利用深度学习系统筛查新冠病毒肺炎

实时逆转录聚合酶链反应(RT-PCR)检测早期新冠病毒肺炎(COVID-19)患者的痰液或鼻咽拭子中的病毒RNA阳性率较低。同时,COVID-19的计算机断层扫描(CT)影像学的临床表现有其自身的特点,不同于甲型流感病毒性肺炎(IAVP)等其他类型的病毒性肺炎。本研究旨在应用深度学习技术,建立COVID-19、IAVP及健康人群肺部CT的早期筛查模型。本研究共采集618份CT样本,其中219份样本来自110例COVID-19患者(平均年龄50岁,其中男性63例,占57.3%),224份样本来自224例IAVP患者(平均年龄61岁,其中男性156例,占69.6%),175份样本来自健康人群(平均年龄39岁,其中男性97例,占55.4%)。所有CT样本均来自浙江省三家COVID-19定点收治医院。我们首先利用胸部CT图像集的三维(3D)深度学习模型分割出候选感染区域,然后利用位置敏感机制深度学习网络将这些分离的图像归类为COVID-19、IAVP以及与感染无关(ITI)的图像,并且输出相应置信度得分。最后,用Noisy-OR贝叶斯函数计算每份CT病例的感染类型及总置信度。测试数据集的实验结果表明,从整体CT病例来看,本研究利用深度学习系统建立的COVID-19患者的早期筛查模型的总体准确率为86.7%。该模型有望成为一线临床医生诊断COVID-19的一种有效的辅助方法。

Contingency management strategies of the Nursing Department in centralized rescue of patients with coronavirus disease 2019

Objectives:This article aims to summarize a series of contingency management strategies of the Nursing Department in the centralized treatment of patients with coronavirus disease 2019(COVID-19).Methods:The strategies of the Nursing Department included an early warning for prevention and control,taking functions of vertically commanding and horizontally coordinating,and reasonably allocating nursing workforce,to facilitate centralized treatment work in the in-hospital fever clinic,isolation wards and ICU,and referral and admission of critical patients.Five special groups were established in charge of training and examination,management and supervision,psychological support,logistical support,and reporting and publicity,respectively.Results:It was achieved that no deaths from critical patients and no medical staff,no other patients were infected.Conclusion:Through the implementation of these strategies,safe and efficient centralized treatment was ensured timely,orderly and sustainably.

Multiplex imaging reveals the architecture of the tumor immune microenvironment

The tumor immune microenvironment(TME)is composed of a variety of components,such as tumor cells,immune cells,and the extracellular matrix.The TME has been studied through transcriptomic,proteomic,metabolomic,and phosphoproteomic approaches,which have provided researchers with a wealth of TME-related molecular information.

mRNA vaccines in disease prevention and treatment

mRNA vaccines have emerged as highly effective strategies in the prophylaxis and treatment of diseases,thanks largely although not totally to their extraordinary performance in recent years against the worldwide plague COVID-19.

Oncolytic virotherapy:basic principles,recent advances and future directions

Oncolytic viruses(OVs)have attracted growing awareness in the twenty-first century,as they are generally considered to have direct oncolysis and cancer immune effects.With the progress in genetic engineering technology,OVs have been adopted as versatile platforms for developing novel antitumor strategies,used alone or in combination with other therapies.Recent studies have yielded eye-catching results that delineate the promising clinical outcomes that OVs would bring about in the future.In this review,we summarized the basic principles of OVs in terms of their classifications,as well as the recent advances in OV-modification strategies based on their characteristics,biofunctions,and cancer hallmarks.Candidate OVs are expected to be designed as“qualified soldiers”first by improving target fidelity and safety,and then equipped with“cold weapons”for a proper cytocidal effect,“hot weapons”capable of activating cancer immunotherapy,or“auxiliary weapons”by harnessing tactics such as anti-angiogenesis,reversed metabolic reprogramming and decomposing extracellular matrix around tumors.Combinations with other cancer therapeutic agents have also been elaborated to show encouraging antitumor effects.Robust results from clinical trials using OV as a treatment congruously suggested its significance in future application directions and challenges in developing OVs as novel weapons for tactical decisions in cancer treatment.

Synergetic treatment of oxygen microcapsules and lenvatinib for enhanced therapy of HCC by alleviating hypoxia condition and activating anti-tumor immunity

Hypoxia is a typical characteristic of hepatocellular carcinoma(HCC), which causes tremendous obstacles to tumor treatments. Current first-line treatment may further deteriorate tumor hypoxia. For example,Lenvatinib, a receptor tyrosine kinase inhibitor(RTKI), suppresses tumor growth via blocking vascular endothelial growth factor(VEGF) signaling, and can also inhibit angiogenesis, thus limiting oxygen supply to tumor sites. Therefore, alleviating tumor microenvironment(TME) hypoxia holds great potential for enhancing the therapeutic effect of RTKI. Here, nanoparticle-stabilized oxygen microcapsules, a stable and biocompatible oxygen-loaded delivery system, are successfully prepared through interfacial polymerization of polydopamine nanoparticles. The microcapsules with a large loading capacity of oxygen in the core show excellent bioavailability and dispersity, which could effectively improve the hypoxic TME when they serve as oxygen delivery vehicles. Synergetic treatments of Lenvatinib and oxygen microcapsules could induce the transition of “cold tumor” in an immune-suppressed state to “hot tumor” in an immune-activated state by improving tumor hypoxic TME and reducing angiogenesis in HCC. It is revealed that combined treatments of oxygen microcapsules and Lenvatinib could polarize tumor-associated macrophages(TAMs) to anti-tumor M1 cells and activate T cell-mediated anti-tumor immune responses.The results suggest that synergetic therapy using oxygen microcapsules and Lenvatinib could alleviate the hypoxic TME and enhance the therapeutic performance of RTKI, demonstrating a promising anti-tumor strategy for enhanced therapy of HCC.

Oxygen microcapsules improve immune checkpoint blockade by ameliorating hypoxia condition in pancreatic ductal adenocarcinoma

Rationale:Hypoxia in tumor microenvironment(TME)represents an obstacle to the efficacy of immunotherapy for pancreatic ductal adenocarcinoma(PDAC)through several aspects such as increasing the expression of immune checkpoints or promoting fibrosis.Reversing hypoxic TME is a potential strategy to improve the validity of immune checkpoint blockade(ICB).Methods:Here,we synthesized polydopamine-nanoparticle-stabilized oxygen microcapsules with excellent stabilization,bioavailability,and biocompatibility for direct oxygen delivery into tumor sites by interfacial polymerization.Results:We observed oxygen microcapsules enhanced the oxygen concentration in the hypoxia environment and maintained the oxygen concentration for a long period both in vitro and in vivo.We found that oxygen microcapsules could significantly improve the efficiency of ICB against PDAC in vivo.Mechanismly,combined treatments using oxygen microcapsules and ICB could reduce the infiltration of tumor-associated macrophages(TAMs)and polarized pro-tumor M2 macrophages into anti-tumor M1 macrophages.In addition,combined treatments could elevate the proportion of T helper subtype 1 cells(Th1 cells)and cytotoxic T lymphocytes cells(CTLs)to mediate anti-tumor immune response in TME.Conclusion:In summary,this pre-clinical study indicated that reversing hypoxia in TME by using oxygen microcapsules was an effective strategy to improve the performances of ICB on PDAC,which holds great potential for treating PDAC in the future.

细胞与基因治疗中大片段的DNA精准插入研究进展

Cell and gene therapy(CGT)shows great therapeutic potential for diverse diseases such as hereditary diseases,cancer,and infectious diseases,with more than 40 food and drug administration(FDA)-approved drugs and lots in preclinical or clinical trials.In the scenario of cell therapy,cells typically isolated from the patients or healthy donors are functionally enhanced in vitro via genome editing before infusion back to patients.

Imatinib blocks tyrosine phosphorylation of Smad4 and restores TGF-β growth-suppressive signaling in BCR-ABL1-positive leukemia

Loss of TGF-β-mediated growth suppression is a major contributor to the development of cancers,best exemplified by loss-offunction mutations in genes encoding components of the TGF-βsignaling pathway in colorectal and pancreatic cancers.Alternatively,gain-of-function oncogene mutations can also disrupt antiproliferative TGF-βsignaling.However,the molecular mechanisms underlying oncogene-induced modulation of TGF-βsignaling have not been extensively investigated.Here,we show that the oncogenic BCR-ABL1 of chronic myelogenous leukemia(CML)and the cellular ABL1 tyrosine kinases phosphorylate and inactivate Smad4 to block antiproliferative TGF-βsignaling.Mechanistically,phosphorylation of Smad4 at Tyr195,Tyr301,and Tyr322 in the linker region interferes with its binding to the transcription co-activator p300/CBP,thereby blocking the ability of Smad4 to activate the expression of cyclin-dependent kinase(CDK)inhibitors and induce cell cycle arrest.In contrast,the inhibition of BCR-ABL1 kinase with Imatinib prevented Smad4 tyrosine phosphorylation and re-sensitized CML cells to TGF-β-induced antiproliferative and pro-apoptotic responses.Furthermore,expression of phosphorylation-site-mutated Y195F/Y301F/Y322F mutant of Smad4 in Smad4-null CML cells enhanced antiproliferative responses to TGF-β,whereas the phosphorylation-mimicking Y195E/Y301E/Y322E mutant interfered with TGF-βsignaling and enhanced the in vivo growth of CML cells.These findings demonstrate the direct role of BCR-ABL1 tyrosine kinase in suppressing TGF-βsignaling in CML and explain how Imatinib-targeted therapy restored beneficial TGF-βanti-growth responses.

Identification of a class of potent USP25/28 inhibitors with broad-spectrum anti-cancer activity

Dear Editor,An increasing body of evidence suggests that USP28 could be a target for cancer treatment^(1-4).To identify its inhibitors,we screened a 100-thousand synthetic compound library and found 3 lead compounds,CT1001-1003,that showed significant inhibitory activity(Supplementary Fig.1a).The optimization of these compounds led to CT1018,a much stronger inhibitor(Supplementary Fig.1b).

Activated cytotoxic lymphocytes promote tumor progression by increasing the ability of 3LL tumor cells to mediate MDSC chemoattraction via Fas signaling

The Fas/FasL system transmits intracellular apoptotic signaling, inducing cell apoptosis. However, Fas signaling also exerts non-apoptotic functions in addition to inducing tumor cell apoptosis. For example, Fas signaling induces lung cancer tumor cells to produce prostaglandin E2 （PGE2） and recruit myeloid-derived suppressor cells （MDSCs）. Activated cytotoxic T lymphocytes （CTLs） induce and express high levels of FasL, but the effects of Fas activation initiated by FasL in CTLs on apoptosis-resistant tumor cells remain largely unclear. We purified activated CD8^＋ T cells from OT-1 mice, evaluated the regulatory effects of Fas activation on tumor cell escape and investigated the relevant mechanisms. We found that CTLs induced tumor cells to secrete PGE2 and increase tumor cell-mediated chemoattraction of MDSCs via Fas signaling, which was favorable to tumor growth. Our results indicate that CTLs may participate in the tumor immune evasion process. To the best of our knowledge, this is a novel mechanism by which CTLs play a role in tumor escape. Our findings implicate a strategy to enhance the antitumor immune response via reduction of negative immune responses to tumors promoted by CTLs through Fas signaling.

Chinese expert consensus on conversion therapy for hepatocellular carcinoma(2021 edition)

Recent advances in systemic and locoregional treatments for patients with unresectable or advanced hepatocellular carcinoma(HCC)have resulted in improved response rates.This has provided an opportunity for selected patients with initially unresectable HCC to achieve adequate tumor downstaging to undergo surgical resection,a‘conversion therapy’strategy.However,conversion therapy is a new approach to the treatment of HCC and its practice and treatment protocols are still being developed.Review the evidence for conversion therapy in HCC and develop consensus statements to guide clinical practice.Evidence review:Many research centers in China have accumulated significant experience implementing HCC conversion therapy.Preliminary findings and data have shown that conversion therapy represents an important strategy to maximize the survival of selected patients with intermediate stage to advanced HCC;however,there are still many urgent clinical and scientific challenges for this therapeutic strategy and its related fields.In order to summarize and learn from past experience and review current challenges,the Chinese Expert Consensus on Conversion Therapy for Hepatocellular Carcinoma(2021 Edition)was developed based on a review of preliminary experience and clinical data from Chinese and non-Chinese studies in this field and combined with recommendations for clinical practice.Sixteen consensus statements on the implementation of conversion therapy for HCC were developed.The statements generated in this review are based on a review of clinical evidence and real clinical experience and will help guide future progress in conversion therapy for patients with HCC.

Auranofin mitigates systemic iron overload and induces ferroptosis via distinct mechanisms

Iron homeostasis is essential for health;moreover,hepcidin-deficiency results in iron overload in both hereditary hemochromatosis and iron-loading anemia.Here,we identified iron modulators by functionally screening hepcidin agonists using a library of 640 FDA-approved drugs in human hepatic Huh7 cells.We validated the results in C57BL/6J mice and a mouse model of hemochromatosis(Hfe^(−/−)mice).Our screen revealed that the anti-rheumatoid arthritis drug auranofin(AUR)potently upregulates hepcidin expression.Interestingly,we found that canonical signaling pathways that regulate iron,including the Bmp/Smad and IL-6/Jak2/Stat3 pathways,play indispensable roles in mediating AUR’s effects.In addition,AUR induces IL-6 via the NF-κB pathway.In C57BL/6J mice,acute treatment with 5 mg/kg AUR activated hepatic IL-6/hepcidin signaling and decreased serum iron and transferrin saturation.Whereas chronically treating male Hfe^(−/−)mice with 5 mg/kg AUR activated hepatic IL-6/hepcidin signaling,decreasing systemic iron overload,but less effective in females.Further analyses revealed that estrogen reduced the ability of AUR to induce IL-6/hepcidin signaling in Huh7 cells,providing a mechanistic explanation for ineffectiveness of AUR in female Hfe^(−/−)mice.Notably,high-dose AUR(25 mg/kg)induces ferroptosis and causes lipid peroxidation through inhibition of thioredoxin reductase(TXNRD)activity.We demonstrate the ferroptosis inhibitor ferrostatin significantly protects liver toxicity induced by highdose AUR without comprising its beneficial effect on iron metabolism.In conclusion,our findings provide compelling evidence that TXNRD is a key regulator of ferroptosis,and AUR is a novel activator of hepcidin and ferroptosis via distinct mechanisms,suggesting a promising approach for treating hemochromatosis and hepcidin-deficiency related disorders.

节段性小肠移植手术中采用自体髂内血管进行血管重建

背景:本研究旨在评估自体髂内动静脉可否用于异体及自体节段性小肠移植手术的血管重建。方法:2011年1月至2019年1月间34例小肠移植患者纳入研究,其中19例为亲属活体移植,15例为自体移植。收集患者临床资料、血管重建类型及术后并发症进行分析。结果:全组男性20例,女性14例,中位年龄35岁。在34例小肠移植中,22例(64.7%,其中异体移植和自体移植各11例)采用自体髂内动脉脉进行血管重建,12例(35.3%)直接行血管吻合。血管重建耗时(21˘6)min。与直接吻合组相比,血管重建组患者手术总时长(530˘226 vs 440˘116 min,P=0.208)和冷缺血时间(159˘49 vs 125˘66 min,P=0.097)均有延长的趋势,但差异并未达到统计学意义。直接吻合组术后血栓形成发生率较血管重建组有增高的趋势(16.7%vs 0%,P=0.118)。中位随访36.9个月,无一例出现静脉狭窄或假性动脉瘤。19例异体移植患者中,4例(21.1%)发生急性排斥反应,1例(5.2%)出现慢性排斥反应。结论:本组数据显示,采用自体髂内动静脉进行血管重建可有力促进小肠移植的开展,同时有望降低术后血管并发症的风险。

Advantages of targeting the tumor immune microenvironment over blocking immune checkpoint in cancer immunotherapy

Despite great success in cancer immunotherapy,immune checkpoint-targeting drugs are not the most popular weapon in the armory of cancer therapy.Accumulating evidence suggests that the tumor immune microenvironment plays a critical role in anticancer immunity,which may result in immune checkpoint blockade therapy being ineffective,in addition to other novel immunotherapies in cancer patients.In the present review,we discuss the deficiencies of current cancer immunotherapies.More importantly,we highlight the critical role of tumor immune microenvironment regulators in tumor immune surveillance,immunological evasion,and the potential for their further translation into clinical practice.Based on their general targetability in clinical therapy,we believe that tumor immune microenvironment regulators are promising cancer immunotherapeutic targets.Targeting the tumor immune microenvironment,alone or in combination with immune checkpoint-targeting drugs,might benefit cancer patients in the future.

Blocking PD-L1 for anti-liver cancer immunity:USP22 represents a critical cotarget

MULTIPLE LEVELS OF PD-L1 REGULATION IN CANCER IMMUNOTHERAPY To date,the PD-1/PD-L1 blockade strategy has been tested in a variety of cancer types.However,only bladder cancer,melanoma,mismatch repair-deficient colorectal cancer,and certain hematopoietic malignancies have been highly responsive in terms of clinical outcomes.1,2 It is presumed that the expression level of the PD-L1 protein largely determines the therapeutic efficacy of PD-1/PD-L1-targeted cancer immunotherapy.3,4 Previous studies have shown that several transcriptional factors are involved in the upregulation of PD-L1 by directly binding to its promoter region.5 For instance,individual activation of STAT1,NF-κB,HIF-1α,c-Myc,or MAPK increased PD-L1 transcription and immune evasion of tumor cells.On the other hand,oncogenic RAS signaling reportedly stabilizes PD-L1 mRNA to promote tumor immunoresistance.

Eating self for not be eaten:Pancreatic cancer suppresses selfimmunogenicity by autophagy-mediated MHC-I degradation

In a recent study in Nature,1 Yamamoto et al.reported that MHC-I is a selective substrate of autophagy in tumor immune evasion.Furthermore,it was reported that autophagy-mediated lysosomal degradation of MHC-I suppresses pancreatic cancer immunogenicity and the effectiveness of immunotherapy.These findings indicate the potential of autophagy inhibition as a strategy to activate anti-pancreatic cancer immunity.

Guidelines for the diagnosis and treatment of acute pancreatitis in China (2021)

Acute pancreatitis(AP)is a common acute abdominal condition of the digestive system.In recent years,treatment concepts,methods,and strategies for the diagnosis of AP have advanced,and this has played an important role in promoting the standardization of AP diagnosis and treatment and improving the treatment quality of AP patients.On the basis of previous guidelines and expert consensus,this guideline adopts an evidence-based,problem-based expression;synthesizes important clinical research data at home and abroad in the most recent 5 years;and forms 29 recommendations through multidisciplinary expert discussion,including diagnosis,treatment,and follow-up.It is expected to provide evidence support for the treatment of AP in the clinical setting in China.

Auto-intestine transplantation for pancreatic tumors with mesenteric root involvement:a systematic review and survival-based analysis

To analyze a long-term survival outcome of an auto-intestine transplantation(aINTx)for the patients with locally advanced pancreatic tumor and identify the potential prognostic factors,databases were carefully searched for the studies reporting the patients with a locally advanced pancreatic tumor which typically underwent aINTx.We performed a database search using PubMed,the Cochrane Library,EMBASE,and MEDLINE to identify multiple case series of the patients who had pancreatic tumors with mesenteric root involvement and underwent aINTx,to evaluate the treatment outcomes,and calculated the patient survival using the Kaplan–Meier method and Cox proportional hazard regression analysis to properly identify an independent predictor of the survival.A total of 9 retrospective studies with a total of 29 patients were included in our study.The calculated 1-,2-,and 3-year survival rates for the patients with pancreatic cancer and benign or low grade pancreatic tumors were 49.64%,22.06%,and 0%versus 100%,100%,and 80%,respectively.The corresponding median survival time was 13.4months and 84months,respectively.Moreover,when stratifying the pancreatic cancer patients undergoing aINTx on the basis of neoadjuvant chemotherapy(aINTx+neoadjuvant vs aINTx-neoadjuvant)there was a significant difference in the survival(P=0.01).The 1-and 2-year survival rates were 75%and 75%versus 34.1%and 0%,respectively.Corresponding median survival times were 24months and 10months,respectively.Our analysis shows the long-term survival benefit with acceptable morbidity and mortality of pancreatoduodenectomy and aINTx for the pancreatic tumors with the mesenteric root involvement that are otherwise unresectable by the conventional surgical techniques.However,from an oncological point of view,a larger study with the control group is required to determine its safety compared to less aggressive surgical treatment.

The current surgical treatment of pancreatic neuroendocrine neoplasms in China: a national wide cross-sectional study

Objective:The aim of this study is to investigate the current status of the diagnosis and treatment of patients with pancreatic neuroendocrine neoplasms(pNENs)undergoing surgery in China.Methods:This is a multicenter cross-sectional study performed in China.Data from patients with pNENs undergoing surgery at 33 high-volume medical centers,where the number of pancreatectomies exceeds 20 cases per year,were collected and analyzed between March 1,2016 and February 28,2017.Results:In total,392 patients with pNENs were enrolled.The male to female ratio was 1.4.The majority of patients were aged between 40 and 70 years.65.6%of the patients had non-functional tumors.Among those with functional tumors,the percentages of insulinomas,gastrinomas,glucagonomas,and vasoactive intestinal peptide-secreting tumors were 94.8%,1.5%,2.2%,and 1.5%,respectively.Multidisciplinary team(MDT)discussion was conducted for 39.0%of the patients.Minimally invasive surgery was performed on 31.1%of the 392 patients.The incidence of grade B/C pancreatic fistula formation was 4.4%.A total of 89.0%of the surgeries achieved R0 resection,and 41.6%of the tumors were well differentiated.Lymph node metastasis was present in 8.9%of the patients.The percentages of patients with grades G1,G2,and G3 disease were 49.2%,45.7%,and 5.1%,respectively.Conclusion:This multicenter cross-sectional study systematically presents the current status of the diagnosis and treatment of patients with pNENs undergoing surgery in China.MDT consultation for pNENs has not been widely implemented in China.Although the incidence of surgical complications is relatively low,minimally invasive procedures should be further promoted.This study shows us how to improve the outcomes of these patients.