TIGIT和PD-1/PD-L1双重阻断途径在肿瘤免疫治疗中的研究进展

程序性死亡蛋白-1和程序性死亡蛋白配体-1(programmed death-1/programmed death-ligand 1,PD-1/PD-L1)作为一种抑制T细胞活化的调节性免疫检查点分子,在肿瘤的免疫治疗发挥着重要的作用。近年来,越来越多的靶向治疗药物得到研发,但是单一免疫检查点阻断剂并不能很好的抑制肿瘤的发生,肿瘤逃逸现象时有发生,而靶向药物的联合治疗可作为抑制肿瘤发生发展的重要手段之一。属于1型脊髓灰质炎病毒受体的抑制性受体T细胞免疫球蛋白和免疫受体酪氨酸抑制基序(immunoreceptor tyrosine-based inhibition motif,ITIM)结构域(T cell immunoglobulin and ITIM domain,TIGIT)是近年靶向药物治疗研究的热点,其与PD-1/PD-L1的联合治疗可减少肿瘤逃逸,更有效地抑制肿瘤的发生。因此,本文就TIGIT和PD-1/PD-L1双重阻断途径在肿瘤免疫治疗中的研究进展进行归纳总结,旨在肿瘤免疫治疗提供一定的理论依据。

A nonsynonymous SNP in human cytosolic sialidase in a small Asian population results in reduced enzyme activity: potential link with severe adverse reactions to oseltamivir

The use of oseltamivir, widely stockpiled as one of the drugs for use in a possible avian influenza pandemic, has been reported to be associated with neuropsychiatric disorders and severe skin reactions, primarily in Japan. Here we identified a nonsynonymous SNP （single nucleotide polymorphism） in dbSNP database, R41Q, near the enzymatic active site of human cytosolic sialidase, a homologue of virus neuraminidase that is the target of oseltamivir. This SNP occurred in 9.29% of Asian population and none of European and African American population. Our structural analyses and Ki measurements using in vitro sialidase assays indicated that this SNP could increase the unintended binding affinity of human sialidase to oseltamivir carboxylate, the active form of oseltamivir, thus reducing sialidase activity. In addition, this SNP itself results in an enzyme with an intrinsically lower sialidase activity, as shown by its increased Km and decreased Vmax values. Theoretically administration of oseltamivir to people with this SNP might further reduce their sialidase activity. We note the similarity between the reported neuropsychiatric side effects ofoseltamivir and the known symptoms of human sialidase-related disorders. We propose that this Asian-enriched sialidase variation caused by the SNP, likely in homozygous form, may be associated with certain severe adverse reactions to oseltamivir.

Metabolic interventions combined with CTLA-4 and PD-1/PD-L1 blockade for the treatment of tumors:mechanisms and strategies

Immunotherapies based on immune checkpoint blockade(ICB)have significantly improved patient outcomes and offered new approaches to cancer therapy over the past decade.To date,immune checkpoint inhibitors(ICIs)of CTLA-4 and PD-1/PD-L1 represent the main class of immunotherapy.Blockade of CTLA-4 and PD-1/PD-L1 has shown remarkable efficacy in several specific types of cancers,however,a large subset of refractory patients presents poor responsiveness to ICB therapy;and the underlying mechanism remains elusive.Recently,numerous studies have revealed that metabolic reprogramming of tumor cells restrains immune responses by remodeling the tumor microenvironment(TME)with various products of metabolism,and combination therapies involving metabolic inhibitors and ICIs provide new approaches to cancer therapy.Nevertheless,a systematic summary is lacking regarding the manner by which different targetable metabolic pathways regulate immune checkpoints to overcome ICI resistance.Here,we demonstrate the generalized mechanism of targeting cancer metabolism at three crucial immune checkpoints(CTLA-4,PD-1,and PD-L1)to influence ICB therapy and propose potential combined immunotherapeutic strategies co-targeting tumor metabolic pathways and immune checkpoints.

ASFV transcription reporter screening system identifies ailanthone as a broad antiviral compound

African swine fever(ASF)is an acute,highly contagious and deadly viral disease in swine that jeopardizes the worldwide pig industry.Unfortunately,there are no authoritative vaccine and antiviral drug available for ASF control.African swine fever virus(ASFV)is the etiological agent of ASF.Among the ASFV proteins,p72 is the most abundant component in the virions and thus a potential target for anti-ASFV drug design.Here,we con-structed a luciferase reporter system driven by the promoter of p72,which is transcribed by the co-transfected ASFV RNA polymerase complex.Using this system,we screened over 3200 natural product compounds and obtained three potent candidates against ASFV.We further evaluated the anti-ASFV effects and proved that among the three candidates,ailanthone(AIL)inhibits the replication of ASFV at the nanomolar concentration(IC_(50)=15 nmol/L).Our in vitro experiments indicated that the antiviral effect of AIL is associated with its inhibition of the HSP90-p23 cochaperone.Finally,we showed the antiviral activity of AIL on Zika virus and hepatitis B virus(HBV),which supports that AIL is a potential broad-spectrum antiviral agent.

hCINAP alleviates senescence by regulating MDM2 via p14ARF and the HDAC1/CoREST complex

Cellular senescence is a major process affected by multiple signals and coordinated by a complex signal response network.Identification of novel regulators of cellular senescence and elucidation of their molecular mechanisms will aid in the discoveryof new treatment strategies for aging-related diseases. In the present study, we identified human coilin-interacting nuclear ATPaseprotein (hCINAP) as a negative regulator of aging. Depletion of cCINAP significantly shortened the lifespan of Caenorhabditiselegans and accelerated primary cell aging. Moreover, mCINAP deletion markedly promoted organismal aging and stimulatedsenescence-associated secretory phenotype in the skeletal muscle and liver from mouse models of radiation-induced senescence.Mechanistically, hCINAP functions through regulating MDM2 status by distinct mechanisms. On the one hand, hCINAP decreasesp53 stability by attenuating the interaction between p14ARF and MDM2;on the other hand, hCINAP promotes MDM2 transcriptionvia inhibiting the deacetylation of H3K9ac in the MDM2 promoter by hindering the HDAC1/CoREST complex integrity. Collectively,our data demonstrate that hCINAP is a negative regulator of aging and provide insight into the molecular mechanisms underlyingthe aging process.

NEDDylation antagonizes ubiquitination of proliferating cell nuclear antigen and regulates the recruitment of polymerase rl in response to oxidative DNA damage

NEDDylation has been shown to participate in the DNA damage pathway, but the substrates of neural precursor cell expressed developmentally downregulated 8 （NEDD8） and the roles of NEDDylation involved in the DNA damage response （DDR） are largely unknown. Translesion synthesis （TLS） is a damage-tolerance mechanism, in which RAD181RAD6-mediated monoubiq- uitinated proliferating cell nuclear antigen （PCNA） pro- motes recruitment of polymerase q （polq） to bypass lesions. Here we identify PCNA as a substrate of NEDD8, and show that E3 ligase RAD18-catalyzed PCNA NEDDylation antagonizes its ubiquitination. In addition, NEDP1 acts as the deNEDDylase of PCNA, and NEDP1 deletion enhances PCNA NEDDylation but reduces its ubiquitination. In response to H202 stimulation, NEDP1 disassociates from PCNA and RAD18-dependent PCNA NEDDylation increases markedly after its ubiquitination. impairment of NEDDylation by Ubc12 knockout enhances PCNA ubiquitination and promotes PCNA-polη interaction, while up-regulation of NEDDylation by NEDD8 overexpression or NEDP1 deletion reduces the excessive accumulation of ubiquitinated PCNA, thus inhibits PCNA-polη interaction and blocks polη foci formation. Moreover, Ubc12 knockout decreases cell sensitivity to H2O2-induced oxidative stress, but NEDP1 deletion aggravates this sensitivity. Collectively, our study elucidates the important role of NEDDylation in the DDR as a modulator of PCNA monoubiquitination and polη recruitment.

hCINAP negatively regulates NF-κB signaling by recruiting the phosphatase PP1 to deactivate IKK complex

Tight regulation of nuclear factor-kB(NF-kB)signaling is essential to maintain homeostasis in immune system in response to various stimuli,which hasbeen studied extensivelyand deeply.However,the molecularmechanisms responsible for its negative regulation are not completely understood.Here we demonstrate that human coilin-interacting nuclear ATPase protein(hCINAP)is a novel negative regulator in NF-kB signaling by deactivating IkB kinase(IKK)complex.In response to TNF stimulation,hCINAP dynamically associates with IKKa and IKKb and inhibits IKK phosphorylation.Notably,hCINAP directly interacts with the catalytic subunits of protein phosphatase 1(PP1)and mediates the formation of IKK–hCINAP–PP1 complex,serving as an adaptor protein that recruits PP1 to dephosphorylate IKK.Furthermore,decreased levels of hCINAP are observed in several inflammatory diseases with NF-kB hyperactivity.Our study suggests a novel mechanism underlying deactivation of IKK and provides new insight into the negative regulation of NF-kB signaling.

Recent progress in liquid desiccant dehumidification and air-conditioning:A review

This paper presents a literature review on the recent research progress in liquid desiccant dehumidification and air conditioning systems.The physical features of various liquid desiccant materials and their dehumidification performances have been summarized.With the aim to improve the dehumidification characteristics,mixed sol-vents desiccants have become research hot topics recently.Various types of dehumidifiers and their integration with liquid desiccant dehumidification system have been reviewed.The combination of liquid desiccant dehumid-ification system with solar collector,vapour compression system,heat pump system,CHP system,etc.have been grouped and compared.It is shown that the majority of the recent research work for liquid desiccant dehumid-ification systems has concentrated on numerical simulations,a considerable amount of works are still required for the practical investigations of innovative material(mixed solvents)and hybrid systems.

The crystal structure of LidA,a translocated substrate of the Legionella pneumophila type IV secretion system

Dear Editor,Legionella pneumophila,a gram-neg-ative bacterium,is the causative agent of Legionnaires’pneumonia by infecting human lung macrophages(Muder et al.,1986).Upon uptake into macrophages,the bacteria are internalized to escape the endocytic pathway and lysosomal network,and establish the Legionella-containing vacuole(LCV)as an intracel-lular replicative organelle(Roy et al.,1998).The LCV hijacks and recruits the early secretory ER-derived vesicles and transforms them into ER-like vacuole.Within the specialized ER-like vacuole,L.pneumophila replicates to a high den-sity and subsequently kills the host cell by lysing the host cell membrane.The released bacteria can infect neighboring cells to initiate a new round of infection(Tilney et al.,2001).

Tip-to-tip interaction in the crystal packing of PACSIN 2 is important in regulating tubulation activity

The F-BAR domain containing proteins PACSINs are cytoplasmic phosphoproteins involved in various mem-brane deformations,such as actin reorganization,vesicle transport and microtubule movement.Our previous study shows that all PACSINs are composed of crescent shaped dimers with two wedge loops,and the wedge loop-mediated lateral interaction between neighboring dimers is important for protein packing and tubulation activity.Here,from the crystal packing of PACSIN 2,we observed a tight tip-to-tip interaction,in addition to the wedge loop-mediated lateral interaction.With this tip-to-tip interaction,the whole packing of PACSIN 2 shows a spiral-like assem-bly with a central hole from the top view.Elimination of this tip-to-tip connection inhibited the tubulation function of PACSIN 2,indicating that tip-to-tip interaction plays an important role in membrane deformation activity.Together with our previous study,we proposed a packing model for the assembly of PACSIN 2 on membrane,where the pro-teins are connected by tip-to-tip and wedge loop-mediated lateral interactions on the surface of membrane to gener-ate various diameter tubules.

Ileal transposition rapidly improves glucose tolerance and gradually improves insulin resistance in non-obese type 2 diabetic rats

Background:Many studies have confirmed that ileal transposition can improve type 2 diabetes mellitus(T2DM),accompanied by increased glucagon-like peptide-1(GLP-1).We performed the experiment on diabetic rats to evaluate the effects and mechanisms of ileal transposition on the glycemic metabolism.Methods:Twenty Goto-Kakizaki(GK)rats were randomly divided into the ileal transposition group(IT group)and the sham operation group(Shamgroup).Weight,food intake,fasting plasma glucose(FPG),fasting insulin(F-ins),oral glucose tolerance test(OGTT)and GLP-1 were determined at baseline and 1,4,8,16 and 24weeks post-operatively.The homeostasis model assessment-insulin resistance(HOMA-IR)index and the area under the curve(AUC)during OGTT were measured.Histological determination of the GLP-1 receptor(GLP-1R)was performed on the pancreas and ileum24weeks post-operatively.Results:In comparison with the Sham group,the IT group showed a higher GLP-1 level and lower AUC at 4,8,16 and 24 weeks post-operatively(all P<0.05)and a lower FPG,F-ins levels and HOMA-IR at 8,16 and 24 weeks post-operatively(all P<0.05).Compared with baseline levels,the plasma GLP-1,AUC and FPG levels decreased significantly at each postoperative time point in the IT group(all P<0.05),but not in the Sham group(all P>0.05);F-ins and HOMA-IR significantly decreased at 8,16 and 24 weeks post-operatively in the IT group(all P<0.05).GLP-1R expression in the IT group was significantly higher than that of the Sham group in both the pancreas and the ileum at 24 weeks post-operatively(P<0.05).Conclusions:Ileal transposition ameliorated glucose metabolism without reduction in weight or food intake in GK rats,which may be induced by the increased GLP-1 expression.However,the delayed improvement of insulin resistance,accompanied by decreased plasma insulin levels,might not directly result from the increased GLP-1.

Switched-capacitor Multi-level Inverter with Equal Distribution of the Capacitors Discharging Phases

A new switched-capacitor(2n+1)levels inverter with a single input source and equal charge of the capacitors at the input voltage V_(in) is presented.Compared with its peers from the same class of inverters,the proposed one features an equal or lower components count referred to the boost factor.And,it presents an additional advantage:each voltage level can be obtained by using different capacitors in the discharging phase,such that the decreasing part of the staircase output waveform can be synthesized with different switching topologies than those used in the increasing part.As a consequence,all the capacitors are discharged at the same voltage value at the end of each half-cycle,allowing for the use of smaller capacitors of equal values.When the capacitors are connected in parallel in the charging phase,there is no need to equalize their voltages,so no additional current spikes appear.This also implies less electromagnetic emission(EMI).Two types of modulation strategies are proposed.A half-height fundamental switching frequency modulation strategy allows for reaching the desired peak of the output voltage during the highest voltage level operation.It is advantageous in application of the inverter as a front end of a grid supplied by green sources of energy.A high frequency(f_(s)=200 kHz)modulation strategy accompanied by a duty-cycle control is advantageous for applications which require miniaturization.A 9-level switched-capacitor multi-level inverter(SCMLI)is analyzed and designed.The power losses are calculated.The experimental results for a 9-level inverter with V_(in)=40 V,V_(out)=110 Vrms 50 Hz,200 W confirm the theoretical expectations.