Combination immunotherapy of glioblastoma with dendritic cell cancer vaccines,anti-PD-1 and poly I:C

Glioblastoma(GBM)is a lethal cancer with limited therapeutic options.Dendritic cell(DC)-based cancer vaccines provide a promising approach for GBM treatment.Clinical studies suggest that other immunotherapeutic agents may be combined with DC vaccines to further enhance antitumor activity.Here,we report a GBM case with combination immunotherapy consisting of DC vaccines,anti-programmed death-1(anti-PD-1)and poly I:C as well as the chemotherapeutic agent cyclophosphamide that was integrated with standard chemoradiation therapy,and the patient remained disease-free for 69 months.The patient received DC vaccines loaded with multiple forms of tumor antigens,including mRNA-tumor associated antigens(TAA),mRNA-neoantigens,and hypochlorous acid(HOCl)-oxidized tumor lysates.Furthermore,mRNA-TAAs were modified with a novel TriVac technology that fuses TAAs with a destabilization domain and inserts TAAs into full-length lysosomal associated membrane protein-1 to enhance major histocompatibility complex(MHC)class I and II antigen presentation.The treatment consisted of 42 DC cancer vaccine infusions,26 anti-PD-1 antibody nivolumab administrations and 126 poly I:C injections for DC infusions.The patient also received 28 doses of cyclophosphamide for depletion of regulatory T cells.No immunotherapy-related adverse events were observed during the treatment.Robust antitumor CD4t and CD8t T-cell responses were detected.The patient remains free of disease progression.This is the first case report on the combination of the above three agents to treat glioblastoma patients.Our results suggest that integrated combination immunotherapy is safe and feasible for long-term treatment in this patient.A large-scale trial to validate these findings is warranted.

Cancer/testis antigens： novel tools for discerning aggressive and non-aggressive prostate cancer

The introduction of serum prostate-specific antigen （PSA） in the 1980s has dramatically altered and benefited the initial diagnosis of prostate cancer. However, the widespread use of PSA testing has resulted in overdetection and overtreatment of potentially indolent disease. Thus, a clinical dilemma today in the management of prostate cancer is to discern men with aggressive disease who need definitive treatment from men whose disease are not lethal. Although several serum and tissue biomarkers have been evaluated during the past decade, improved markers are still needed to enhance the accuracy, with which patients at risk can be discerned and treated more aggressively. The cancer/testis antigens （CTAs） are a group of proteins that are restricted to the testis in the normal adult, but are aberrantly expressed in several types of cancers. Because of their restricted expression pattern, the CTAs represent attractive biomarker candidates for cancer diagnosis/prognosis. Furthermore, several studies to date have reported the differential expression of CTAs in prostate cancer. Here, we review recent developments that demonstrate the potential of the CTAs as biomarkers to discern the a^ressive Dhenotvoe of orostate cancer.

Cyr61 is a potential prognostic marker for prostate cancer

Cysteine-rich angiogenic inducer 61 （Cyr61） is an extracellular matrix protein involved in the transduction of growth factor and hormone signaling that is frequently altered in expression in several types of cancers. In prostate cancer （PCa）, Cyr61 is highly expressed in organ-confined disease. Further, Cyr61 expression levels are associated with a lower risk of disease recurrence, and can be quantitatively measured in the serum. Considered together, these results indicate that Cyr61 is a potential and clinically useful tissue, as well as serum-based biomarker for differentiating lethal and non-lethal PCa.

信使分子与细胞死亡——对治疗的意义

程序性细胞死亡（也称凋亡）不仅参与正常生理过程（如免疫系统的发育），也参与许多疾病的发生。细胞不能正常死亡可发生于肿瘤，而细胞死亡过多则见于各种神经变性疾病。我们讨论了3个不同的调控细胞死亡的通路。第一，胆红素。以往认为。胆红素是血红素代谢的最终毒性产物，但是，在生理上却起着细胞保护剂的作用，可使很多疾患减轻。第二，糖酵解酶甘油醛-3-磷酸脱氢酶（glyceraldehyde-3 phosphate dehydrogenase，GAPDH）。GAPDH介导一个新的细胞死亡级联反应（cascade）。细胞毒性刺激，通过一氧化氮导致GAPDH与Saih1蛋白结合，GAPDH-Siah1转位到细胞核，细胞最后死亡。第三，细胞色素C。细胞凋亡早期从线粒体释出的细胞色素C，与肌醇-1，4，5-三磷酸盐（IP3）协同作用，引起大量的细胞钙释放，结果细胞死亡。这些通路可在各种病理状态下调控细胞的存活，为新型治疗提供了众多的靶标。

A NIR ratiometric fluorescent biosensor for sensitive detection and imaging of α-L-fucosidase in living cells and HCC tumor-bearing mice

Detection and imaging of α-L-fucosidase(AFU)is of great value to understand its roles in hepatocellular carcinoma(HCC)and tumor early diagnosis,but ideal assays are still lacking.Herein,a near-infrared(NIR)fluorescent biosensor(α-Fuc-DCM)was elaborately designed and synthesized for rapid and ratiometric detection of AFU activity in cells and HCC tumor mouse models.In the presence of AFU,this biosensor shows an enhancement in NIR emission in a ratiometric manner,which significantly improves the detection accuracy with the limit of detection as low as 4.8 mU/mL.Taking advantage of these merits,the activity of AFU in lysosomes could be visualized using ratiometric and NIR dual modality in living cells.Furthermore,its remarkable application for monitoring of endogenous AFU activity in HCC tumor-bearing mouse model is also demonstrated with bright fluorescence signal,which indicated that the biosensor could clearly monitor the liver tumor in the early stage.Importantly,the α-Fuc-DCM probe can be utilized to detect the AFU in serum from HCC patients.This strategy offers a promising biosensor system for early diagnosis of HCC and studying the roles of AFU in cancers.

E-DNA scaffold sensors and the reagentless, single- step, measurement of HIV-diagnostic antibodies in human serum

The multiplexed,point-of-care measurement of specific antibodies could improve the speed with which diseases are diagnosed and their treatment initiated.To this end,we are developing E-DNA scaffold sensors,which consist of a rigid,nucleic acid“scaffold”attached on one end to an electrode and presenting both a redox reporter and an epitope on the other.In the absence of antibody,the reporter efficiently transfers electrons when interrogated electrochemically.Binding-induced steric hindrance limits movement,reducing electron transfer in a manner that is both easily measured and quantitatively related to target concentration.Previously we have used monoclonal antibodies to explore the analytical performance of E-DNA sensors,showing that they support the rapid,single-step,quantitative detection of multiple antibodies in small volume samples.Here,in contrast,we employ authentic human samples to better explore the platform’s clinical potential.Specifically,we developed E-DNA sensors targeting three HIV-specific antibodies and then compared the analytical and clinical performance of these against those of gold standard serological techniques.Doing so we find that,although the multistep amplification of an ELISA leads to a lower detection limits,the clinical sensitivity of ELISAs,E-DNA sensors and lateral-flow dipsticks are indistinguishable across our test set.It thus appears that,by merging the quantitation and multiplexing of ELISAs with the convenience and speed of dipsticks,E-DNA scaffold sensors could significantly improve on current serological practice.

Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in an Alzheimer’s disease mouse model

Background Cognitive decline in Alzheimer’s disease(AD)is associated with hyperphosphorylated tau(pTau)propagation between neurons along synaptically connected networks,in part via extracellular vesicles(EVs).EV biogenesis is triggered by ceramide enrichment at the plasma membrane from neutral sphingomyelinase2(nSMase2)-mediated cleavage of sphingomyelin.We report,for the first time,that human tau expression elevates brain ceramides and nSMase2 activity.Methods To determine the therapeutic benefit of inhibiting this elevation,we evaluated PDDC,the first potent,selective,orally bioavailable,and brain-penetrable nSMase2 inhibitor in the transgenic PS19 AD mouse model.Additionally,we directly evaluated the effect of PDDC on tau propagation in a mouse model where an adeno-associated virus(AAV)encoding P301L/S320F double mutant human tau was stereotaxically-injected unilaterally into the hippocampus.The contralateral transfer of the double mutant human tau to the dentate gyrus was monitored.We examined ceramide levels,histopathological changes,and pTau content within EVs isolated from the mouse plasma.Results Similar to human AD,the PS19 mice exhibited increased brain ceramide levels and nSMase2 activity;both were completely normalized by PDDC treatment.The PS19 mice also exhibited elevated tau immunostaining,thinning of hippocampal neuronal cell layers,increased mossy fiber synaptophysin immunostaining,and glial activation,all of which were pathologic features of human AD.PDDC treatment reduced these changes.The plasma of PDDC-treated PS19 mice had reduced levels of neuronal-and microglial-derived EVs,the former carrying lower pTau levels,compared to untreated mice.In the tau propagation model,PDDC normalized the tau-induced increase in brain ceramides and significantly reduced the amount of tau propagation to the contralateral side.Conclusions PDDC is a first-in-class therapeutic candidate that normalizes elevated brain ceramides and nSMase2 activity,leading to the slowing of tau spread in AD mice.

Interactome Mapping: Using Protein Microarray Technology to Reconstruct Diverse Protein Networks

A major focus of systems biology is to characterize interactions between cellular compo- nents, in order to develop an accurate picture of the intricate networks within biological systems. Over the past decade, protein microarrays have greatly contributed to advances in proteomics and are becoming an important platform for systems biology. Protein microarrays are highly flex- ible, ranging from large-scale proteome microarrays to smaller customizable microarrays, making the technology amenable for detection of a broad spectrum of biochemical properties of proteins. In this article, we will focus on the numerous studies that have utilized protein microarrays to recon- struct biological networks including protein-DNA interactions, posttranslational protein modifica- tions （PTMs）, lectin glycan recognition, pathogen-host interactions and hierarchical signaling cascades. The diversity in applications allows for integration of interaction data from numerous molecular classes and cellular states, providing insight into the structure of complex biological sys- tems. We will also discuss emerging applications and future directions of protein microarray tech- nology in the global frontier.

Functional protein microarray： an ideal platform for investigating protein binding property

Functional protein microarray is an important tool for high-throughput and large-scale systems biology studies. Besides the progresses that have been made for protein microarray fabrication, significant advancements have also been achieved for applying protein microarrays on determining a variety of protein biochemical activities. Among these applications, detection of protein binding properties, such as protein-protein interactions （PPIs）, protein-DNA interactions （PDIs）, protein-RNA interactions, and antigen-antibody interactions, are straightforward and have substantial impacts on many research fields. In this review, we will focus on the recent progresses in protein-protein, protein-DNA, protein-RNA, protein-small molecule, protein-lipid, protein-glycan, and antigen-antibody interactions. We will also discuss the challenges and future directions of protein microarray technologies. We strongly believe that protein microarrays will soon become an indispensible tool for both basic research and clinical applications.

Ethacrynic acid targets GSTM1 to ameliorate obesity by promoting browning of white adipocytes

Dear Editor,Obesity is caused by an imbalance between energy intake and expenditure,and has become a global epidemic with over 650 million adults affected.Adipose tissues in mammals are composed of white adipose tissue(WAT)and classical brown adipose tissue(BAT),and their balance is highly related to the occurrence of obesity.The browning of white adipocytes results in“beige”or“brite”adipocytes,which appear functionally similar to classical brown adipocytes,and can be detected in WAT deposits of animals that have been exposed to cold or other inducers(Fu et al.,2015).

BET family protein degraders poised to join the senolytic arsenal

In a recent study published in Nature Communications,Wakita et al.identified BET family protein degrader(BETd)as a novel senolytic drug through high-throughput screening and biofunctional assays.1 BETd preferentially eliminated senescent cells by targeting nonhomologus end joining(NHEJ)and autophagy and significantly reduced tumor growth in vivo,suggesting that BETd could be used as a new therapy against cancer and agerelated disease(Fig.1).