NiMOF was fabricated through coordination post-synthetic modification(PSM)strategy.With Tb^(3+)ions as the secondary fluorescent signal and sensing active sites,Tb^(3+)@NiMOF presents great potentials in visually and efficiently monitoring EPI in serum,with high sensitivity and selectivity,fast response,excellent recyclable,and the low detection limit(LOD,3.06 ng/mL).Furthermore,a tandem combinational logic gate based intelligent detection system was constructed to improve the practicability and convenience of epinephrine(EPI)detection in serum by comparing the light emitted colour with the series standard colour cards preset in the smartphone.This work provides a promising approach of developing metal-organic frameworks(MOFs)based self-calibrating sensors for intelligent detection of bioactive molecules.

驱动基因阳性肺癌脑转移患者的靶向治疗进展

脑是晚期肺癌转移最常见的部位,驱动基因阳性者脑转移发病率更高,肺癌脑转移患者预后较差,且不同治疗方式的选择影响肺癌脑转移患者的病程转归及预后。近年来,随着精准医学的发展,针对肺癌脑转移,尤其是具有特殊靶点的驱动基因阳性患者治疗方式的选择越来越成为人们的研究热点,并逐步取得进展。本文主要阐述了肺癌脑转移治疗存在的挑战,系统综述了驱动基因阳性肺癌脑转移的靶向治疗进展,以期在精准医学时代下,指导此类患者临床实践中个体化精准治疗方案的抉择。

聚己内酯增强生物基聚酯弹性体

针对生物基聚酯弹性体(BEE)力学性能较差的问题,采用聚己内酯(PCL)作为BEE的增强相,通过溶液共混及橡胶传统硫化工艺,制备了具有较高力学性能的生物基BEE/PCL硫化胶。通过动态力学性能、扫描电镜、差示扫描量热法、X射线衍射、力学性能测试等,对BEE/PCL硫化胶的相容性、微观相态、热性能及结晶性能、力学性能进行了表征。BEE/PCL硫化胶只有1个玻璃化转变温度,为热力学相容体系,但扫描电镜分析结果表明,BEE/PCL硫化胶为微观相分离体系。随着PCL含量的增加,BEE/PCL硫化胶的结晶度逐渐增加,拉伸强度逐渐增加,断裂伸长率先增加后降低。研究发现,当BEE与PCL的质量比为8∶2,BEE/PCL硫化胶的力学性能较优,拉伸强度为5.1 MPa、断裂伸长率为292%。

Exogenous abscisic acid coordinating leaf senescence and transport of assimilates into wheat grains under drought stress by regulating hormones homeostasis

Drought at the grain filling stage of wheat will cause premature leaf senescence, thus leading to considerable loss of wheat yield. Therefore, this paper aims to establish a cultivation technology for strong drought resistance, delayed senescence, and yield improvement based on the analysis of hormones homeostasis obtained by applying chemical control substances. Experiments were conducted with two genotypes of wheat. Four water irrigation treatments were applied to impose the water deficit, including well-watered control treatment(WW), mild water deficit(MiWD), moderate water deficit(MoWD), and severe water deficit(SWD). Exogenous abscisic acid(ABA) was sprayed on the plants at the anthesis stage of the wheat. As a result, exogenous ABA reduced initial senescence rate(r0), total duration of chlorophyll(Chltotal), rapid senescence phase(Chlloss), and the accumulated temperature at an inflection point(M) but improved the persistence phase(Chlper) of flag leaves under all of the four treatments. However, exogenous ABA produced inconsistent effects on photoassimilate relocation and grain weight under different treatments. It produced positive regulatory effects on grain weight under WW, MiWD, and MoWD treatments. On the one hand, spraying ABA during the persistence phase of flag leaves reduced the ratios of zeatin to gibberellin(Z/GA3), spermine to spermidine(Spm/Spd), and salicylic acid to ABA(SA/ABA),which prolonged active photosynthesis by stimulating high level of proline(Pro) and increased the activities of antioxidant enzymes, such as superoxide dismutase(SOD), peroxidase(POD), catalase(CAT), and ascorbate peroxidase(APX). Therefore, drought tolerance was enhanced, and more photosynthetic assimilates were accumulated. On the other hand, the rapid senescence phase and the transport rate of assimilates into grains were accelerated, resulting in higher grain weight, yield, and water use efficiency(WUE). However, under SWD treatment, exogenous ABA improved the ratio of SA/ABA, leading to low Pro content and low antioxidant enzyme activity of flag leaves in the rapid loss phase. Meanwhile,drought resistance declined and the transport duration of assimilates into grains was shortened, thus making photosynthetic assimilates redundant. Therefore, exogenous ABA can lead to the reduction in grain weight, yield, and WUE of wheat under SWD treatment.

Interactions between cytokinin and nitrogen contribute to grain mass in wheat cultivars by regulating the flag leaf senescence process

Premature senescence after anthesis reduces crop yields.Delaying leaf senescence could maintain photosynthetic activity for a longer period and lead to a higher photosynthetic rate.Recent studies have provided some insights into the interaction between cytokinin and nitrogen(N)in the regulation of plant development.In the present study,foliar application of exogenous 6-benzylaminopurine(6-BA)and lovastatin,an inhibitor of cytokinin synthesis,was combined with three N rates[0 kg ha^(-1)(low nitrogen,LN),240 kg ha^(-1)(normal nitrogen,NN),and 360 kg ha^(-1)(high nitrogen,HN)]in two wheat cultivars,Wennong 6(with a staygreen phenotype)and Jimai 20(with a non-staygreen phenotype).Flag leaf senescence was assessed using a Gompertz growth curve.Grain mass,dry matter accumulation and distribution,total N of flag leaf,and concentrations of zeatin riboside(ZR)and abscisic acid(ABA)were also used to evaluate the functional characteristics of flag leaves.Grain mass was negatively correlated with initial senescence rate(r_0)and duration of rapid chlorophyll loss(Chl_(loss)),whereas it was positively correlated with maximum senescence rate(r_(max)),average senescence rate(r_(aver)),persistence phase(Chl_(per)),total duration of flag leaf(Chl_(total))and inflection point cumulative temperature(M).Compared to Jimai 20,Wennong 6 had larger r_(aver),Chl_(per),and Chl_(total).The concentration of ZR was highest under the 6-BA×NN treatment,followed by the 6-BA×HN and 6-BA×LN treatments.However,the concentration of ABA showed the opposite trend.It was concluded that the staygreen phenotype Wennong 6 was associated with greater grain mass and altered cytokinin metabolism and could be classified as a functional staygreen type.Foliar application of 6-BA interacting with N at the NN level(240 kg ha^(-1))may be a beneficial strategy for improving grain yield of wheat by regulating endogenous hormones and the flag leaf senescence process.Increasing endogenous cytokinin promoted the transport of dry matter to grain.

A Multi-Stage Green Barrier Strategy for the Control of Global SARS-CoV-2 Transmission via Cold Chain Goods

1.The object-to-human transmission route of SARS-CoV-2 At the time of writing,coronavirus disease 2019(COVID-19),which is caused by the severe acute respiratory syndrome coron-avirus 2(SARS-CoV-2),has been a global pandemic for more than a year.As of 22 September 2021,the global cumulative incidence exceeds 229 million cases,and the number of deaths has exceeded 4.75 million[1].The current situation of epidemic prevention and control within the countries around the world can be roughly divided into two stages:the pandemic stage that the United States,the United Kingdom,and India are still experiencing(as of 23 September 2021,newly reported cases in the last 24 h in the United States,United Kingdom,and India are 202840,31095,and 26964,respectively[1]);and the normalized epidemic pre-vention and control stage that countries such as China and New Zealand are currently in.

Coexisting opportunities and challenges:In which scenarios can minimal/measurable residual disease play a role in advanced non-small cell lung cancer?

Curative therapy was not previously available for patients with advanced non-small cell lung cancer(NSCLC);thus,the concept of minimal/measurable(or molecular)residual disease(MRD)was not applicable to these patients.However,advances in targeted and immunotherapy have revolutionized the treatment landscape for patients with advanced NSCLC,with emerging evidence of long-term survival and even the hope of complete remission(CR)by imaging examination.The latest research shows that patients with oligometastatic lung cancer can benefit from local treatment.After removing the lesions,the choice of follow-up therapy and monitoring of the lesions could remain uncertain.MRD plays a role in identifying early-stage NSCLC patients with high risks of recurrence and determining adjuvant therapy after radical treatment.In recent years,evidence has been accumulating regarding the use of circulating cell-free tumor DNA(ctDNA)to assess MRD in solid tumors.This study discussed the possible applications of ctDNA-based MRD monitoring in advanced NSCLC and described the current challenges and unresolved problems in the application of MRD in advanced NSCLC.

The Protective Effect of CoQ10 on ox-LDL——induced HUVEC Injury by AP-1 and PON2

[Objectives] To explore the protective effect and possible mechanisms of the coenzyme Q10( CoQ 10) on the human umbilical vein endothelial cell( HUVEC) injury induced by the oxidized low-density lipoprotein( ox-LDL). [Methods]With the human umbilical vein endothelial cells( HUVECs) cultured in vitro as the test target,the HUVECs were randomly divided into 5 groups: normal control group; model group; low concentration CoQ10 group( 12. 5); medium concentration CoQ10 group( 25); high concentration CoQ10 group( 50). The CCK-8 method was used to test the cell viability,and the drug concentration was screened in 60 μM of CoQ 10 toxic concentration; the total protein was extracted and Western blot was used to detect the protein expression of c-fos,c-jun and PON2; the RT-PCR method was used for determination of the content of c-fos,c-jun and PON2 mRNA. [Results]Compared with the normal group,the cell viability was significantly reduced in the 35 μg/m L high ox-LDL model group,and the cell injury was induced; compared with model group,after 12 h pre-protection,12. 5 μM,25 μM,50 μM CoQ10 could all significantly improve the survival of injured cells( P < 0. 05); compared with the normal group;the protein and mRNA levels of c-fos,c-jun,PON2 in the model group all declined; compared with the model group,the protein level and mRNA expression of c-fos,c-jun,PON2 in different CoQ10 groups increased to varying degrees( P < 0. 05). [Conclusions] CoQ 10 could reduce the HUVEC injury induced by high ox-LDL,and possible mechanism was achieved by upregulating the expression of AP-1 and PON2.

韧性领导如何影响员工即兴行为?——基于VUCA时代背景的研究

随着全球环境的不确定性加剧,企业经营面临挑战。即兴行为在不可预料的情境下产生,与韧性领导一起灵活地应对环境的变化。本文基于资源保存理论,对收集的243份数据利用SPSS以及Amos软件进行分析,探讨韧性领导对员工即兴行为的影响。研究结果发现:韧性领导对员工即兴行为具有促进作用。韧性领导通过提高员工的心理授权水平进而激发员工即兴行为。并且,在差错管理氛围的调节作用下,韧性领导对员工即兴行为的影响得到加强。研究结论不仅丰富了员工即兴行为的研究,并且为管理者应对多变的环境提供有效思路。

An extended numerical model of the first exothermic peak for three dimensional printed cement-based materials

The first exothermic peak of cement-based material occurs a few minutes after mixing,and the properties of three dimensional(3D)printed concrete,such as setting time,are very sensitive to this.Against this background,based on the classical Park cement exothermic model of hydration,we propose and construct a numerical model of the first exothermic peak,taking into account the proportions of C_(3)S,C_(3)A and quicklime in particular.The calculated parameters are calibrated by means of relevant published exothermic test data.It is found that this developed model offers a good simulation of the first exothermic peak of hydration for C_(3)S and C_(3)A proportions from 0 to 100% of cement clinker and reflects the effect of quicklime content at 8%-10%.The unique value of this research is provision of an important computational tool for applications that are sensitive to the first exothermic peak of hydration,such as 3D printing.

基于靶点和活性成分的筛选探讨连翘抗病毒作用机制

连翘作为传统中药,具有显著的抗病毒作用,尤其是在治疗新冠肺炎方面。然而,其抗病毒有效化合物及其靶点尚不清楚。本论文利用网络药理学技术筛选连翘中的抗病毒成分和靶标,并利用分子对接技术分析了它们之间的相互作用。最终,从连翘中筛选出11个活性化合物(1–11)和7个抗病毒靶标(AKT1、TP53、MYC、PTEN、CASP8、MMP9和VEGFA),并利用基因本体论分析预测了潜在靶标可能的生物信号通路。基于分子对接结果,我们讨论了活性化合物的构效关系。此外,对活性化合物的吸收、分布、代谢、排泄和毒性(ADMET)特性进行了预测和分析。本研究阐明了连翘多个靶点和途径在治疗病毒性疾病中的协同作用,以及活性化合物的可药用性。本研究为开发和设计新型抗病毒药物提供了依据。

Epidermal growth factor receptor compound and concomitant mutations:advances in precision treatment strategies

Epidermal growth factor receptor(EGFR)mutations are common oncogenic driver mutations in patients with non-small cell lung cancer(NSCLC).The application of EGFR-tyrosine kinase inhibitors(TKIs)is beneficial for patients with advanced and early-stage NSCLC.With the development of next-generation sequencing technology,numerous patients have been found to have more than one genetic mutation in addition to a single EGFR mutation;however,the efficacy of conventional EGFR-TKIs and the optimal treatments for such patients remain largely unknown.Thus,we review the incidence,prognosis,and current treatment regimens of EGFR compound mutations and EGFR concomitant mutations to provide treatment recommendations and guidance for patients with these mutations.

Timing and Source of the Hermyingyi W-Sn Deposit in Southern Myanmar, SE Asia: Evidence from Molybdenite Re-Os Age and Sulfur Isotopic Composition

The Hermyingyi W-Sn deposit, situated in southern Myanmar, SE Asia, is a typical quartz-vein type W-Sn deposit. The ore-bearing quartz veins are mainly hosted by the Hermyingyi monzogranite which intruded into the Carboniferous metasedimentary rocks of Mergui Series. According to mineral assemblages and crosscutting relationships, four ore-forming stages are recognized:(1) silicate-oxide stage;(2) quartz-sulfide stage;(3) barren quartz vein stage;(4) supergene stage. Five molybdenite samples from the deposit yield Re-Os model ages ranging from 67.8±1.6 to 69.2±1.6 Ma(weighted mean age of 68.7±1.2 Ma), and a well-defined isochron age of 68.4±2.5 Ma(MSWD=0.18, 2σ). This Re-Os age is consistent with the previously published zircon U-Pb age of the Hermyingyi monzogranite(70.0±0.4 Ma)(MSWD=0.9, 2σ) within errors, which indicates a genetic link between the monzogranitic magmatism and W-Sn mineralization. The new high-precision geochronological data reveal that the granitic magmatism and associated W-Sn mineralization in southern Myanmar took place during the Late Cretaceous(70–68 Ma). The extremely low Re contents(22.9 ppb to 299 ppb) in molybdenite, coupled with sulfide δ^(34)S values in the range of +1.9‰ to +5.6‰ suggest that ore-forming metals were predominately sourced from the crustal-derived granitic magma.

Pillar[5]arene based conjugated macrocycle polymers with unique photocatalytic selectivity

The development of heterogeneous catalysts with substrate shape,size or electronic constitution selectivity is a huge challenge in photocatalysis.Reported herein is a host-guest interaction strategy to endow photocatalysts with special selectivity.By adjusting the precursors,conjugated macrocycle polymers(CMPs)with pillar[5]arene struts(CMP-1 and CMP-2)and a corresponding non-pillar[5]are necontained conjugated organic polymer(COP-1)were prepared and the photocatalytic activities toward sulfide derivatives were investigated.The sulfides showed similar conve rsions when COP-1 was used as a photocatalyst,but exhibited significant differences when it turned to the CMPs.Remarkably,the conversion yield of S-1 achieved near 18 folds over the one of S-2 when CMP-2 was used as a catalyst.Mechanism studies confirmed that the"host-guest"effect of pillar[5]arene struts in CMPs was the main cause of the difference.The present work establishes CMPs as novel heterogeneous photocatalysts with substrate selectivity,and such a method will inspire the researchers concerning preparation of heterogeneous catalysts with excellent selectivity.

Bootstrap LM Tests for Spatial Dependence in Panel Data Models with Fixed Effects

This paper applies bootstrap methods to LM tests(including LM-lag test and LM-error test) for spatial dependence in panel data models with fixed effects, and removes fixed effects based on orthogonal transformation method proposed by Lee and Yu(2010). The consistencies of LM tests and their bootstrap versions are proved, and then some asymptotic refinements of bootstrap LM tests are obtained. It shows that the convergence rate of bootstrap LM tests is O((N T)-2) and that of fast double bootstrap LM tests is O((NT)-5/2). Extensive Monte Carlo experiments suggest that,compared to aysmptotic LM tests, the size of bootstrap LM tests gets closer to the nominal level of signifiance, and the power of bootstrap LM tests is higher, especially in the cases with small spatial correlation. Moreover, when the error is not normal or with heteroskedastic, asymptotic LM tests suffer from severe size distortion, but the size of bootstrap LM tests is close to the nominal significance level.Bootstrap LM tests are superior to aysmptotic LM tests in terms of size and power.