Viro-immune therapy:A new strategy for treatment ofpancreatic cancer

Pancreatic ductal adenocarcinoma(PDAC) is an almost uniformly lethal disease with less than 5% survival at five years. This is largely due to metastatic disease, which is already present in the majority of patients when diagnosed. Even when the primary cancer can be removed by radical surgery, local recurrence occurs within one year in 50%-80% of cases. Therefore, it is imperative to develop new approaches for the treatment of advanced cancer and the prevention of recurrence after surgery. Tumour-targeted oncolytic viruses(TOVs) have become an attractive therapeutic agent as TOVs can kill cancer cells through multiple mechanisms of action, especially via virus-induced engagement of the immune response specifically against tumour cells. To attack tumour cells effectively, tumour-specific T cells need to overcome negative regulatory signals that suppress their activation or that induce tolerance programmes such as anergy or exhaustion in the tumour microenvironment. In this regard, the recent breakthrough in immunotherapy achieved with immune checkpoint blockade agents, such as anti-cytotoxic T-lymphocyte-associate protein 4, programmed death 1(PD-1) or PD-L1 antibodies, has demonstrated the possibility of relieving immune suppression in PDAC. Therefore, the combination of oncolytic virotherapy and immune checkpoint blockade agents may synergistically function to enhance the antitumour response, lending the opportunity to be the future for treatment of pancreatic cancer.

Immune checkpoint inhibitors in cancer therapy

In recent years immune checkpoint inhibitors have garnered attention as being one of the most promising types of immunotherapy on the horizon. There has been particular focus on the immune checkpoint molecules, cytotoxic Tlymphocyte antigen-4（CTLA-4） and programmed cell death protein 1（PD-1） which have been shown to have potent immunomodulatory effects through their function as negative regulators of T cell activation. CTLA-4, through engagement with its ligands B7-1（CD80） and B7-2（CD86）, plays a pivotal role in attenuating the activation of naive and memory T cells. In contrast, PD-1 is primarily involved in modulating T cell activity in peripheral tissues via its interaction with PD-L1 and PD-L2. The discovery of these negative regulators of the immune response was crucial in the development of checkpoint inhibitors. This shifted the focus from developing therapies that targeted activation of the host immune system against cancer to checkpoint inhibitors, which aimed to mediate tumor cell destruction through the removal of coinhibitory signals blocking anti-tumor T cell responses.

Circulating cancer stem cells:the importance to select

It has been demonstrated that even localized tumors withottt chnically apparent metastasis give rise to circulating tumor cells （CTCs）. A growing number of technically diverse platforms are being developed for detecting/isolating CTCs in the circulating blood. Despite the technical challenges of isolating rare CTCs from blood, recent studies have already shown the predictive value of CTCs enumeration. Thus, it is becoming increasingly accepted that CTC numbers are linked to patients＇ outcome and may also be used to monitor treatment response and disease relapse, respectively. Further CTCs provide a non-invasive source for tumor material, ＇liquid biopsy＇, which is particularly important for patients, where no biopsy material can be obtained or where serial biopsies of the tumor, e.g., following treatment, are practically impossible. On the other hand the molecular and biological characterization of CTCs has still remained at a rather experimental stage. Future studies are necessary to define CTC heterogeneity to establish the crucial role of circulating cancer stem cells for driving metastasis, which represent a distinct subpopulation of CTCs that bear metastasis-initiating capabilities based on their sternness properties and invasiveness and thus are critical for the patients＇ clinical outcome. As compared to non-tumorigenic/metastatic bulk CTCs, circulating cancer stem cells may not only be capable of evading from the primary tumor, but also escape from immune surveillance, survive in the circulating blood and subsequently form metastases in distant organs. Thus, circulating cancer stem cells represent a subset of exclusively tumorigenic cancer stem cells characterized by their invasive characteristics and are potential therapeutic targets for preventing disease progression. To date, only a few original reports and reviews have been published focusing on circulating cancer stem cells. This review discusses the potential importance of isolating and characterizing these circulating cancer stem cells, but also highlights current technological limitations.

Diffusion-weighted magnetic resonance imaging in cancer: Reported apparent diffusion coefficients,in-vitro and invivo reproducibility

There is considerable disparity in the published apparent diffusion coefficient(ADC) values across different anatomies. Institutions are increasingly assessing repeatability and reproducibility of the derived ADC to determine its variation,which could potentially be used as an indicator in determining tumour aggressiveness or assessing tumour response. In this manuscript,a review of selected articles published to date in healthy extracranial body diffusion-weighted magnetic resonance imaging is presented,detailing reported ADC values and discussing their variation across different studies. In total 115 studies were selected including 28 for liver parenchyma,15 for kidney(renal parenchyma),14 for spleen,13 for pancreatic body,6 for gallbladder,13 for prostate,13 for uterus(endometrium,myometrium,cervix) and 13 for fibroglandular breast tissue. Median ADC values in selected studies were found to be 1.28 × 10-3 mm2/s in liver,1.94 × 10-3 mm2/s in kidney,1.60 × 10-3 mm2/s in pancreatic body,0.85 × 10-3 mm2/s in spleen,2.73 × 10-3 mm2/s in gallbladder,1.64 × 10-3 mm2/s and 1.31 × 10-3 mm2/s in prostate peripheral zone and central gland respectively(combined median value of 1.54×10-3 mm2/s),1.44 × 10-3 mm2/s in endometrium,1.53 × 10-3 mm2/s in myometrium,1.71 × 10-3 mm2/s in cervix and 1.92 × 10-3 mm2/s in breast. In addition,six phantom studies and thirteen in vivo studies were summarized to compare repeatability and reproducibility of the measured ADC. All selected phantom studies demonstrated lower intra-scanner and inter-scanner variation compared to in vivo studies. Based on the findings of this manuscript,it is recommended that protocols need to be optimised for the body part studied and that system-induced variability must be established using a standardized phantom in any clinical study. Reproducibility of the measured ADC must also be assessed in a volunteer population,as variations are far more significant in vivo compared with phantom studies.

Promising xenograft animal model recapitulating the features of human pancreatic cancer

BACKGROUND Multiple sites of metastasis and desmoplastic reactions in the stroma are key features of human pancreatic cancer(PC).There are currently no simple and reliable animal models that can mimic these features for accurate disease modeling.AIM To create a new xenograft animal model that can faithfully recapitulate the features of human PC.METHODS Interleukin 2 receptor subunit gamma(IL2RG)gene knockout Syrian hamster was created and characterized.A panel of human PC cell lines were transplanted into IL2RG knockout Syrian hamsters and severe immune-deficient mice subcutaneously or orthotopically.Tumor growth,local invasion,remote organ metastasis,histopathology,and molecular alterations of tumor cells and stroma were compared over time.RESULTS The Syrian hamster with IL2RG gene knockout(named ZZU001)demonstrated an immune-deficient phenotype and function.ZZU001 hamsters faithfully recapitulated most features of human PC,in particular,they developed metastasis at multiple sites.PC tissues derived from ZZU001 hamsters displayed desmoplastic reactions in the stroma and epithelial to mesenchymal transition phenotypes,whereas PC tissues derived from immune-deficient mice did not present such features.CONCLUSION ZZU001 hamsters engrafted with human PC cells are a superior animal model compared to immune-deficient mice.ZZU001 hamsters can be a valuable animal model for better understanding the molecular mechanism of tumorigenesis and metastasis and the evaluation of new drugs targeting human PC.

Pancreatic cancer organotypics: High throughput, preclinical models for pharmacological agent evaluation

Pancreatic cancer carries a terrible prognosis,as the fourth most common cause of cancer death in the Western world.There is clearly a need for new therapies to treat this disease.One of the reasons no effective treatment has been developed in the past decade may in part,be explained by the diverse influences exerted by the tumour microenvironment.The tumour stroma cross-talk in pancreatic cancer can influence chemotherapy delivery and response rate.Thus,appropriate preclinical in vitro models which can bridge simple 2D in vitro cell based assays and complex in vivo models are required to understand the biology of pancreatic cancer.Here we discuss the evolution of 3D organotypic models,which recapitulare the morphological and functional features of pancreatic ductal adenocarcinoma(PDAC).Organotypic cultures are a valid high throughput preclinical in vitro model that maybe a useful tool to help establish new therapies for PDAC.A huge advantage of the organotypic model system is that any component of the model can be easily modulated in a short timeframe.This allows new therapies that can target the cancer,the stromal compartment or both to be tested in a model that mirrors the in vivo situation.A major challenge for the future is to expand the cellular composition of the organotypic model to further develop a system that mimics the PDAC environment more precisely.We discuss how this challenge is being met to increase our understanding of this terrible disease and develop novel therapies that can improve the prognosis for patients.

B cells in pancreatic cancer stroma

Pancreatic cancer is a disease with high unmet clinical need.Pancreatic cancer is also characterised by an intense fibrotic stroma,which harbours many immune cells.Studies in both human and animal models have demonstrated that the immune system plays a crucial role in modulating tumour onset and progression.In human pancreatic ductal adenocarcinoma,high B-cell infiltration correlates with better patient survival.Hence,B cells have received recent interest in pancreatic cancer as potential therapeutic targets.However,the data on the role of B cells in murine models is unclear as it is dependent on the pancreatic cancer model used to study.Nevertheless,it appears that B cells do organise along with other immune cells such as a network of follicular dendritic cells(DCs),surrounded by T cells and DCs to form tertiary lymphoid structures(TLS).TLS are increasingly recognised as sites for antigen presentation,T-cell activation,Bcell maturation and differentiation in plasma cells.In this review we dissect the role of B cells and provide directions for future studies to harness the role of B cells in treatment of human pancreatic cancer.

《2019年世界急诊外科学会重症急性胰腺炎诊治共识》摘译

1介绍急性胰腺炎(acute pancreatitis,AP)是胰腺的一种炎症疾病,其中重症急性胰腺炎(severe acute pancreatitis,SAP)占比20%~30%,是一种危及生命的疾病,院内病死率约为15%。胰腺和胰周坏死的感染,与器官衰竭是SAP的主要特征。

《2019年美国放射治疗及肿瘤学会临床实践指南:胰腺癌的放射治疗》摘译

1背景美国放射治疗及肿瘤学会(ASTRO)召集一个多样化的专责小组,针对放射治疗的7个关键问题(包括剂量分配、治疗量、模拟和治疗计划,以及辐射相关毒性的预防等),采用循证方法,根据美国国家医学科学院标准制定指南建议,使用人群、干预、对比参照、结果、时机、背景框架评估从关键问题中获得的证据,创建证据表,并使用该证据表,根据证据分级(表1),形成推荐建议。

Why bortezomib cannot go with ‘green'?

Eat more‘green’or eat‘five a day’is one of the most important healthy lifestyle behaviours in the 21 century.Aiming to fight cancer effectively,more than half patients use vitamins or herbs concurrently with conventional anticancer treatment.Flavonoids or polyphenols existing in vegetables,fruits and green tea are common plant pigments with antioxidant properties and considered acting as cancer preventing or anti-cancer agents.Recently it was found that some flavonoids and vitamin C in diet or supplements have antagonistic effect with the anti-cancer drug bortezomib.Bortezomib is a specific inhibitor for proteasome and is currently used for treatment of relapsed and refractory multiple myeloma.Despite its successful rates in treating multiple myeloma and other solid tumors,it is unable to kill leukemic cells in the blood.It was recently revealed that some flavonoids and vitamin C present in green leaves and green teas in the blood can neutralize bortezomib by directly interaction between two chemicals.Here we summarize why dietary flavonoids should be avoided in patients who take bortezomib as chemotherapeutic drug.

Characterization of SHARPIN knockout Syrian hamsters developed using CRISPR/Cas9 system

Background : SHARPIN (SHANK- associated RH domain interactor) is a component ofthe linear ubiquitination complex that regulates the NF- κB signaling pathway. To betterunderstand the function of SHARPIN, we sought to establish a novel geneticallyengineered Syrian hamster with SHARPIN disruption using the CRISPR/Cas9 system.Methods : A single- guide ribonucleic acid targeting exon 1 of SHARPIN gene was designedand constructed. The zygotes generated by cytoplasmic injection of the Cas9/gRNA ribonucleoprotein were transferred into pseudopregnant hamsters. Neonatalmutants were identified by genotyping. SHARPIN protein expression was detectedusing Western blotting assay. Splenic, mesenteric lymph nodes (MLNs), and thymicweights were measured, and organ coefficients were calculated. Histopathologicalexamination of the spleen, liver, lung, small intestine, and esophagus was performedindependently by a pathologist. The expression of lymphocytic markers and cytokineswas evaluated using reverse transcriptase- quantitative polymerase chain reaction.Results : All the offspring harbored germline- transmitted SHARPIN mutations.Compared with wild- type hamsters, SHARPIN protein was undetectable in SHARPIN −/−hamsters. Spleen enlargement and splenic coefficient elevation were spotted inSHARPIN −/− hamsters, with the descent of MLNs and thymuses. Further, eosinophilinfiltration and structural alteration in spleens, livers, lungs, small intestines, and esophagiwere obvious after the deletion of SHARPIN. Notably, the expression of CD94 and CD22 was downregulated in the spleens of knockout (KO) animals. Nonetheless,the expression of CCR3, CCL11, Il4 , and Il13 was upregulated in the esophagi. Theexpression of NF- κB and phosphorylation of NF- κB and IκB protein significantly diminishedin SHARPIN −/− animals.Conclusions : A novel SHARPIN KO hamster was successfully established using theCRISPR/Cas9 system. Abnormal development of secondary lymphoid organs andeosinophil infiltration in multiple organs reveal its potential in delineating SHARPINfunction and chronic inflammation.

COVID-19 Resulting in Potential Hearing Damage of Rodents

Objectives To find out the association between the sensorineural hearing loss and coronavirus disease 2019(COVID-19),the expression of ACE2 and TMPRSS2 in hamsters and mice was detected.Design Using the public data from the National Center for Biotechnology Information and the Global Initiative on Sharing All Influenza Data,the expression of ACE2 and TMPRSS2 at the transcriptomic,DNA,and protein levels of ACE2 in the brain,inner ear,and muscle from the golden Syrian hamsters(Mesocricetus auratus)and mice(Mus musculus)was assessed.Results We identified ACE2 and TMPRSS2 expressed at different levels in the inner ear and brain at DNA and transcriptomic levels of both mice and hamsters.The protein expression from the brain and inner ear showed a similar pattern,while the expression of ACE2 from the inner ear was relatively higher than that from the muscle.Conclusion Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)shows genetic potential to infect the hearing system of rodents and lead to sudden sensorineural hearing loss that can be used as a characteristic to detect asymptomatic patients of COVID-19.

Right Hepatectomy, Open vs Laparoscopy: A Systematic Review

Minimal access procedures show successes in various several medical fields. This issue brings a specific use of laparoscopy to the front to discuss in more detail which is the liver tumour resection. And, it’s the high time for laparoscopy to be highlighted regarding to hepatobilliary system. It is significantly important to gain most of the benefits of the laparoscopy technology. Its advantages are already achieved in other operation type inside the body cavity such as cholecystectomy.

The role of modern immunotherapy in metastatic urothelial cancer:mini review

The approval of immune checkpoint inhibitors(ICIs)has changed the treatment landscape in many aspects of urothelial cancer(UC),in both non-muscle-invasive bladder cancer and muscle-invasive bladder cancer and has introduced the concept of long-term remission for some patients in the metastatic setting.Front-line chemotherapy remains superior at achieving initial control of disease compared to front-line immune therapy.However,long-term durable responses are limited by chemotherapy resistance.The maintenance approach,sequencing chemotherapy with ICIs,could be considered a best of both worlds approach,achieving initial control with chemotherapy,which is maintained in some individuals with avelumab.However,outcomes for patients with metastatic UC remain poor.There are three steps to improving outcomes for these patients;the first is to develop better drugs and combinations of therapies,the second is the development of novel biomarkers and techniques to better select patients for treatment,and the third area of development is to give the drugs in the most optimal setting.

CD8^+ T cell response mediates the therapeutic effects of oncolytic adenovirus in an immunocompetent mouse model

The role of anti-tumor immune responses in oncolytic adenoviral therapy has not been well studied due to lack of efficacious tu- mor model in immunocompetent mice.Here,we evaluated the contributions of immune components to the therapeutic effects of oncolytic adenoviruse in an immunocompetent murine tumor model permissive for infection and replication of adenovirus.We found that CD8+T cells were critical mediator for antitumor efficacy by oncolytic adenovirus.Intratumoral viral therapy induced intensive infiltration of CD8+T cells in tumor,increased tumor-specific IFN-?(interferon-?)production and CTL(cytotoxic T lymphocyte)activity of lymphocytes,and generated a long-term tumor-specific immune memory.Boosting CD8+T cell responses by agonistic anti-4-1BB(cluster differentiation 137,CD137)antibody showed synergistic anticancer effects with oncolytic viro- therapy.Our results provide insight into antitumor mechanisms of oncolytic adenovirus in addition to their direct oncolytic effect.

PNAS:维生素A和C如何擦除细胞记忆?

维生素A和C不只是对我们的健康有益，其还会影响到机体的DNA，日前一项刊登于国际杂志PNAS上的研究论文中，来自巴布拉汉研究所（Babraham Institute）等机构的研究人员通过研究揭示了维生素A和C如何修饰细胞的表观遗传记忆。相关研究或为后期研究者们开发新型再生医学疗法或者对细胞重编程提供一定的思路。

Integrative phosphoproteomics defines two biologically distinct groups of KMT2A rearranged acute myeloid leukaemia with different drug response phenotypes

Acute myeloid leukaemia(AML)patients harbouring certain chromosome abnormalities have particularly adverse prognosis.For these patients,targeted therapies have not yet made a significant clinical impact.To understand the molecular landscape of poor prognosis AML we profiled 74 patients from two different centres(in UK and Finland)at the proteomic,phosphoproteomic and drug response phenotypic levels.These data were complemented with transcriptomics analysis for 39 cases.Data integration highlighted a phosphoproteomics signature that define two biologically distinct groups of KMT2A rearranged leukaemia,which we term MLLGA and MLLGB.MLLGA presented increased DOT1L phosphorylation,HOXA gene expression,CDK1 activity and phosphorylation of proteins involved in RNA metabolism,replication and DNA damage when compared to MLLGB and no KMT2A rearranged samples.MLLGA was particularly sensitive to 15 compounds including genotoxic drugs and inhibitors of mitotic kinases and inosine-5-monosphosphate dehydrogenase(IMPDH)relative to other cases.Intermediate-risk KMT2A-MLLT3 cases were mainly represented in a third group closer to MLLGA than to MLLGB.The expression of IMPDH2 and multiple nucleolar proteins was higher in MLLGA and correlated with the response to IMPDH inhibition in KMT2A rearranged leukaemia,suggesting a role of the nucleolar activity in sensitivity to treatment.In summary,our multilayer molecular profiling of AML with poor prognosis and KMT2A-MLLT3 karyotypes identified a phosphoproteomics signature that defines two biologically and phenotypically distinct groups of KMT2A rearranged leukaemia.These data provide a rationale for the potential development of specific therapies for AML patients characterised by the MLLGA phosphoproteomics signature identified in this study.