帕博利珠单抗联合以铂类为基础的化疗治疗非小细胞肺癌合并稳定性脑转移患者的结局:KEYNOTE-021、-189和-407研究的汇总分析

背景与目的此项探索性分析回顾评价了晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者的结局,旨在确定基线时合并脑转移是否会影响一线应用帕博利珠单抗联合化疗(pembrolizumab plus chemotherapy,PC)比对单用化疗的疗效。患者和方法对KEYNOTE-021队列G(非鳞癌)、KEYNOTE-189(非鳞癌)和KEYNOTE-407(鳞癌)三项研究晚期NSCLC患者的数据进行汇总分析。患者接受含铂两药化疗和/或35个周期帕博利珠单抗治疗(每3周200 mg)。所有研究均纳入了经治或初治的稳定性脑转移患者(KEYNOTE-189与KEYNOTE-407研究纳入初治脑转移患者)。经治的脑转移患者已处于病情稳定的状态≥2周(KEYNOTE-021队列G患者≥4周),无新发或脑转移病灶扩大的证据且入组前至少3天以上未使用激素。初治的无症状脑转移患者需定期接受脑部影像学检查。结果共纳入1298例患者,其中171例有基线脑转移,1127例无脑转移。两组的中位随访时间(范围)在数据截止时分别为10.9(0.1-35.1)个月和11.0(0.1-34.9)个月。合并脑转移和无脑转移患者的总生存期[0.48(95%CI:0.32-0.70)和0.63(95%CI:0.53-0.75)]和无进展生存期[0.44(95%CI:0.31-0.62)和0.55(95%CI:0.48-0.63)]的风险比(PC/化疗)相似。合并脑转移的患者中,PC组和单用化疗组患者的中位总生存期分别为18.8个月和7.6个月,中位无进展生存期分别为6.9个月和4.1个月。无论是否合并脑转移,PC组患者的客观缓解率都高于单用化疗组,且缓解持续时间有显著延长。合并脑转移的患者中,PC组与单用化疗组的治疗相关不良事件发生率分别为88.2%和82.8%;而无脑转移的患者中,两组治疗相关不良事件的发生率分别为94.5%和90.6%。结论无论是否合并脑转移,与单用化疗相比,帕博利珠单抗联合以铂类为基础的组织学特异性化疗可改善所有PD-L1亚组的临床结局,其中包括PD-L1肿瘤比例评分<1%的患者,并且在晚期NSCLC患者中安全性良好。该方案是晚期NSCLC初治患者的标准方案,并可用于合并稳定性脑转移的患者。

The burden of depression,anxiety and schizophrenia among the older population in ageing and aged countries:an analysis of the Global Burden of Disease Study 2019

Background Depression,anxiety and schizophrenia among older persons have become global public health challenges.However,the burden of these disorders in ageing and aged countries has not been analysed.Aims To investigate the burden of depression,anxiety and schizophrenia among older adults in ageing and aged countries.Methods Using data from the Global Burden of Disease Study 2019,we calculated the estimated annual percentage change(EAPC)in the age-standardised incidence rates(ASiR)and age-standardised disability-adjusted life years(DALYs)rates(ASDR)for depression,anxiety and schizophrenia of older people in ageing countries(China,India,Indonesia)and aged countries(Japan,Italy,Portugal)between 1990 and 2019.Trends in incidence and DALYs were analysed by gender and age.Results In 2019,the highest incidence of depression,anxiety and schizophrenia in the older population in aged countries was in Japan(927271.3(752552.3-1125796.5),51498.2(37625.7-70487.3)and 126.0(61.0-223.2),respectively),while the highest incidence in ageing countries was in China(5797556.9(4599403.4-7133006.5),330256.1(246448.9-445987.4)and 1067.7(556.2-1775.9),respectively).DALYs for these disorders were similar,with the highest in Japan and China.From 1990 to 2019,the ASIR for depressive disorders decreased in aged countries but increased in ageing countries;the ASIR for anxiety disorders and schizophrenia declined in both ageing and aged countries.The ASDR for depressive disorders was consistent with the ASIR but not for anxiety disorders and schizophrenia.The ASIR for depressive disorders was higher in older women,while the opposite was observed in anxiety disorders and schizophrenia.Notably,the conditions of burden of depressive disorders,anxiety disorders and schizophrenia in the 65-70-year-old age group were the most burdensome.Conclusions The incidence and DALYs of these three mental disorders increased while exhibiting differences between ageing and aged countries.Raising awareness about formulating health policies for preventing and treating mental disorders in the older population is necessary to reduce the future burden posed by the ageing challenge.

Enhancement of anti-PD-L1 antibody plus anlotinib efficacy due to downregulation of PD-L1 in the micro-conduit endothelium within the tumor:a randomized double-blind trial

Objective:The possible enhancing effect of anlotinib on programmed death receptor ligand(PD-L1)antibody and the efficacy-predicting power of PD-L1 in micro-conduit endothelium,including lymphatic endothelial cells(LECs)and blood endothelial cells(BECs),were determined to identify patients who would benefit from this treatment.Methods:PD-L1 positivity in LECs,BECs,and tumor cells(TCs)was assessed using paraffin sections with multicolor immunofluorescence in an investigator’s brochure clinical trial of TQB2450(PD-L1 antibody)alone or in combination with anlotinib in patients with non-small cell lung cancer.Progression-free survival(PFS)with different levels of PD-L1 expression was compared between the two groups.Results:Among 75 patients,the median PFS(mPFS)was longer in patients who received TQB2450 with anlotinib[10 and 12 mg(161 and 194 days,respectively)]than patients receiving TQB2450 alone(61 days)[hazard ratio(HR)_(10 mg)=0.390(95%confidence interval{CI},0.201–0.756),P=0.005;HR_(12 mg)=0.397(0.208–0.756),P=0.005].The results were similar among 58 patients with high PD-L1 expression in LECs and TCs[159 and 209 vs.82 days,HR_(10 mg)=0.445(0.210–0.939),P=0.034;HR_(12 mg)=0.369(0.174–0.784),P=0.009],and 53 patients with high PD-L1 expression in BECs and TCs[161 and 209 vs.41 days,HR_(10 mg)=0.340(0.156–0.742),P=0.007;HR_(12 mg)=0.340(0.159–0.727),P=0.005].No differences were detected in the mPFS between the TQB2450 and combination therapy groups in 13 low/no LEC-expressing and 18 low/no BEC-expressing PD-L1 cases.Conclusions:Mono-immunotherapy is not effective in patients with high PD-L1 expression in LECs and/or BECs.Anlotinib may increase efficacy by downregulating PD-L1 expression in LECs and/or BECs,which is presumed to be a feasible marker for screening the optimal immune patient population undergoing anti-angiogenic therapy.

Tislelizumab in previously treated,locally advanced unresectable/metastatic microsatellite instability-high/mismatch repair-deficient solid tumors

Objective:The open-label,phase II RATIONALE-209 study evaluated tislelizumab(anti-programmed cell death protein 1 antibody)as a tissue-agnostic monotherapy for microsatellite instability-high(MSI-H)/mismatch repair-deficient(dMMR)tumors.Methods:Adults with previously treated,locally advanced unresectable or metastatic MSI-H/dMMR solid tumors were enrolled.Patients received tislelizumab 200 mg intravenously every 3 weeks.Objective response rate(ORR;primary endpoint),duration of response(DoR),and progression-free survival(PFS)were assessed by independent review committee(Response Evaluation Criteria in Solid Tumors v1.1).Results:Eighty patients were enrolled and treated;75(93.8%)patients had measurable disease at baseline.Most had metastatic disease and received at least one prior therapy for advanced/metastatic disease(n=79;98.8%).At primary analysis(data cutoff July 8,2021;median follow-up 15.2 months),overall ORR[46.7%;95%confidence interval(95%CI),35.1−58.6;one-sided P<0.0001]and ORR across tumor-specific subgroups[colorectal(n=46):39.1%(95%CI,25.1–54.6);gastric/gastroesophageal junction(n=9):55.6%(95%CI,21.2−86.3);others(n=20):60.0%(95%CI,36.1−80.9)]were significantly greater with tislelizumab vs.a prespecified historical control ORR of 10%;five(6.7%)patients had complete responses.Median DoR,PFS,and overall survival were not reached with long-term follow-up(data cutoff December 5,2022;median follow-up 28.9 months).Tislelizumab was well tolerated with no unexpected safety signals.Treatment-related adverse events(TRAEs)of grade≥3 occurred in 53.8%of patients;7.5%of patients discontinued treatment due to TRAEs.Conclusions:Tislelizumab demonstrated a significant ORR improvement in patients with previously treated,locally advanced unresectable or metastatic MSI-H/dMMR tumors and was generally well tolerated.

Facile preparation of Fe-Beta zeolite-supported transition metal oxide catalysts and their catalytic performance for the simultaneous removal of NO_(x) and soot

Diesel engine exhaust comprises nitrogen oxides(NOx)and soot particles,which cause serious air pollution.However,owing to the contradictory nature of NO_(x)reduction and soot oxidation,a trade-off exists in the simultaneous removal of NO_(x)and soot.Consequently,catalytic technology has become a hot research topic.This study prepared MOδ/Fe-Beta(M=Fe,Co,Ni,Mn,Cu)catalysts through incipient wetness impregnation using Fe-Beta as the support and explored the catalytic performance of the above catalysts.The results exhibited the good performance of the prepared catalysts.The introduction of Mn resulted in a lower peak temperature of soot combustion for the catalyst,and slightly decreased deNOx performance of Fe-Beta.The soot combustion temperature was as low as 422℃,and the temperature window for 80%NO conversion was 164-423℃.The interaction between MnOd and zeolite can regulate the acid sites and produce sufficient active oxygen species for the catalyst.The catalytic activity of the MnOδ/Fe-Beta catalyst is due to its strong redox property,the appropriate number of acid sites,and sufficient number of active oxygen species.In addition,the catalyst had good stability and water and sulfur resistance,therefore it had great potential for future application in the simultaneous removal of NO_(x)and soot from diesel engine exhaust.

N,S,Br co-doped carbon dots:One-step synthesis and fluorescent detection of 6-mercaptopurine in tablet

6-mercaptopurine(6-MP),a purine derivative(3,7-dihydropurine-6-thione),has been utilized as an effective immunosuppressive drug for clinically treating leukemia and other autoimmune diseases[1].6-MP and its corresponding metabolites can suppress the function of RnaseH,and thus they are cytotoxic and threaten the human health[2].Therefore,the accurate quantification of 6-MP is crucial.To date,researchers continue to expend considerable effort in developing 6-MP detection methods.Fluorescence analysis eliminates disadvantages,such as toxic solvents,expensive equipment.

中国非小细胞肺癌免疫检查点抑制剂治疗专家共识(2020年版)

非小细胞肺癌(non-small cell lung cancer,NSCLC)是肺癌最常见的病理类型。晚期NSCLC的系统性抗肿瘤治疗经历了化疗、靶向治疗及免疫治疗的变革,患者总体生存时间不断延长。免疫检查点抑制剂(immune checkpoint inhibitors,ICIs),尤其是程序性死亡分子-1(programmed cell death protein 1,PD-1)/程序性死亡分子配体-1(programmed death-ligand 1,PD-L1)抗体已成为表皮生长因子受体(epidermal growth factor receptor,EGFR)/间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)阴性晚期NSCLC一线及二线的标准治疗和局部晚期NSCLC同步放化疗后标准治疗,并在辅助/新辅助治疗中显示出可喜的结果,改变了NSCLC整体治疗格局。随着越来越多的ICIs在国内获批肺癌适应证,中国临床肿瘤学会(Chinese Society of Clinical Oncology,CSCO)NSCLC专家委员会牵头,组织该领域的专家,结合2019年版专家共识,参考最新国内外文献、临床研究数据及系统评价,在专家共同讨论的基础上,达成统一意见并制定、更新本共识,为国内同行更好地应用ICIs治疗NSCLC提供参考意见。

传统合法化资源与农民工的利益表达——基于农民工1733份领导留言的文本分析

农民工的利益表达一直是地方政府非常重视的议题。但是,其表达方式尤其是他们是如何把自己的利益赋予合法性仍缺乏中国化的研究。论文通过对1733份农民工领导留言的文本分析,深入观察到诉求者“利”的合法化方式和策略,以及内化的“情”“理”“法”的文化心理结构。研究发现,在“重义轻利”为主导的文化心理框架下,诉求者需要把“利”合法化。通过“情”“理”“法”来赋予“利”以道德涵义和逻辑,从而形成了“情”“理”“法”的交互关系。由此,论文根据“情”“理”“法”的三者关系把合法化结构分为三种类型:传统型的情理法模式、理想型的法理情模式和现实型的理情法模式。以“理”作为评判底层民众利益表达行为的标准和尺度存在模糊性的风险。现实型的理情法文化心理模式意味着诉求者的心理结构仍然处于从传统型向现代型转变过程之中。为此,政府在处理诉求者的利益表达时需要加强法治化的引导。

摭谈高三数学一轮复习应重视的几个问题

高三数学一轮复习,主要是利用教材和复习资料,引导学生系统复习回顾以前所学习过的基础知识、基本技能、基本思想、基本方法,教会学生解决基本题型,教会学生自主复习的方法,教会学生整理错题集,并合理利用“错解资源”,教会学生规范解题,培养学生解后反思的习惯等等.

Prognostic factors of refractory NSCLC patients receiving anlotinib hydrochloride as the third-or further-line treatment

Objective:Anlotinib hydrochloride is a multitarget tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor,fibroblast growth factor receptor,platelet-derived growth factor receptor,c-Kit,and c-MET;therefore,it exhibits both antitumor and anti-angiogenetic activities.A phase III trial has shown that anlotinib improved progression-free survival(PFS)and overall survival(OS)in patients with advanced non-small cell lung cancer(NSCLC),who presented with progressive disease or intolerance after standard chemotherapy.This study aimed to analyze the characteristics of patients receiving anlotinib treatment to determine the dominant populations who are fit for the treatment.Methods:Data were collected from March 2015 to January 2017 from a randomized,double-blind,placebo-controlled,multicenter,phase III trial of anlotinib(ALTER0303).A total of 437 patients were enrolled and randomly allocated(2:1)to the anlotinib and placebo groups.Kaplan–Meier analysis and log-rank test were performed to compare PFS and OS.Cox proportional hazards model was adopted for multivariate prognostic analysis.Results:Multivariate analysis indicated that high post-therapeutic peripheral blood granulocyte/lymphocyte ratio and elevated alkaline phosphatase levels were independent risk factors for PFS.Meanwhile,elevated thyroid-stimulating hormone,blood glucose,and triglyceride levels;hypertension;and hand–foot syndrome were independent protective factors of PFS.High posttherapeutic peripheral blood granulocyte/lymphocyte ratio,an Eastern Cooperative Oncology Group(ECOG)score≥2,and the sum of the maximal target lesion length at baseline were independent risk factors of OS,and hypertriglyceridemia was an independent protective factor of OS.Conclusions:This study preliminarily explored the possible factors that affected PFS and OS after anlotinib treatment in patients with advanced refractory NSCLC,and the baseline characteristics of the therapeutically dominant populations were then identified.

Double-balloon enteroscopy in small bowel tumors: A Chinese single-center study

AIM: To analyze the clinical characteristics of small bowel tumors detected by double-balloon enteroscopy (DBE) and to evaluate the diagnostic value of DBE in tumors. METHODS: Four hundred and forty consecutive DBE examinations were performed in 400 patients (250 males and 150 females, mean age 46.9 ± 16.3 years, range 14-86 years) between January 2007 and April 2012. Of these, 252 patients underwent the antegrade approach, and 188 patients underwent the retrograde approach. All the patients enrolled in our study were suspected of having small bowel diseases with a negative etiological diagnosis following other routine examinations, such as upper and lower gastrointestinal endoscopy and radiography tests. Data on tumors, such as clinical information, endoscopic findings and opera-tion results, were retrospectively collected. RESULTS: Small bowel tumors were diagnosed in 78 patients, of whom 67 were diagnosed using DBE, resulting in a diagnostic yield of 16.8% (67/400); the other 11 patients had negative DBE findings and were diagnosed through surgery or capsule endoscopy. Adenocarcinoma (29.5%, 23/78), gastrointestinal stromal tumor (24.4%, 19/78) and lymphoma (15.4%, 12/78) were the most common tumors. Among the 78 tumors, 60.3% (47/78) were located in the jejunum, and the overall number of malignant tumors was 74.4% (58/78). DBE examinations were frequently performed in patients with obscure gastrointestinal bleeding (47.4%) and abdominal pain (24.4%). The positive detection rate for DBE in the 78 patients with small bowel tumors was 85.9% (67/78), which was higher than that of a computed tomography scan (72.9%, 51/70). Based on the operation results, the accuracy rates of DBE for locating small bowel neoplasms, such as adenocarcinoma, gastrointestinal stromal tumor and lymphoma, were 94.4%, 100% and 100%, respectively. The positive biopsy rates for adenocarcinoma and lymphoma were 71.4% and 60%, respectively. CONCLUSION: DBE is a useful diagnostic tool with high clinical practice value and should be considered the gold standard for the investigation of small bowel tumors.

Application of next-generation sequencing technology to precision medicine in cancer: joint consensus of the Tumor Biomarker Committee of the Chinese Society of Clinical Oncology

Next-generation sequencing(NGS) technology is capable of sequencing millions or billions of DNA molecules simultaneously.Therefore, it represents a promising tool for the analysis of molecular targets for the initial diagnosis of disease, monitoring of disease progression, and identifying the mechanism of drug resistance. On behalf of the Tumor Biomarker Committee of the Chinese Society of Clinical Oncology(CSCO) and the China Actionable Genome Consortium(CAGC), the present expert group hereby proposes advisory guidelines on clinical applications of NGS technology for the analysis of cancer driver genes for precision cancer therapy. This group comprises an assembly of laboratory cancer geneticists, clinical oncologists, bioinformaticians,pathologists, and other professionals. After multiple rounds of discussions and revisions, the expert group has reached a preliminary consensus on the need of NGS in clinical diagnosis, its regulation, and compliance standards in clinical sample collection. Moreover, it has prepared NGS criteria, the sequencing standard operation procedure(SOP), data analysis, report, and NGS platform certification and validation.

Current management of chemotherapy-induced neutropenia in adults:key points and new challenges

Chemotherapy-induced neutropenia(CIN)is a potentially fatal and common complication in myelosuppressive chemotherapy.The timing and grade of CIN may play prognostic and predictive roles in cancer therapy.CIN is associated with older age,poor functional and nutritional status,the presence of significant comorbidities,the type of cancer,previous chemotherapy cycles,the stage of the disease,specific chemotherapy regimens,and combined therapies.There are many key points and new challenges in the management of CIN in adults including:(1)Genetic risk factors to evaluate the patient’s risk for CIN remain unclear.However,these risk factors urgently need to be identified.(2)Febrile neutropenia(FN)remains one of the most common reasons for oncological emergency.No consensus nomogram for FN risk assessment has been established.(3)Different assessment tools[e.g.,Multinational Association for Supportive Care in Cancer(MASCC),the Clinical Index of Stable Febrile Neutropenia(CISNE)score model,and other tools]have been suggested to help stratify the risk of complications in patients with FN.However,current tools have limitations.The CISNE score model is useful to support decision-making,especially for patients with stable FN.(4)There are still some challenges,including the benefits of granulocyte colony stimulating factor treatment and the optimal antibiotic regimen in emergency management of FN.In view of the current reports,our group discusses the key points,new challenges,and management of CIN.

A study on vestibular-evoked myogenic potentials via galvanic vestibular stimulation in normal people

Objectives: The aim of our study is to examine vestibular-evoked myogenic potentials(VEMPs) elicited by the galvanic vestibular stimulation in the sternocleidomastoid muscle(SCM) in healthy subjects for clinical applications of auditory neuropathy or vestibular neuropathy in the future.Methods: We enrolled sixteen healthy subjects to record the average responses of SCM to galvanic vestibular stimulation(GVS) [current 3 mA;duration 1 ms] by electromyography(EMG). SPSS 18.0 software was used to analyze the obtained data for mean and standard deviation.Results: In all healthy subjects mastoid-forehead galvanic vestibular stimulation produced a positive-negative biphasic EMG responses on SCM ipsilateral to the cathodal electrode. The latency of p13 was 11.7 ± 3.0 ms. The latency of n23 was 17.8 ± 3.4 ms. The amplitude of p13-n23 was147.0 ± 69.0 μV. The interaural asymmetry ratio(AR) of p13, n23 latency and the amplitude was respectively 0.12 ± 0.09, 0.08 ± 0.08 and0.16 ± 0.10.Discussions: Galvanic vestibular stimulation could elicit biphasic EMG responses from SCM via the vestibular nerve but not from the otolith organs. Galvanic stimulation together with air conducted sound(ACS) or bone conducted vibration(BCV) can elicit VEMPs and may enable the differentiation of retrolabyrinthine lesions from labyrinthine lesions in vestibular system.

Achievement of complete response to nivolumab in a patient with advanced sarcomatoid hepatocellular carcinoma:A case report

BACKGROUND Sarcomatoid hepatocellular carcinoma(SHC)is a rare subtype of hepatocellular carcinoma(HCC),with a high recurrence rate after surgery.In addition to limited effective treatment for the advanced stage of SHC,the prognosis of patients with this malignancy is worse than that of patients with conventional HCC.CASE SUMMARY We present the case of a 54-year-old man with SHC who underwent radical segmental hepatectomy,which relapsed 4 mo after surgery due to lymphatic metastasis in the porta hepatis.Although a second surgery was performed,new metastasis developed in the mediastinal lymph nodes.Therefore,sorafenib and lenvatinib were sequentially administered as first-and second-line systemic therapies,respectively.However,progressive disease was confirmed based on a recurrent hepatic lesion and new metastatic lesion in the abdominal cavity.Percutaneous transhepatic cholangial drainage was performed to alleviate the biliary obstruction.Because the tumor was strongly positive for programmed death-ligand 1,the patient was started on nivolumab.Imaging studies revealed that after two cycles of immunotherapy,the metastatic lesions decreased to undetectable levels.CONCLUSION The patient experienced continuous complete remission for 8 mo.Immune checkpoint inhibitors are useful for the treatment of advanced SHC.

Understanding autism spectrum disorders with animal models:applications,insights,and perspectives

Autism spectrum disorder(ASD)is typically characterized by common deficits in social skills and repetitive/stereotyped behaviors.It is widely accepted that genetic and environmental factors solely or in combination cause ASD.However,the underlying pathogenic mechanism is unclear due to its highly heterogeneous nature.To better understand the pathogenesis of ASD,various animal models have been generated,which can be generally divided into genetic,environment-induced,and idiopathic animal models.In this review,we summarize the common animals used for ASD study and then discuss the applications,clinical insights,as well as challenges and prospects of current ASD animal models.

YC-1 exerts inhibitory effects on MDA-MB-468 breast cancer cells by targeting EGFR in vitro and in vivo under normoxic condition

3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole(YC-1),the hypoxia-inducible factor-1 alpha(HIF-1α) inhibitor,suppresses tumor proliferation and metastasis by down-regulating HIF-1α expression under hypoxic conditions.Our previous studies demonstrated that YC-1 inhibited breast cancer cell proliferation under normoxic conditions.In the current study,we investigated the targets of YC-1 and mechanism of its action in MDA-MB-468 breast cancer cells.In the in vitro experiments,we found that YC-1 significantly inhibited MDA-MB-468 cell proliferation in normoxia and hypoxia.Under normoxic conditions,YC-1 induced apoptosis of MDA-MB-468 cells and blocked cell cycle in the G1 phase,and these effects were possibly related to caspase 8,p21,and p27 expression.RT-PCR and Western blotting results showed that YC-1 primarily inhibited HIF-1α at the mRNA and protein levels under hypoxic conditions,but suppressed the expression of epidermal growth factor receptor(EGFR) at the mRNA and protein levels under normoxic conditions.In vivo,YC-1 prolonged survival,increased survival rate,decreased tumor size and metastasis rate,and inhibited tissue EGFR and HIF-1α expression.However,YC-1 exerted no obvious effect on body weight.These results indicate that YC-1 inhibits the proliferation of MDA-MB-468 cells by acting on multiple targets with minimal side effects.Thus,YC-1 is a promising target drug for breast cancer.

Protective effect of zinc: a potent heat shock protein inducer in cold preservation of rat liver

Objective: To study the synthesis of heat shock pro- tein 70 (HSP70) by zinc ( ZnSO_4) and its protective effect during cold preservation in rat liver by estab- lishment of a simple cold preservation model. Methods: Wistar rats were divided into 5 groups (n =6): control group untreated before operation; Zn- 1, Zn-2, and Zn-3 groups treated before operation with zinc sulfate (Zn^(2+) 5 mg/kg, 10 mg/kg, 15 mg/ kg respectively); H group treated with heat shock (42.5 ℃×15 min). The livers of the rats were pre- served in UW solution for 6, 12, 24 hours. The re- sults of heat shock protein (HSP) synthesis were ana- lyzed with Western blot. The aspartate aminotrans- ferase (AST) and lactic dehydrogenase (LDH) values of perfusion and histological findings were evaluated. Results: A great amount of HSPs was synthesized af- ter pretreatment with zinc and heat shock. The AST and LDH values of the Zn-1, Zn-2 and H groups were significantly lower than those of the C group (P <0.05). But the value of the Zn-3 group was much higher. Histologically, mild injury was observed in the Zn-1, Zn-2 and H groups, but severe injury in the Zn-3 group. Conclusions: Zn^(2+), as a potent and feasible inducer of HSP expression, is able to protect the liver for cold preservation. Proper induction dosage of Zn^(2+) ranges from 5 mg/kg to 10 mg/kg, and Zn^(2+) 15 mg/ kg could not be a stress conditioning factor for its ad- verse effect on rat liver.

Trispecific killer engager 161519 enhances natural killer cell function and provides anti-tumor activity against CD19-positive cancers

Objective:Natural killer(NK)cells have gained considerable attention due to their potential in treating"cold tumors,"and are therefore considered as one of the new strategies for curing cancer,by using worldwide development of their new possibilities and interventions with NK cell-related therapeutic products.Methods:We constructed a trispecific killer engager(TriKE)consisting of anti-CD16,IL-15,and anti-CD19.This TriKE was designed to attract CD19^(+)tumor cells to CD16^(+)NK cells,whereas IL-15 sustained the proliferation,development,and survival of NK cells.Results:Treatment with 161519 TriKE in the presence of CD19^(+)targets upregulated expression of CD69,CD107 a,TRAIL,IFN-γ,and TNF-α in NK cells,and significantly improved the proliferation and cytotoxicity of NK cells.NK cells"armed"with 161519 TriKE showed stronger cytolysis against CD19+targets compared with that of"unarmed"NK cells.A preclinical model of B-cell lymphoma in human peripheral blood mononuclear cell-reconstituted xenograft mice showed significant inhibition of tumor growth and prolonged overall survival after treatment with 161519 TriKE,when compared with that in control mice or mice treated with 1619 BiKE.Combined use of IL-2 was a more effective treatment with 1619 BiKE,when compared with that using 161519 TriKE.Conclusions:The newly generated 161519 TriKE enhanced the proliferation,activation,cytokine secretion,and cytotoxicity of NK cells in the presence of CD19+tumor cells.The 161519 TriKE aided inhibition of tumor growth and prolonged the overall survival of murine xenografts,and could be used to treat CD19-positive cancers.

Prediction of rat liver transplantation outcomes using energy metabolites measured by microdialysis

Background: Warm ischemia jeopardizes graft quality and recipient survival in donation after cardiac death(DCD) transplantation. Currently, there is no system to objectively evaluate the liver quality from DCD. The present study tried to use energy metabolites to evaluate the donor liver quality. Methods: We divided 195 Sprague-Dawley rats into five groups: the control( n = 39), warm ischemic time(WIT) 15 min( n = 39), WIT 30 min( n = 39), WIT 45 min( n = 39), and WIT 60 min( n = 39) groups. Three rats from each group were randomly selected for pretransplant histologic evaluation of warm ischemiarelated damage. The remaining 36 rats were randomly divided into donors and recipients of 18 liver transplantations, and were subjected to postoperative liver function and survival analyses. Between cardiac arrest and cold storage, liver energy metabolites including glucose, lactate, pyruvate, and glycerol were measured by microdialysis. The lactate to pyruvate ratio(LPR) was calculated. Results: The changes in preoperative pathology with warm ischemia were inconspicuous, but the trends in postoperative pathology and aminotransferase levels were consistent with preoperative energy metabolite measurements. The 30-day survival rates of the control and WIT 15, 30, 45, and 60 min groups were 100%, 81.82%, 76.92%, 58.33%, and 25.00%, respectively. The areas under the receiver operating characteristic curves of glucose, lactate, glycerol, and LPR were 0.87, 0.88, 0.88, and 0.92, respectively. Conclusion: Glucose, lactate, glycerol, and LPR are predictors of graft quality and survival outcomes in DCD transplantation.