From dichotomy to diversity:deciphering the multifaceted roles of tumor-associated macrophages in cancer progression and therapy

Macrophages are innate immune cells that are ubiquitously distributed throughout the vertebrate body.Macrophages orchestrate sophisticated processes in development,homeostasis,immunity,and disease1.Macrophages residing in tumor tissues are commonly known as tumor-associated macrophages(TAMs)and promote or inhibit tumor growth depending on the activation state2.

Identification of differentially expressed genes in ulcerative colitis and verification in a colitis mouse model by bioinformatics analyses

BACKGROUND Ulcerative colitis(UC)is an inflammatory bowel disease that is difficult to diagnose and treat.To date,the degree of inflammation in patients with UC has mainly been determined by measuring the levels of nonspecific indicators,such as C-reactive protein and the erythrocyte sedimentation rate,but these indicators have an unsatisfactory specificity.In this study,we performed bioinformatics analysis using data from the National Center for Biotechnology Information-Gene Expression Omnibus(NCBI-GEO)databases and verified the selected core genes in a mouse model of dextran sulfate sodium(DSS)-induced colitis.AIM To identify UC-related differentially expressed genes(DEGs)using a bioinformatics analysis and verify them in vivo and to identify novel biomarkers and the underlying mechanisms of UC.METHODS Two microarray datasets from the NCBI-GEO database were used,and DEGs between patients with UC and healthy controls were analyzed using GEO2R and Venn diagrams.We annotated these genes based on their functions and signaling pathways,and then protein-protein interactions(PPIs)were identified using the Search Tool for the Retrieval of Interacting Genes.The data were further analyzed with Cytoscape software and the Molecular Complex Detection(MCODE)app.The core genes were selected and a Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis was performed.Finally,colitis model mice were established by administering DSS,and the top three core genes were verified in colitis mice using real-time polymerase chain reaction(PCR).RESULTS One hundred and seventy-seven DEGs,118 upregulated and 59 downregulated,were initially identified from the GEO2R analysis and predominantly participated in inflammation-related pathways.Seven clusters with close interactions in UC formed:Seventeen core genes were upregulated[C-X-C motif chemokine ligand 13(CXCL13),C-X-C motif chemokine receptor 2(CXCR2),CXCL9,CXCL5,C-C motif chemokine ligand 18,interleukin 1 beta,matrix metallopeptidase 9,CXCL3,formyl peptide receptor 1,complement component 3,CXCL8,CXCL1,CXCL10,CXCL2,CXCL6,CXCL11 and hydroxycarboxylic acid receptor 3]and one was downregulated[neuropeptide Y receptor Y1(NYP1R)]in the top cluster according to the PPI and MCODE analyses.These genes were substantially enriched in the cytokinecytokine receptor interaction and chemokine signaling pathways.The top three core genes(CXCL13,NYP1R,and CXCR2)were selected and verified in a mouse model of colitis using real-time PCR Increased expression was observed compared with the control mice,but only CXCR2 expression was significantly different.CONCLUSION Core DEGs identified in UC are related to inflammation and immunity inflammation,indicating that these reactions are core features of the pathogenesis of UC.CXCR2 may reflect the degree of inflammation in patients with UC.

Use of Neutron Activation Analysis and Inductively Coupled Plasma Mass Spectrometry for the Determination of Trace Elements in Pediatric and Young Adult Prostate

The questions about the androgen control and the involvement of trace elements in prostatic reproductive function still remain unanswered. One valuable way to elucidate the situation is to compare the values for the prostatic mass fractions of trace elements in pre-and post-pubertal boys. The effect of age on the mass fraction of 54 trace elements in intact prostate of 50 apparently healthy 0-30 years old males was investigated by neutron activation analysis and inductively coupled plasma mass spectrometry. Mean values (M ± SΕΜ) for mass fraction (milligram per kilogram, on dry-weight basis) of trace elements were: Ag 0.062 ± 0.008, Al 80 ± 18, Au 0.0092 ± 0.0024, B 5.9 ± 3.5, Be 0.0034 ± 0.0009, Bi 0.018 ± 0.010, Br 26 ± 3, Cd 0.26 ± 0.05, Ce 0.049 ± 0.012, Co 0.035 ± 0.004, Cr 0.49 ± 0.07, Cs 0.036 ± 0.005, Dy 0.0072 ± 0.0018, Er 0.0040 ± 0.0011, Fe 100 ± 10, Gd 0.0065 ± 0.0018, Hg 0.031 ± 0.004, Ho 0.0013 ± 0.0004, La 0.034 ± 0.007, Li 0.064 ± 0.009, Mn 1.69 ± 0.15, Mo 0.54 ± 0.13, Nb 0.013 ± 0.004, Nd 0.025 ± 0.006, Ni 4.1 ± 0.6, Pb 1.3 ± 0.2, Pr 0.0058 ± 0.0015, Rb 14.5 ± 0.8, Sb 0.051 ± 0.006, Sc 0.013 ± 0.002, Se 0.54 ± 0.03, Sm 0.0055 ± 0.0015, Sn 0.22 ± 0.05, Tb 0.0012 ± 0.0004, Th 0.0076 ± 0.0020, Ti 2.8 ± 0.5, Tl 0.0032 ± 0.0009, Tm 0.00064 ± 0.00017, U 0.0025 ± 0.0004, Y 0.036 ± 0.010, Yb 0.0037 ± 0.0012, Zn 281 ± 32, and Zr 0.16 ± 0.04. The upper limit of mean mass fraction of As, Eu, Ga, Hf, Ir, Lu, Pd, Pt, Re, and Ta were: As ≤ 0.069, Eu ≤ 0.0012, Ga ≤ 0.071, Hf ≤ 0.049, Ir ≤ 0.00054, Lu ≤ 0.00063, Pd ≤ 0.014, Pt ≤ 0.0029, Re ≤ 0.0048, and Ta ≤ 0.010. This work revealed that there is a significant tendency for the mass fractions of Cd, Se and Zn in the prostate tissue of healthy individuals to increase with age from the time of birth up to 30 years. It was also shown that high levels of Al, Au, B, Br, Cr, Ga, Li, and Ni mass fraction in prostate tissue do not indicate a direct involvement of these elements in the reproductive function of prostate.

Up-Regulation of Local TGF-β Contributes to a Decrease in Renal Tubular Na+-K+ ATPase and Hyperkalemia in a Mouse Model of Crush Syndrome

Hyperkalemia is one of the most important risk factors in patients suffering from crush syndrome with rhabdomyolysis. Glycerol-injected animals have been used as an experimental model of rhabdomyolysis-induced acute kidney injury (AKI), but little information is available for the onset and molecular mechanism of hyperkalemia. In our murine model, plasma potassium levels increased after a single injection of 50%-glycerol solution (10 ml/kg, i.m.) during the progression of muscular and renal injuries. Renal tubular Na+-K+-ATPase functions as ion-exchange pomp for potassium clearance from blood into renal tubular epithelial cells. Renal histochemistry revealed an apparent decrease in the tubular Na+-K+-ATPase expression, especially at 24 hours post-glycerol challenge in our AKI model. In contrast to the loss in active Na+-K+-ATPase, there was a significant increase in the renal levels of transforming growth factor-β (TGF-β) that is known to suppress Na+-K+-ATPase production in vitro. When anti-TGF-β antibody was administered in mice after the glycerol challenge, the suppression of renal Na+-K+-ATPase activity was partially restored. As a result, hyperkalemia was improved in the TGF-β-neutralized AKI mice, associated with a significant decrease in plasma potassium concentration. Taken together, we predict that endogenous TGF-β is a key regulator for inhibiting Na+-K+-ATPase production and, in part, enhancing hyperkalemia during progression of rhabdomyolysis-induced AKI. This is, to our knowledge, the first report to determine a critical role of endogenous TGF-β in renal potassium metabolism during crush syndrome.

The effect of laser acupuncture on hypoxia tolerance and inflammation reaction in mice with optical fiber acupuncture needle intra body

Hypoxia is a disorder in which the tissues are not oxygenated adequately.The lack of oxygen may cause irreversible damage to the major organs such as the brain,heart and lungs.In severe cases,coma,seizures,and death may happen.In addition to the routine medication,acupuncture.treatment has been applied as a complementary treatment to counter hypoxia.In this paper,the optical fiber acupuncture needle was fabricated using the optical fiber imbedding into the metal capillary tube with needle tip,therefore made it easy to insert into the body for the laser treatment.The laser optical fiber needle treatment to the ST36 acupoint conducted with the laser.irradiation intra body.The normobaric hypoxia tolerance test results in mice show that the optical fber needle treatment to the ST36 acupoint with laser acupuncture appears to improve the tolerance to hypoxia.The mice treated with laser acupuncture expressed high level of IL-1βin serum.Our results suggest that laser optical fiber needle acupuncture may serve as a potential treatment for hypoxia.

The impact of heavy metals on bacterial tolerance of antibiotic resistance and growth in the aquatic environment of Vietnam

Heavy metals may induce bacterial antibiotic resistance and affect their growth in the ecosystem.In this study,we aim to determine bacterial growth and antibiotic resistance in the pressure of heavy metals.Observed the changing morphology by gram staining was checked for bacterial toleration with heavy metal,developing of the colony form unit(CFU)was analysed bacterial kinetic growths and their biofilm formation.The disk diffusion test was used to perform bacterial susceptibility profiles with Ceftazidime(30μg),Ceftriaxone(30μg),Colistin sulfate(10μg),Meropenem or Imipenem(10μg),Ciprofloxacin(5μg)and Azithromycin(15μg)and the CLSI was applied for interpreting the data.The bacterial morphology remarkably changed from normal to short,round shape at a high concentration of heavy metals after 1 month.Their changing shape adapted to heavy metals by survival growing and resisted to Azithromycin,Ciprofloxacin,and Colistin without biofilm formation after 1 month,that was continued increasing after 2 months.The bacterial growth and antibiotic resistance were significant differences between provinces(P=0.01),type of bacterial species,and concentration of heavy metals.These results indicate that heavy metals are a crucial factor-driven for enhancing bacterial adaptation in pollution water resources and inducing their antimicrobial resistance in the aquatic environment.

DETECTION OF E6, E7 AND CELL-TYPE SPECIFIC ENHANCER OF HUMAN PAPILLOMAVIRUS TYPE 16 IN BREAST CARCINOMA

Objective To detect HPV16 E6, E7 genes and cell-type specific enhancer （CTSE） of long control region （LCR） in breast carcinoma （BC）. Methods HPV16 E6 ,E7 genes and CTSE were detected in 40 BCs and 20 normal breast tissue （NBT） using polymerase chain reaction （PCR）. Results The positive rates of HPV16 E6 , E7genes and CTSE were 60% （ 24/40 ） , 55% （ 22/40 ） and 67. 5% （ 27/40 ） respectively in BCs, whereas only 5% （1/20）, 5% （1/20） and 15% （3/20） in NBTs （ P 〈 O. 05）. There exited significant correlation between E6 gene and CTSE in BCs （ P 〈0. 05） , as well as E7 gene and CTSE. The infection of HPV16 E6, E7 and CTSE had no statistic relationship with pathological features. Conclusion There were HPV16 E6 , E7 genes and CTSE together in BCs and CTSE may play an important role in pathogenesis of BC.

The differences and similarities between two-sample t-test and paired t-test

临床研究中经常遇到比较实验组和对照组之间的结果。双样本t检验(又称为独立样本t检验)和配对t检验可能是运用于比较两个样本之间均值的最广泛的统计方法。然而,这两种方法的运用会产生混淆,从而导致使用不当。本文中,我们讨论了这两种t检验之间的异同性,并运用三个范例来阐述双样本t检验和配对t检验的计算过程。

Regulatory T Cells and Their Clinical Applications in Antitumor Immunotherapy

Cancer is a potentially life-threatening disease characterized by the immortalization of tumor cells in the host. Immunotherapy has recently gained increasing interest among researchers due to its tremendous potential for preventing tumor progression and metastasis. Regulatory T cells (Tregs) are a subgroup of suppressive CD4^+ T cells that play a vital role in the maintenance of host immune homeostasis. Treg deficiency can induce severe autoimmune, hypersensitivity, and auto-inflammatory disorders, among other diseases. Tregs are commonly enriched in a tumor microenvironment, and a greater number of immune-suppressive Tregs often indicates a poorer prognosis;therefore, there is renewed interest in the function of Tregs and in their clinical application in antitumor immunotherapy. Accumulating strategies that focus on the depletion of Tregs have appeared to be effective in antitumor immunity. It is expected that Treg-targeting strategies will provide great opportunities for improving antitumor efficiency in combination with other therapeutics (e.g., chimeric antigen receptor T cell (CAR-T)-based cell therapy or immune checkpoint blockading).

Chemotactic signaling and beyond: link between interleukin-16 and axonal degeneration in multiple sclerosis

Multiple sclerosis（MS）is a progressive inflammatory,and chronic demyelinating,neurodegenerative disease of central nervous system（CNS）.Autoimmune responses to myelin and other CNS antigens mediated by cluster of differentiation 4（CD4＋）T cells are critical for initiation and progression of disease.Migration of autoimmune T cells from the peripheral lymph organs into CNS parenchyma leads to inflammation,demyelination and damage of axonal cytoskeleton, which manifest in decreased impulse conduction velocity of motor and sensory nerves. Myelin and axonal pathology causes motor, sensory and autonomic nerve dysfunction, including optic nerve damage leading to double or distorted vision; paresis and paralysis of extremities, painful sensations, and bladder sphincter dysfunction, manifested as bladder incontinence. Gray matter pa- thology in cortical and subcortical regions, including cerebellum and hippocampus underlies cognitive and behavioral dysfunction consisting of memory deficits, depression, and ataxic gait and tremor.

Recent advances on the role of long non-coding RNAs in Alzheimer’s disease

Dementia is a progressive cognitive impairment that affects the activities of daily living.Alzheimer’s disease (AD) is the most common form of the dementia worldwide accounting for 60-80%of all dementia cases.With an estimated cost exceeding$290 billion in the USA,understanding and development of future therapeutic strategies is vital.In this perspective,we will be examining the current thinking of AD research and therapeutic strategies,while proposing a possible new direction for diagnosis,understanding,and treatment targets.

Engineered T cells and their therapeutic applications in autoimmune diseases

Chimeric antigen receptor T cells(CAR-T cells) are engineered recombinant T cells, which were initially used to treat hematopoietic malignancies and are now widely used in the treatment of various diseases. Considering their intrinsic targeting efficiency, CAR-T cells show considerable potential in the treatment of autoimmune diseases.Furthermore, regulatory T cells(Treg), a subset of CD4 T cells exhibiting immunosuppressive functions,have attracted increasing attention regarding CARTreg cell production. In this review, we report on recent developments in preclinical and clinical studies on CAR-T cells in autoimmune diseases and provide an outlook on opportunities and challenges of CAR-T application in such diseases.

Molecular mechanisms of DNA lesion and repair during antibody somatic hypermutation

Antibody diversification is essential for an effective immune response,with somatic hypermutation(SHM)serving as a key molecular process in this adaptation.Activation-induced cytidine deaminase(AID)initiates SHM by inducing DNA lesions,which are ultimately resolved into point mutations,as well as small insertions and deletions(indels).These mutational outcomes contribute to antibody affinity maturation.The mechanisms responsible for generating point mutations and indels involve the base excision repair(BER)and mismatch repair(MMR)pathways,which are well coordinated to maintain genomic integrity while allowing for beneficial mutations to occur.In this regard,translesion synthesis(TLS)polymerases contribute to the diversity of mutational outcomes in antibody genes by enabling the bypass of DNA lesions.This review summarizes our current understanding of the distinct molecular mechanisms that generate point mutations and indels during SHM.Understanding these mechanisms is critical for elucidating the development of broadly neutralizing antibodies(bnAbs)and autoantibodies,and has implications for vaccine design and therapeutics.

Updated thoughts on SARS-CoV-2 and coronavirus therapies,fighting and surviving

From late December 2019 a new human-adapted coronavirus,SARS-CoV-2,was observed and isolated in clustered patients in Wuhan,China.It has been proved to be able to transmit human-to-human and cause pneumonia,leading to about 2%fatality.Its genome characteristics,immune responses and related potential treatments,such as chemical drugs,serum transfusion and vaccines including DNA vaccines,are discussed in this review for a brief summary.

Lineage structure of the human antibody repertoire in response to influenza vaccination

The adaptive immune system produces a large and diverse set of antibodies,each with an individual evolutionary and clonal history.This so called"antibody repertoire"protects each individual against insults such as infection and cancer,and responds to vaccination with B cell proliferation in response to the antigenic stimulation.Hybridomas and antigen-specific FACSbased analysis have given us much insight on how the immune system generates the complex and diverse immune response required to protect the body from the wide variety of potential pathogens.However,these methods have not been sufficient to make global and unbiased characterizations of the clonal structure of the immune system of a particular individual。

Identification of two migratory colon ILC2 populations differentially expressing IL-17A and IL-5/IL-13

Group 2 innate lymphoid cells(ILC2s)play important tissue resident roles in anti-parasite immunity,allergic immune response,tissue homeostasis,and tumor immunity.ILC2s are considered tissue resident cells with little proliferation at steady state.Recent studies have shown that a subset of small intestinal ILC2s could leave their residing tissues,circulate and migrate to different organs,including lung,liver,mesenteric LN and spleen,upon activation.However,it remains unknown whether other ILC populations with migratory behavior exist.In this study,we find two major colon ILC2 populations with potential to migrate to the lung in response to IL-25 stimulation.One subset expresses IL-17A and resembles inflammatory ILC2s(iILC2s)but lacks CD27 expression,whereas the other expresses CD27 but not IL-17A.In addition,the IL-17A^(+)ILC2s express lower levels of CD127,CD25,and ST2 than CD27^(+)ILC2s,which express higher levels of IL-5 and IL-13.Surprisingly,we found that both colon ILC2 populations still maintained their colonic features of preferential expression of IL-17A and CD27,IL-5/IL-13,respectively.Together,our study identifies two migratory colon ILC2 subsets with unique surface markers and cytokine profiles which are critical in regulating lung and colon immunity and homeostasis.

Role of T cells in cancer immunotherapy:Opportunities and challenges

Immunotherapies boosting the immune system's ability to target cancer cells are promising for the treatment of various tumor types,yet clinical responses differ among patients and cancers.Recently,there has been increasing interest in novel cancer immunotherapy practices aimed at triggering T cell-mediated anti-tumor responses.Antigen-directed cytotoxicity mediated by T lymphocytes has become a central focal point in the battle against cancer utilizing the immune system.The molecular and cellular mechanisms involved in the actions of T lymphocytes have directed new therapeutic approaches in cancer immunotherapy,including checkpoint blockade,adoptive and chimeric antigen receptor(CAR)T cell therapy,and cancer vaccinology.This review addresses all the strategies targeting tumor pathogenesis,including metabolic pathways,to evaluate the clinical significance of current and future immunotherapies for patients with cancer,which are further engaged in T cell activation,differentiation,and response against tumors.

Regulation of CD8^(+)T memory and exhaustion by the mTOR signals

CD8^(+)T cells are the key executioners of the adaptive immune arm,which mediates antitumor and antiviral immunity.Naïve CD8^(+)T cells develop in the thymus and are quickly activated in the periphery after encountering a cognate antigen,which induces these cells to proliferate and differentiate into effector cells that fight the initial infection.Simultaneously,a fraction of these cells become long-lived memory CD8^(+)T cells that combat future infections.Notably,the generation and maintenance of memory cells is profoundly affected by various in vivo conditions,such as the mode of primary activation(e.g.,acute vs.chronic immunization)or fluctuations in host metabolic,inflammatory,or aging factors.Therefore,many T cells may be lost or become exhausted and no longer functional.Complicated intracellular signaling pathways,transcription factors,epigenetic modifications,and metabolic processes are involved in this process.Therefore,understanding the cellular and molecular basis for the generation and fate of memory and exhausted CD8^(+)cells is central for harnessing cellular immunity.In this review,we focus on mammalian target of rapamycin(mTOR),particularly signaling mediated by mTOR complex(mTORC)2 in memory and exhausted CD8^(+)T cells at the molecular level.

Fli1 acts in parallel with Pu.1 to control macrophage and neutrophil fate in zebrafish

Macrophages and neutrophils are key components of myeloid cells and play critical roles in innate immune responses,organ formation,and tissue homeostasis.The integrity of their functions heavily relies on the generation of a proper number of mature macrophages and neutrophils through embryonic and adult myelopoiesis.In mammalian adult myelopoiesis,oligopotent common myeloid progenitors(CMPs)are known to be the earliest myeloid progenitors,which give rise to granulocyte-macrophage progenitors(GMPs),subsequently differentiate into unipotent neutrophil and macrophage precursors,and finally,mature macrophages and neutrophils(Orkin and Zon,2008).In contrast,the ontogeny of embryonic myelopoiesis and the mechanism underlying the formation of macrophages and neutrophils remainless understood.

Biomolecular condensates and disease pathogenesis

Biomolecular condensates or membraneless organelles(MLOs)formed by liquid-liquid phase separation(LLPS)divide intracellular spaces into discrete compartments for specific functions.Dysregulation of LLPS or aberrant phase transition that disturbs the formation or material states of MLOs is closely correlated with neurodegeneration,tumorigenesis,and many other pathological processes.Herein,we summarize the recent progress in development of methods to monitor phase separation and we discuss the biogenesis and function of MLOs formed through phase separation.We then present emerging proof-of-concept examples regarding the disruption of phase separation homeostasis in a diverse array of clinical conditions including neurodegenerative disorders,hearing loss,cancers,and immunological diseases.Finally,we describe the emerging discovery of chemical modulators of phase separation.