DNA damage response-related immune activation signature predicts the response to immune checkpoint inhibitors: from gastrointestinal cancer analysis to pan-cancer validation

Objective: DNA damage response(DDR) deficiency has emerged as a prominent determinant of tumor immunogenicity. This study aimed to construct a DDR-related immune activation(DRIA) signature and evaluate the predictive accuracy of the DRIA signature for response to immune checkpoint inhibitor(ICI) therapy in gastrointestinal(GI) cancer.Methods: A DRIA signature was established based on two previously reported DNA damage immune response assays. Clinical and gene expression data from two published GI cancer cohorts were used to assess and validate the association between the DRIA score and response to ICI therapy. The predictive accuracy of the DRIA score was validated based on one ICI-treated melanoma and three pan-cancer published cohorts.Results: The DRIA signature includes three genes(CXCL10, IDO1, and IFI44L). In the discovery cancer cohort, DRIA-high patients with gastric cancer achieved a higher response rate to ICI therapy than DRIA-low patients(81.8% vs. 8.8%;P < 0.001), and the predictive accuracy of the DRIA score [area under the receiver operating characteristic curve(AUC) = 0.845] was superior to the predictive accuracy of PD-L1 expression, tumor mutational burden, microsatellite instability, and Epstein–Barr virus status. The validation cohort demonstrated that the DRIA score identified responders with microsatellite-stable colorectal and pancreatic adenocarcinoma who received dual PD-1 and CTLA-4 blockade with radiation therapy. Furthermore, the predictive performance of the DRIA score was shown to be robust through an extended validation in melanoma, urothelial cancer, and pan-cancer.Conclusions: The DRIA signature has superior and robust predictive accuracy for the efficacy of ICI therapy in GI cancer and pancancer, indicating that the DRIA signature may serve as a powerful biomarker for guiding ICI therapy decisions.

Driving Forces of AIDS Pathogenesis:Massive CD4^+ T Lymphocyte Depletion and Abnormal Immune Activation

The occurrence of massive CD4+ T cell depletion is one of the most prominent characteristics of human immunodeficiency virus type 1 (HIV-1) infection during acute phase, resulting in unrestorable destruction to the immune system. The infected host undergoes an asymptomatic period lasting several years with low viral load and ostensibly healthy status, which is presumably due to virus-specific adaptive immune responses. In the absence of therapy, an overwhelming majority of cases develop to AIDS within 8-10 years of latent infection. In this review, we discuss the roles in AIDS pathogenesis played by massive CD4+ T lymphocytes depletion in gut-associated lymphoid tissue (GALT) during acute infection and abnormal immune activation emerging in the later part of chronic phase.

Self-oriented central-tumor delivery of legumain-cleavable vehicles governed by circulating monocyte/macrophage for precise tumor enrichment and immune activation

Compressed blood and intratumoral lymphatic vessels induced by proliferated tumor cells and elevated interstitial fluid pressure produce regional hypoxic and necrotic region within tumors,which severely reduced the accessibility of immunogenic cell death(ICD)related drugs and immune-related cells.Herein,the strategy of self-oriented deep tumor delivery by circulating monocyte/macrophage was proposed.Briefly,CS-AI including an indoleamine 2,3-dioxygenase(IDO)inhibitor indoximod(IND)and hydrophilic chitosan(CSO)linked with alanine-alanine-asparagine(AAN)was prepared,which could be selectively cleaved by legumain overexpressed in macrophages and promote the collapse in structure.Then,CS-AI was modified with mannose on the surface and further encapsulated the ICD inducer doxorubicin(DOX)to obtain M-CS-AI/DOX.Upon intravenous injection,MCS-AI/DOX was specially recognized and internalized by circulating monocyte in vivo.The formed drugs/monocyte tend to distribute in hypoxia/necrosis region guided by the homing signals released by tumor.Accumulated monocytes then further differentiated into macrophages,up-regulating the expression of legumain and promoting the sensitive-release of chemo-drug DOX,IND,and the mannose-modified CSO(M-CSO).The released IND would specifically regulate immunosuppressive tumor microenvironment,and synergistically inhibit tumor growth with immune activation elements,ICD-induced DOX,and the favorable adjuvant M-CSO.In summary,the self-oriented deep tumor delivery of legumain-cleavable nanovesicles through circulating monocyte makes it possible for reaching tumor regions inaccessible for nanoparticles and provides a novel insight for precise tumor enrichment and immune activation.

Ferroptosis-inducing inorganic arsenic(II)sulfide nanocrystals enhance immune activation

Arsenic(II)sulfide is a stable inorganic arsenic compound with a different valence from arsenic trioxide,and has been widely applied to treat various diseases with low toxic side effects for a long time.However,its low solubility and complicated formulations restrict its further applications in modern medical industry.Meanwhile,as the tumour with the highest incidence rate among women,the low recurrence risk of breast cancer has been confirmed to be closely related to the high infiltration of immune cells.Herein,we synthesized and filtered novel biocompatible PEGylated arsenic(II)sulfide nanocrystals AsS@PEG with a size of 93.14±0.49 nm by the gel method,which displayed excellent anticancer and immune activation activity in breast cancer model.Proteomic analysis suggested that the AsS@PEG induce ferroptosis in cancer cells and further activate antitumour immune responses via B-cell lymphoma 9-like(BCL9L)protein inhibition.Furthermore,mechanism studies revealed notable glutathione peroxidase 4(GPX4)downregulation in cancer cells,dendritic cells(DCs)maturation and subsequent effector CD8^(+)T-cells production induced by the AsS@PEG in the tumour microenvironment.This study highlights biocompatible arsenic(II)sulfide nanocrystals that induce ferroptotic cell death and activate antitumour immune responses,providing insights into the path towards the immunotherapy assisted chemotherapy for breast cancer.

HLA-DR expression on regulatory T cells is closely associated with the global immune activation in HIV-1 infected subjects naive to antiretroviral therapy

Background The frequencies of regulatory T cells （Tregs） increased over the HIV infection but its counts actually decreased. We proposed that the decrease of Treg counts may cause the reduction of inhibitory effect and thereby account for the over-activation of Tregs during HIV infection. However, it remains unknown whether Tregs are also over-activated and thereafter the activation induced death may lead to the decrease of Tregs. Methods Tregs were defined as CD4＋CD25＋CD127lo/-T cells. Eighty-one HIV-1 infected patients were enrolled in our study, and twenty-two HIV-1 seronegative donors were recruited as the control. The levels of HLA-DR on Tregs were determined by FACSAria flow cytometer. Results Compared to HIV-1 seronegative donors, the levels of HLA-DR on CD4＋CD25＋CD127lo/- Tregs were significantly increased in HIV-1 infected patients, and its increase was positively associated with viral loads （r=0.3163, P=-0.004） and negatively with CD4 T-cell counts （r=-0.4153, P 〈0.0001）. In addition, significant associations between HLA-DR expression on CD4＋CD25＋CD127lo/- Tregs and the percentages of HLA-DR, CD38, Ki67 expressing CD4＋ and CD8＋ T cells were also identified. Conclusion HLA-DR on Tregs is a good marker for viral replication and disease progression. The over-activation of Tregs might result in the decrease of Tregs.

STING and TLR7/8 agonists-based nanovaccines for synergistic antitumor immune activation

Immunostimulatory therapies based on pattern recognition receptors(PRRs)have emerged as an effective approach in the fight against cancer,with the ability to recruit tumor-specific lymphocytes in a low-immunogenicity tumor environment.The agonist cyclic dinucleotides(CDNs)of the stimulator of interferon gene(STING)are a group of very promising anticancer molecules that increase tumor immunogenicity by activating innate immunity.However,the tumor immune efficacy of CDNs is limited by several factors,including relatively narrow cytokine production,inefficient delivery to STING,and rapid clearance.In addition,a single adjuvant molecule is unable to elicit a broad cytokine response and thus cannot further amplify the anticancer effect.To address this problem,two or more agonist molecules are often used together to synergistically enhance immune efficacy.In this work,we found that a combination of the STING agonist CDGSF and the Toll-like receptor 7/8(TLR7/8)agonist 522 produced a broader cytokine response.Subsequently,we developed multicomponent nanovaccines(MCNVs)consisting of a PC7A polymer as a nanocarrier encapsulating the antigen OVA and adjuvant molecules.These MCNVs activate bone marrow-derived dendritic cells(BMDCs)to produce multiple proinflammatory factors that promote antigen cross-presentation to stimulate specific antitumor Tcell responses.In in vivo experiments,we observed that MCNVs triggered a strong T-cell response in tumor-infiltrating lymphocytes,resulting in significant tumor regression and,notably,a 100%survival rate in mice through 25 days without other partnering therapies.These data suggest that our nanovaccines have great potential to advance cancer immunotherapy with increased durability and potency.

Effects of immune activation on the retrieval of spatial memory

Objective It has been shown that there are extensive interactions between the central nervous system and the immune system.The present study focused on the effects of lipopolysaccharide（LPS）on memory retrieval,to explore the interaction between immune activation and memory.Methods C57BL/6J mice（8 weeks old）were first trained in the Morris water maze to reach asymptotic performance.Then mice were tested 24 h after the last training session and LPS was administered（1.25 mg/kg,i.p.）4 h prior to the testing.The retrieval of spatial memory was tested by probe trial,and the time spent in the target quadrant and the number of platform location crosses were recorded.ELISA was performed to detect interleukin-1β（IL-1β）protein level in the hippocampus of mice tested in the water maze.Results Although LPS induced overt sickness behavior and a significant increase in the level of IL-1β in the hippocampus of mice,there was no significant difference in the time spent in the target quadrant or in the number of platform location crosses between LPS-treated and control groups in the probe trial testing.Conclusion Immune activation induced by LPS does not impair the retrieval of spatial memory.

Evoking immune system to potentiate nanocatalytic therapy through activation of cGAS-STING pathway

Nanocatalytic therapy shows great potential for therapeutic interventions.However,therapeutic efficiency is often limited by unsatisfactory enzyme activity and lack of the coordination of immune system.Therefore,engineering nanozymes activity enhancement while activating immune system will be an effective strategy to achieve efficient tumor therapy.Herein,we synthesize a DSPE-PEG-FA modified manganese dioxide-based dual-atom nanozyme(MDF),on which iridium and platinum atoms are anchored.The obtained MDF can simultaneously mimic four enzyme activities of catalase,oxidase,peroxidase,and glutathione oxidase,set off a reactive oxygen species(ROS)storm,cause tumor cell death.The enzyme activity of MDF can be enhanced by its own photothermal effect.Meanwhile,MDF can consume intracellular glutathione and release Mn^(2+),which can prevent generated ROS from consumption and further activate cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes(cGAS-STING)pathway and promote the secretion of type I interferon,which will help promote dendritic cells maturation,present antigens to T lymphocytes to help kill tumor cells.Ultimately,MDF shows excellent tumor suppressive effects.This work provides a new paradigm for the field of nanozymes and offers a new reference for involvement of cGAS-STING pathway activation in tumor catalytic therapy.

Studies on Active Polysaccharides from Ganoderma lucidum vith Immune Activity

从云头状灵芝[Ganoderma Lucidum(Leyss.ex Fr.)Karst.]中分离得到三种灵芝多糖BN3A，BN3B及BN3C，它们均表现明显免疫调节作用。从灵芝多糖BN3B及BN3C中各分离得到四个多糖均一体，对其中主要成分BN3C1，BN3C3，BN3B1及BN3B3进行了物理及化学研究，它们的平均分子量依次为1.6×10^4，2.5×10^4，3.5×10^4及4.0×10^4。经完全酸水解、红外光谱测定、过碘酸氧化、甲酸生成、Smith降解等证明，BN3B1及BN3C1均为β－（1→6)(1→3）甙键相连的葡聚糖。BN3B3为阿拉伯半乳聚糖。BN3C3为由葡萄糖和阿拉伯糖组成的肽多糖。它们均为β－（1→6）（1→3）甙键相连。

Pathophysiology of autism spectrum disorders:Revisiting gastrointestinal involvement and immune imbalance

Autism spectrum disorders(ASD)comprise a group of neurodevelopmental abnormalities that begin in early childhood and are characterized by impairment of social communication and behavioral problems including restricted interests and repetitive behaviors.Several genes have been implicated in the pathogenesis of ASD,most of them are involved in neuronal synaptogenesis.A number of environmental factors and associated conditions such as gastrointestinal(GI)abnormalities and immune imbalance have been linked to the pathophysiology of ASD.According to the March 2012 report released by United States Centers for Disease Control and Prevention,the prevalence of ASD has sharply increased during the recent years and one out of 88 children suffers now from ASD symptoms.Although there is a strong genetic base for the disease,several associated factors could have a direct link to the pathogenesis of ASD or act as modifiers of the genes thus aggravating the initial problem.Many children suffering from ASD have GI problems such as abdominal pain,chronic diarrhea,constipation,vomiting,gastroesophageal reflux,and intestinal infections.A number of studies focusing on the intestinal mucosa,its permeability,abnormal gut development,leaky gut,and other GI problem raised many questions but studies were somehow inconclusive and an expert panel of American Academy of Pediatrics has strongly recommended further investigation in these areas.GI tract has a direct connection with the immune system and an imbalanced immune response is usually seen in ASD children.Maternal infection or autoimmune diseases have been suspected.Activation of the immune system during early development may have deleterious effect on various organs including the nervous system.In this review we revisited briefly the GI and immune system abnormalities and neuropeptide imbalance and their role in the pathophysiology of ASD and discussed some future research directions.

Oncological Hyperthermia: Where to Go from Here?

Oncological hyperthermia is one of the most versatile forms of oncotherapy. It can complement every conventional treatment method and be applied to any tumorous cancer, irrespective of its stages and localization. Numerous technical realizations are conventionally compared by their thermal effect, measured by temperature. However, nonthermal (mainly electric) excitation effects are more recognized nowadays. The technical variants alter the synergy between thermal and nonthermal energy components. Nonthermal energy absorption-induced molecular mechanisms include essential behaviors like selectivity and immunogenicity. The nonthermal electromagnetic effects excite molecular changes, intracellular signals, gene expressions, and many other chemical reactions. Their synergy with thermal conditions is based on the Arrhenius law, which describes the rapid growth of chemical reactions with temperature. A unique technical realization of hyperthermia, modulated electrohyperthermia (mEHT) tries to optimize the thermal and nonthermal effects. The results look very perspective, containing the high accuracy of targeting the tumor cells, the immunogenic cell death, and the activation of tumor-specific immune reactions restoring the healthy immune surveillance to destroy the cancer.

Survival,growth and immune activity of scallop Chlamys farreri cultured at different depths in Haizhou Bay(Yellow Sea,China) during hot season

Survival, growth and immune response of the scallop, Chlamys farreri, cultured in lantern nets at five different depths (2, 5, 10, 15, and 20 m below the sea surface) were studied in Haizhou Bay during the hot season (summer and autumn) of 2007. Survival and growth rates were quantified bimonthly. Immune activities in hemolymph (superoxide dismutase (SOD) and acid phosphatase (ACP)) were measured to evaluate the health of scallops at the end of the study. Environmental parameters at the five depths were also monitored during the experiment. Mortalities mainly occurred during summer. Survival of scallops suspended at 15 m (78.0%) and 20 m (86.7%) was significantly higher than at 2 m (62.9%), 5 m (60.8%) or 10 m (66.8%) at the end of the study. Mean shell height grew significantly faster at 10 m (205.0 μm/d) and 20 m (236.9 μm/d) than at 2, 5 or 15 m in summer (July 9 to September 1); however, shell growth rate at 20 m was significantly lower than at the other four depths in autumn (September 2 to November 6). In contrast to summer, scallops at 5 m grew faster (262.9 μm/d) during autumn. The growth of soft tissue at different depths showed a similar trend to the shell. Growth rates of shell height and soft tissue were faster in autumn than in summer, with the exception of shell height at 20 m. SOD activity of scallops increased with depth, and ACP activity was significantly higher at 15 and 20 m than at other depths, which suggests that scallops were healthier near the bottom. Factors explaining the depth-related mortality and growth of scallops are also discussed. We conclude that the mass mortality of scallop, C. farreri, during summer can be prevented by moving the culture area to deeper water and yield can be maximized by suspending the scallops in deep water during summer and then transferring them to shallow water in autumn.

Immune Killing Activity of Lymphocytes on Hela Cells Expressing Interleukin-12 In Vitro

The killing effects of lymphocytes on Hela cells expressing interleukin-12 （IL-12） in vitro were explored. By using gene transfection technique, full length IL-12 gene was transfected into Hela cells. The expression of IL-12 in Hela cells was detected quantitatively by ELISA; Changes in killing effects of lymphocytes on Hela cells expressing IL-12 were observed by MTT. It was found that Hela cells could express IL- 12 between 24 h and 72 h after transfection. Killing activity of lymphocytes on Hela cells expressing IL-12 was significantly enhanced. It was concluded by cell transfection technique, Hela cells could express 1L-12 and were more easily killed by lymphocytes.

Effects of Pseudoalteromonas sp. BC228 on Digestive Enzyme Activity and Immune Response of Juvenile Sea Cucumber(Apostichopus japonicus)

A marine bacterium, Pseudoalteromonas sp. BC228 was supplemented to feed in a feeding experiment aiming to determine its ability of enhancing the digestive enzyme activity and immune response of juvenile Apostichopus japonicus. Sea cucumber individuals were fed with the diets containing 0(control), 105, 107 and 109 CFU g-1 diet of BC228 for 45 days. Results showed that intestinal trypsin and lipase activities were significantly enhanced by 107 and 109 CFU g-1 diet of BC228 in comparison with control(P < 0.01). The phagocytic activity in the coelomocytes of sea cucumber fed the diet supplemented with 107 CFU g-1 diet of BC228 was significantly higher than that of those fed control diet(P < 0.05). In addition, 105 and 107 CFU g-1 diet of BC228 significantly enhanced lysozyme and phenoloxidase activities in the coelomic fluid of sea cucumber, respectively, in comparison with other diets(P < 0.01). Sea cucumbers, 10 each diet, were challenged with Vibrio splendidus NB13 after 45 days of feeding. It was found that the cumulative incidence and mortality of sea cucumber fed with BC228 containing diets were lower than those of animals fed control diet. Our findings evidenced that BC228 supplemented in diets improved the digestive enzyme activity of juvenile sea cucumber, stimulated its immune response and enhanced its resistance to the infection of V. splendidus.

Synthesis of TP3 FragmentviaOne Pot Strategy and Its Immune Regulatory Activity

We have modified the previously described one-pot peptide synthesis method. The modified method has been successfully applied to the synthesis of TP3. Furthermore, the immune regulatory activity of TP3 has been characterized. The results show that the modified one-pot method can be used to synthesize the biological active peptide with the advantages of low cost and high productivity. Moreover, TP3 has a higher immune regulatory activity than TP5.

Prenatal programing of motivated behaviors:can innate immunity prime behavior?

Prenatal programming during pregnancy sets physiological outcomes in the offspring by integrating external or internal stimuli.Accordingly,pregnancy is an important stage of physiological adaptations to the environment where the fetus becomes exposed and adapted to the maternal milieu.Maternal exposure to high-energy dense diets can affect motivated behavior in the offs p ring leading to addiction and impaired sociability.A high-energy dense exposure also increases the pro-inflammatory cytokines profile in plasma and brain and favors microglia activation in the offspring.While still under investigation,prenatal exposure to high-energy dense diets promotes structural abnormalities in selective brain regions regulating motivation and social behavior in the offspring.The current review addresses the role of energy-dense foods programming central and peripheral inflammatory profiles during embryonic development and its effect on motivated behavior in the offspring.We provide preclinical and clinical evidence that supports the contribution of prenatal programming in shaping immune profiles that favor structural and brain circuit disruption leading to aberrant motivated behaviors after birth.We hope this minireview encourages future research on novel insights into the mechanisms underlying maternal programming of motivated behavior by central immune networks.

Emerging roles of plasmacytoid dendritic cell crosstalk in tumor immunity

Plasmacytoid dendritic cells(pDCs)are a pioneer cell type that produces type I interferon(IFN-I)and promotes antiviral immune responses.However,they are tolerogenic and,when recruited to the tumor microenvironment(TME),play complex roles that have long been a research focus.The interactions between p DCs and other components of the TME,whether direct or indirect,can either promote or hinder tumor development;consequently,p DCs are an intriguing target for therapeutic intervention.This review provides a comprehensive overview of p DC crosstalk in the TME,including crosstalk with various cell types,biochemical factors,and microorganisms.An in-depth understanding of p DC crosstalk in TME should facilitate the development of novel p DC-based therapeutic methods.

Exosome regulation of immune response mechanism:Pros and cons in immunotherapy

Due to its multiple features,including the ability to orchestrate remote communication between different tissues,the exosomes are the extracellular vesicles arousing the highest interest in the scientific community.Their size,established as an average of 30-150 nm,allows them to be easily uptaken by most cells.According to the type of cells-derived exosomes,they may carry specific biomolecular cargoes used to reprogram the cells they are interacting with.In certain circumstances,exosomes stimulate the immune response by facilitating or amplifying the release of foreign antigens-killing cells,inflammatory factors,or antibodies(immune activation).Meanwhile,in other cases,they are efficiently used by malignant elements such as cancer cells to mislead the immune recognition mechanism,carrying and transferring their cancerous cargoes to distant healthy cells,thus contributing to antigenic invasion(immune suppression).Exosome dichotomic patterns upon immune system regulation present broad advantages in immunotherapy.Its perfect comprehension,from its early biogenesis to its specific interaction with recipient cells,will promote a significant enhancement of immunotherapy employing molecular biology,nanomedicine,and nanotechnology.

Exposure to Hyaluronan and Radon-Containing Water during the Treatment of Periodontal Pockets

Hyaluronic acid (HA) preparations have emerged as pivotal components in contemporary dentistry, gaining widespread recognition for their multifaceted roles in various biological functions. Extensive literature underscores the significance of HA in maintaining tissue water balance, fostering cell proliferation, promoting rapid cell migration, influencing cell differentiation during organism development, and facilitating tissue regeneration. Notably, HA’s interactions with cell surface receptors contribute to the viscosity of synovial fluid, activate the immune system, and enhance cartilage elasticity. Beyond these established functions, HA has also been investigated for its potential involvement in determining and studying the hormetic effects of radon water, adding a novel dimension to its applications in dental research. A thorough exploration of existing studies reveals a nuanced understanding of how HA interventions impact the outcomes of dental procedures. The comprehensive scope of these investigations allows for a more accurate assessment of the potential effectiveness of specific interventions and provides valuable insights into post-procedural prognoses for individual patients. This synthesis of literature serves as the foundation for elucidating the intricate interplay between HA, radon exposure, and their relevance in modern dental practices.

Impact of psychological stress on irritable bowel syndrome

Psychological stress is an important factor for the development of irritable bowel syndrome(IBS). More and more clinical and experimental evidence showed that IBS is a combination of irritable bowel and irritable brain. In the present review we discuss the potential role of psychological stress in the pathogenesis of IBS and provide comprehensive approaches in clinical treatment. Evidence from clinical and experimental studies showed that psychological stresses have marked impact on intestinal sensitivity, motility, secretion and permeability, and the underlying mechanism has a close correlation with mucosal immune activation, alterations in central nervous system, peripheral neurons and gastrointestinal microbiota. Stress-induced alterations in neuro-endocrine-immune pathways acts on the gut-brain axis and microbiota-gut-brain axis, and cause symptom flare-ups or exaggeration in IBS. IBS is a stresssensitive disorder, therefore, the treatment of IBS should focus on managing stress and stress-induced responses. Now, non-pharmacological approaches and pharmacological strategies that target on stress-related alterations, such as antidepressants, antipsychotics, miscellaneous agents, 5-HT synthesis inhibitors, selective 5-HT reuptake inhibitors, and specific 5-HT receptor antagonists or agonists have shown a critical role in IBS management. A integrative approach for IBS management is a necessary.