Cellular Immunosuppression Research Articles

Testosterone leads to Trypanosoma cruzi glycoprotein synthesis and increased of inflammatory mediators in bone marrow-derived macrophages

Despite all the scientific progress in recent decades to unravel the immune processes and the way the parasite bypasses the immune system, Chagas disease is still a major public health problem, affecting an estimated 3.5 million people. Among the components that may participate in the response against the parasite, testosterone has been gaining more and more visibility. Studies indicate that the parasite itself seems to carry out steroidogenesis, in which, in co-culture with androgen precursors, T. cruzi has been shown to produce TS, but the purpose of the TS synthesized by the parasite and how this can influence its invasion glycoproteins is still unclear unknown. The aim of this study was to evaluate the influence of testosterone in Trypanosoma cruzi infection on the immune response of bone marrow-derived macrophages. Bone marrow from male rats was extracted and cultured with RMPI medium containing 30% L929 cell supernatant for macrophage differentiation. The cells were incubated for 10 days and, after this period, they were seeded in 96 wells in the amount of 1 x 105 cells per well. TS was added at different concentrations of 20 μM, 10 μM, 5 μM and 1 μM and then infected with the Y strain of T. cruzi, at a rate of 10 parasites per cell, with the culture remaining for six, 12 and 24 h. The supernatant was collected and the production of nitric oxide (NO), tumor necrosis factor (TNF) and the number of cell parasites was assessed by staining with 4′-6′-diamino-2-phenylindole (DAPI) and ranked by high Content Screening (HSC). The parasite was then cultured with the addition of TS, at the mentioned concentrations, leaving it for six and 12 h and then performing the RT-PCR of the mucins. DAPI staining revealed a significant increase in the number of parasites in cells containing TS. The exception was observed when 1 μM of hormone/well was used. A reduction in TNF production was found with 20 and 10 μM of TS for 6 h stimulation, although increased levels were observed with 5 and 1 μM, similar to the infected control. However, there was an increase in TNF production and not after 12 h. The relative expression of parasite glycoprotein 82 was increased with the presence of TS in the medium, regardless of time. Our data suggest that TS may contribute to cellular immunosuppression, increasing parasite infection in the cell, as well as inflammatory mediators that lead to cell and tissue damage in infected individuals, as well as the possible use of TS to allow their invasion into the cell hosts.

Unfolding the Complexity of Exosome-Cellular Interactions on Tumour Immunity and Their Clinical Prospects in Nasopharyngeal Carcinoma.

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy situated in the posterolateral nasopharynx. NPC poses grave concerns in Southeast Asia due to its late diagnosis. Together with resistance to standard treatment combining chemo- and radiotherapy, NPC presents high metastatic rates and common recurrence. Despite advancements in immune-checkpoint inhibitors (ICIs) and cytotoxic-T-lymphocytes (CTLs)-based cellular therapy, the exhaustive T cell profile and other signs of immunosuppression within the NPC tumour microenvironment (TME) remain as concerns to immunotherapy response. Exosomes, extracellular vesicles of 30-150 nm in diameter, are increasingly studied and linked to tumourigenesis in oncology. These bilipid-membrane-bound vesicles are packaged with a variety of signalling molecules, mediating cell-cell communications. Within the TME, exosomes can originate from tumour, immune, or stromal cells. Although there are studies on tumour-derived exosomes (TEX) in NPC and their effects on tumour processes like angiogenesis, metastasis, therapeutic resistance, there is a lack of research on their involvement in immune evasion. In this review, we aim to enhance the comprehension of how NPC TEX contribute to cellular immunosuppression. Furthermore, considering the detectability of TEX in bodily fluids, we will also discuss the potential development of TEX-related biomarkers for liquid biopsy in NPC as this could facilitate early diagnosis and prognostication of the disease.

IFI16 plays a critical role in avian reovirus induced cellular immunosuppression and suppresses virus replication

Avian reovirus (ARV), which commonly induces viral arthritis or tenosynovitis and immunosuppression in chickens, is associated with the nonstructural protein p17 that plays a crucial role in viral replication and regulates cellular signaling pathways through its interaction with cellular proteins. In our previous study, we identified the host protein IFN-γ-inducible protein-16 (IFI16) as an interacting partner of ARV p17 through yeast two-hybrid screening. In the current study, we further confirmed the interaction between IFI16 and p17 protein using coimmunoprecipitation, glutathione S-transferase (GST)-pulldown assay, and laser confocal microscopy techniques. Additionally, we found that the amino acid of p1761-119 is responsible for mediating the interaction with the HINa and HINb domains of IFI16. Interestingly, we observed a significant increase in IFI16 expression upon ARV infection or p17 protein exposure. Moreover, the replication of ARV was found to be largely influenced by the quantity of IFI16 protein. Overexpression of IFI16 led to a significant decrease in ARV replication, while knockdown of the IFI16 expression led to the contrary result. Additionally, our findings demonstrate that IFI16 plays a crucial role in the induction of inflammatory cytokines IFN-β and IL-1β during ARV infection as confirmed by qRT-PCR and ELISA analyses. In conclusion, our study provides novel insights into the functional role of p17 protein and the pathogenic mechanism underlying ARV infection, particularly its association with inflammatory response. Furthermore, it offers new perspectives for identifying potential therapeutic targets against ARV infection.

Discovery of Potential Natural STAT3 Inhibitors: An in silico Molecular Docking and Molecular Dynamics Study

Cancer is a mechanistically complex and diverse disease with a plethora of fundamental genetic and epigenetic factors. Signal transducer and activator of transcription-3 (STAT3) is a transcription factor, and its constitutive activation executes promotion of cellular proliferation, cell cycle, angiogenesis, metastasis, immunosuppression, and chemo-resistance in cancer cells. Here, we aimed to design natural potential STAT3 inhibitors. For this purpose, we investigated 92 phytochemical compounds by molecular docking studies because they are diversified, multitargeted, affordable, easily available, and less- or non-toxic. We selected only 6 compounds such as sarsasapogenin (L3), peiminine (L9), solasodine (L10), tormentic acid (L23), obacunone (L29), and echinocystic acid (L34) due to their greater binding affinity than reference STAT3 inhibitor (S3I-201) with STAT3. The study was further continued by molecular dynamic (MD) simulations and ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis. The results of molecular docking showed that all selected ligands exhibited binding affinity range from -9.3 Kcal/mol to -7.9 Kcal/mol and predicted inhibition constant ([Formula: see text].) values range from 0.14 [Formula: see text]M to 1.5 [Formula: see text]M. These compounds showed effective hydrogen bonding and hydrophobic interactions with DNA binding domain as well as SH2-domain of STAT3. The MD simulations performed by nanoscale molecular dynamics (NAMD) calculated root mean square deviations (RMSD), root mean square fluctuations (RMSF), radius of gyration ([Formula: see text]), solvent accessible surface area (SASA) and number of hydrogen bond dynamics. All selected ligands with protein exhibited stability over 120 ns by MD simulation. Moreover, these ligands showed favorable ADMET profiling and drug likeness. So, our current computational investigations showed that these novel drug candidates can be potential STAT3 inhibitors and evoke the scientific interest for their further verification by in vitro and in vivo studies.

Antimicrobial Prophylaxis in Lymphoma by Chemotherapy Regimen

Treatment of lymphomas involves a wide variety of chemotherapy, immunotherapy, and targeted-agents tailored to disease biology and patient characteristics. Each of these regimens carry their own risk of opportunistic infections in an immunocompromised population. In addition to the treatment associated immunosuppression, lymphoma itself is immunosuppressive. Lymphoma associated immunosuppression is secondary to increased production of abnormal lymphocytes resulting in decreased production of normally functioning lymphocytes. Additionally, lymphoma cells induce both humoral and cellular immunosuppression through effects on numerous cytokines, T-cells, myeloid-derived suppressor cells, and macrophages. Clinical trials, patient co-morbidities, and institutional preferences all play a role in determining the preferred antimicrobial prophylaxis. While there is a paucity of data on systematic reviews and guidelines for standardized chemotherapy regimens in lymphoma patients, the efficacy and recommendations for antimicrobial prophylaxis in specific chemotherapy regimens for lymphoma has not been fully reviewed. According to the National Comprehensive Cancer Network, lymphoma is generally regarded as an ‘intermediate risk’ cancer with regards to overall infection risk. This results in discordance between research data and clinical practice. This is reiterated in the SIGNIFICANT trial which reported that while guidelines previously advised against fluoroquinolone prophylaxis in lymphoma and solid cancers, a survey of 3,600 physicians revealed that 45% routinely used fluoroquinolone prophylaxis despite these recommendations. This review article analyzes numerous research studies with summarization of findings and antimicrobial prophylaxis recommendations based on specific lymphoma chemotherapy regimens. With regards to each specific chemotherapy regimen assessed, indications for antibacterial, anti-viral, anti-fungal, and Pneumocystis jiroveci pneumonia (PJP) prophylaxis were determined for each regimen. The degree of immunosuppression and the necessary prophylaxis varies across different regimens and lymphoma subgroups; and thus, an individualized approach is necessary to optimize the supportive care during lymphoma treatment.

Rombo encephalitis and cerebellar abscess due to Listeria monocytogenes with fulminant course in an immunocompetent elderly patient: A case report

Listeria Monocytogenes (LM) is an opportunistic bacterium that can cause from mild infections to severe clinical pictures with neurological involvement, being responsible for sporadic cases, epidemic outbreaks and a high mortality and case fatality rate. Neurolisteriosis may present as meningitis, meningoencephalitis, rhomboencephalitis or brain abscesses. LM rhomboencephalitis is a rare disease for which advanced age and cellular immunosuppression are common risk factors, although it may occur in patients without prior immunosuppression. Spread to the CNS occurs haematogenously through the blood-brain barrier, by direct invasion or by retrograde brain migration through nerve tracts. Different diagnostic subtyping methods are available, although DNA sequencing is the technique of choice for epidemiological studies. The combination of ampicillin with gentamicin for 6-8 weeks is usually the recommended treatment, and neurosurgery may improve the prognosis in patients with brain abscess, although there are no clinical practice guidelines available with a high level of evidence. The diagnosis of LM rhomboencephalitis should be suspected in any patient with an infectious condition with evidence of meningeal or brainstem involvement. Mortality from neurolisteriosis is increasing in Europe due to the ageing population and the increase in immunocompromised patients, and can reach up to 51%. The case described in this article is exceptional, presenting acute rhomboencephalitis with cerebellar abscesses in a healthy patient with no risk factors and a fulminant course.

Risk Assessment of Venous Thrombolic Disease in Hospitalized Advanced HIV Patients in a Resource-Limited Setting

HIV infection is known to be a factor associated with cardiovascular disease. The objective of this work is to draw the attention of clinicians working in a resource-limited environment to the risk run by these patients in hospitalization in order to be able to prevent and ensure early and adequate management allowing the reduction of thrombotic risk andits complications. This is a descriptive cross-sectional study from January 2022 to May 2023, all patients hospitalized for advanced HIV disease were assessed by the Padua score supported by the D-dimer test. The data was collected in strict confidentiality. Out of a total of 400 hospitalized patients 40 were identified as being at being at risk of developing venous thromboembolic disease (VTE). The average age was 33, 6 years, 28 patients were female (70%).Coma (37,5%) and dyspnea(30%) were the main reasons for consultation. Cellular immunosuppression was severe (CD4∠200 mm3) in 95% of patients disseminated tuberculosis(50%), pneumocystosis carini pneumonia(25%), sepsis(12,5%), neuromeningeal cryptococcosis(7,5%) and Kaposi’s sarcoma (5%) were the main associated opportunistic conditions. 28(70%) patients were naïve to antiretrovirals and 12(30%) had been on retroviral treatment for six months. 12(30%) patients died, 8(20%) patients progressed well, and 20(50%) were lost sight of for lack financed mean.

#5456 TUBERCULOSIS IN DIALYSIS PATIENTS IN THE CENTRAL REGION OF MOROCCO: WHAT IS THE HEALTH-CARE DELAY?

Abstract Background and Aims Due to the predominantly cellular immunosuppression, infections are frequent in chronic dialysis patients, in particular tuberculosis (TB). The main objective of our study is to evaluate tuberculosis healthcare delay in dialysis patients and to raise the diagnostic challenge in these patients. Method The study is retrospective and multicenter including tuberculosis cases of chronic dialysis patients either in hemodialysis (HD) or peritoneal dialysis (PD) in the central region of Morocco during a 10-year period between 2012 and 2021. Results We included 94 patients, five of whom were in PD, with a mean age of 50.79 ± 16.72 years, and a sex ratio of 0.67. The time between the initiation of dialysis and the onset of the clinical and biological presentation was 50.3 ± 67.12 months. The most frequent initial manifestations were an alteration of the general state (85.1%), a biological inflammatory syndrome (83%) or a prolonged fever (70.1%). Among our 94 patients, the diagnosis was confirmed with bacteriological evidence only in 18 cases (19.1%), by identification of Koch's Bacillus (BK) in 13 cases, by molecular biology test (GeneXpert; Cepheid, Inc., Sunnyvale, CA, USA) in five cases. The diagnosis of tuberculosis was presumptive in most cases (79 cases), i.e. 80.9%. Twenty-one patients underwent the interferon gamma release essay test (QuantiFERON; Qiagen, Hilden, Germany) which was positive in 14 patients. Thirty-four (36.1%) cases had a histological diagnosis. The remaining patients were offered a trial treatment. Tuberculosis localization was mostly extrapulmonary (75.5%): lymph node (23.4%), pleural (13.8%), peritoneal (13.8%), whereas it was pulmonary in 23 cases (24.5%). Most of our patients had a clear delay in management from symptom onset to initiation of anti-TB treatment 78.9% (time >21days) vs 21.1% (time ≤21days). The median time to management delay was 46.5 interquartile range (IQR) (28.5-90), the mean delay was 78.4 ± 87.9 (6-360). All patients were treated according to the RHZE/RH protocol (R: rifampicin, H: isoniazid Z: pyrazinamide and E: ethambutol), with a duration between six and 18 months. Side effects associated with anti-tuberculosis treatment were observed in half of the patients (51.1%). The evolution was favorable with remission and improvement of the general condition in 90% of cases. Two cases of resistance were noted in our series. The overall mortality was 7.7%. Conclusion We have confirmed a delay in the diagnosis and treatment of tuberculosis in chronic dialysis patients. This can be explained by the often atypical or incomplete clinical and paraclinical presentation and the extra-pulmonary localizations, making diagnosis difficult in this population whose prognosis remains poor. It is therefore necessary to establish a diagnostic approach that is adapted to the specificities of these high-risk patients within the framework of a national tuberculosis control program.

Clinical characteristics and outcomes of children with Kawasaki disease combined with sepsis in the pediatric intensive care unit.

Kawasaki disease (KD) is a vascular inflammatory disease with unknown pathogenesis. There are few studies on KD combined with sepsis worldwide. To provide valuable data regarding clinical characteristics and outcomes related to pediatric patients with KD combined with sepsis in pediatric intensive care unit (PICU). We retrospectively analyzed the clinical data of 44 pediatric patients admitted in PICU at Hunan Children's Hospital with KD combined with sepsis between January 2018 and July 2021. Of the 44 pediatric patients (mean age, 28.18 ± 24.28 months), 29 were males and 15 were female. We further divided the 44 patients into two groups: KD combined with severe sepsis (n=19) and KD combined with non-severe sepsis (n=25). There were no significant between-group differences in leukocyte, C-reactive protein, and erythrocyte sedimentation rate. Interleukin-6, interleukin-2, interleukin-4 and procalcitonin in KD with severe sepsis group were significantly higher than those in KD with non-severe sepsis group. And the percentage of suppressor T lymphocyte and natural killer cell in severe sepsis group were significantly higher than those in non-severe group, while the CD4+/CD8+ T lymphocyte ratio was significantly lower in KD with severe sepsis group than in KD with non-severe sepsis group. All 44 children survived and were successfully treated after intravenous immune globulin (IVIG) combined with antibiotics. Children who develop with KD combined with sepsis have different degrees of inflammatory response and cellular immunosuppression, and the degree of inflammatory response and cellular immunosuppression is significantly correlated with the severity of the disease.

Tuberculosis in Dialysis Patients in the Central Region of Morocco: What Is the Health-Care Delay?

Introduction: Due to the predominantly cellular immunosuppression, infections are frequent in chronic dialysis patients, in particular tuberculosis (TB). The main objective of our study is to evaluate tuberculosis healthcare delay in dialysis patients and to raise the diagnostic challenge in these patients.Material and methods: The study is retrospective and multicenter including tuberculosis cases of chronic dialysis patients either in hemodialysis (HD) or peritoneal dialysis (PD) in the central region of Morocco during a 10-year period between 2012 and 2021.Results: We included 94 patients, five of whom were in PD, with a mean age of 50.79 ± 16.72 years, and a sex ratio of 0.67. The time between the initiation of dialysis and the onset of the clinical and biological presentation was 50.3 ± 67.12 months. The most frequent initial manifestations were an alteration of the general state (85.1%), a biological inflammatory syndrome (83%) or a prolonged fever (70.1%). Among our 94 patients, the diagnosis was confirmed with bacteriological evidence only in 18 cases (19.1%), by identification of Koch's Bacillus (BK) in 13 cases, by molecular biology test (GeneXpert; Cepheid, Inc., Sunnyvale, CA, USA) in five cases. The diagnosis of tuberculosis was presumptive in most cases (79 cases), i.e. 80.9%. Twenty-one patients underwent the interferon gamma release essay test (QuantiFERON; Qiagen, Hilden, Germany) which was positive in 14 patients. Thirty-four (36.1%) cases had a histological diagnosis. The remaining patients were offered a trial treatment. Tuberculosis localization was mostly extra-pulmonary (75.5%): lymph node (23.4%), pleural (13.8%), peritoneal (13.8%), whereas it was pulmonary in 23 cases (24.5%).Most of our patients had a clear delay in management from symptom onset to initiation of anti-TB treatment 78.9% (time >21days) vs 21.1% (time ≤21days). The median time to management delay was 46.5 interquartile range (IQR) (28.5-90), the mean delay was 78.4 ± 87.9 (6-360). All patients were treated according to the RHZE/RH protocol (R: rifampicin, H: isoniazid Z: pyrazinamide and E: ethambutol), with a duration between six and 18 months. Side effects associated with anti-tuberculosis treatment were observed in half of the patients (51.1%). The evolution was favorable with remission and improvement of the general condition in 90% of cases. Two cases of resistance were noted in our series. The overall mortality was 7.7%.Conclusion: We have confirmed a delay in the diagnosis and treatment of tuberculosis in chronic dialysis patients. This can be explained by the often atypical or incomplete clinical and paraclinical presentation and the extra-pulmonary localizations, making diagnosis difficult in this population whose prognosis remains poor. It is therefore necessary to establish a diagnostic approach that is adapted to the specificities of these high-risk patients within the framework of a national tuberculosis control program.

Biological characteristics and pulp regeneration potential of stem cells from canine deciduous teeth compared with those of permanent teeth

BackgroundClinical studies have demonstrated that dental pulp stem cells isolated from permanent teeth (PT-DPSCs) are safe and efficacious for complete pulp regeneration in mature pulpectomized permanent teeth with complete apical closure. Moreover, dental pulp stem cells from deciduous teeth (DT-DPSCs) have also been shown to be useful for pulp regenerative cell therapy of injured immature permanent teeth. However, direct comparisons of the pulp regenerative potential of DT-DPSCs and PT-DPSCs from the same individual have not been performed. This study aimed to compare the differences in stem cell properties and pulp regenerative potential of DT-DPSCs and PT-DPSCs of identical origin.MethodsDT-DPSCs and PT-DPSCs were isolated from the same individual dogs at 4 months and 9 months of age, respectively. The expression of cell surface antigen markers, proliferation and migration activities, and gene expression of stem cell markers, angiogenic/neurotrophic factors and senescence markers were compared. The effects of conditioned medium (CM) derived from these cells on cellular proliferation, migration, angiogenesis, neurite outgrowth and immunosuppression were also compared. Autologous transplantation of DT-DPSCs or PT-DPSCs together with G-CSF was performed to treat pulpectomized teeth in individual dogs. The vascularization and reinnervation of the regenerated pulp tissues were qualitatively and quantitatively compared between groups by histomorphometric analyses.ResultsThe rates of positive CXCR4 and G-CSFR expression in DT-DPSCs were significantly higher than those in PT-DPSCs. DT-DPSCs migrated at a higher rate with/without G-CSF and exhibited increased expression of the stem cell markers Oct3/4 and CXCR4 and the angiogenic factor VEGF and decreased expression of the senescence marker p16 than PT-DPSCs. DT-DPSC-derived CM promoted increased cell proliferation, migration with G-CSF, and angiogenesis compared with PT-DPSC-derived CM; however, no difference was observed in neurite outgrowth or immunosuppression. The regenerated pulp tissues in the pulpectomized teeth were quantitatively and qualitatively similar between the DT-DPSCs and PT-DPSCs transplant groups.ConclusionsThese results demonstrated that DT-DPSCs could be a potential clinical alternative to PT-DPSCs for pulp regenerative therapy. DT-DPSCs can be preserved in an individual cell bank and used for potential future pulp regenerative therapy before the supply of an individual’s own sound discarded teeth has been exhausted.

Bifidobacterium infantis Promotes Foxp3 Expression in Colon Cells via PD-L1-Mediated Inhibition of the PI3K-Akt-mTOR Signaling Pathway.

AimOur objective was to investigate whether Bifidobacterium infantis inhibits PI3K-Akt-mTOR signaling and upregulates Foxp3 expression through PD-L1 and to explore the possible mechanism of action of B. infantis in cellular immunosuppression. MethodThe effects of B. infantis supernatant on PD-L1, PD-1, Foxp3, and the PI3K-Akt-mTOR signaling pathway were observed by culturing HCT-116 cells. Simultaneously, the effects of blocking PD-L1 on PD-1, on Foxp3 protein and mRNA, and on the PI3K-Akt-mTOR signaling pathway protein were observed.ResultsB. infantis supernatant was able to upregulate the protein and mRNA expression of PD-L1 and Foxp3 and downregulate the phosphorylated protein expression of PI3K, Akt, and mTOR (P < 0.05); however, for PI3K, Akt, and mTOR, there was no change in the total protein expression. After the blocking of PD-L1, the stimulatory effect of B. infantis supernatant on Foxp3 and the inhibitory effect on the phosphorylated protein expression of PI3K, Akt, and mTOR were weakened.ConclusionB. infantis may inhibit the PI3K-Akt-mTOR signaling pathway and promote the expression of Foxp3 through PD-L1, which may be a target via which B. infantis exerts its immunosuppressive effect.

Rare Case of Cryptococcal Meningitis in Non-HIV Patient with Mantle Cell Lymphoma Associated with Acalabrutinib (Tyrosine Kinase Inhibitor)

Cryptococcus neoformans infections are more common among immunosuppressed individuals, causing the most widespread opportunistic CNS infection among HIV-positive patients [1]. Specifically, those with cellular immunosuppression, such as patients with HIV positive CD4 counts less than 100. When a patient presents with atypical symptoms, it can be difficult to diagnose due to its infrequent presentation in HIV negative patients. Due to the rarity of encounters in HIV-negative patients, when atypical symptoms are present, it poses a diagnostic challenge. Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin B-cell lymphoma that is known to be associated with cellular immunosuppression [2]. This demonstrates the need for early diagnosis and recognition of cryptococcal infections and as a physician should be vigilant to diagnose cryptococcal who is on Acalabrutinib with MCL [3]. CLL patients receiving ibrutinib should be evaluated for cryptococcal infection, which is potentially life threatening if overlooked [4]. Meningitis caused by Cryptococcus mainly presents with fever and altered mental status but in this case, our patient 78-year-old male with mantle cell lymphoma, undergoing a regimen of Rituximab-Bendamustine (BR) in combination with acalabrutinib (TKI), presented with hypotension to ED in June 2021. Cryptococcal infection in patient receiving ibrutinib were mostly reported in patients with Chronic lymphocytic leukemia, who have poor immune reconstitution. Here we are reporting case of cryptococcal meningoencephalitis in patient with MCL on acalabrutinib which is never reported before.

Effects of Different Anesthetic and Analgesic Methods on Cellular Immune Function and Stress Hormone Levels in Patients Undergoing Esophageal Cancer Surgery.

The change of perioperative immune function in patients with esophageal cancer is mainly caused by the joint action of surgical trauma and anesthesia. In our study, we aimed to investigate the effects of different anesthetic methods on the changes of T lymphocyte subsets and cytokines in peripheral blood of patients with esophageal cancer surgery. 50 patients with esophageal cancer were divided into the study group and the control group. Among them, the patients in the control group chose intravenous anesthesia and received self-controlled intravenous analgesia after surgery. Patients in the study group chose thoracic epidural anesthesia combined with general anesthesia, undergoing self-controlled epidural analgesia after surgery; serum interleukin-2 (IL-2) and soluble interleukin-2 receptor (sIL-2R) were measured by ELISA. Serum stress hormones GH and sIL-8 were measured by radioimmunoassay. Both groups of patients achieved significant postoperative analgesia, but the VAS score in the study group at the T2–T4 time point was lower than that in the control group. The serum GH concentration in the study group increased at T1 and reached its highest peak at T2, then decreased. The serum IL-8 concentration of the two groups showed a downward trend from T1 to T4. Thoracic epidural anesthesia combined with general anesthesia for postoperative epidural analgesia can relieve the degree of cellular immunosuppression during and after surgery. Moreover, the thoracic epidural block combined with general anesthesia for esophageal cancer surgery and epidural analgesia after surgery for patients are anesthetic and analgesic methods with clinically significant effects. Our research results have a positive effect on the promotion of postoperative rehabilitation in patients with malignant cell tumors.

Infecciones por Listeria, Corynebacterium y Bacillus

Listeria, Corynebacterium, and Bacillus are ubiquitous gram-positive bacilli. L. monocytogenes is a zoonotic pathogen that is transmitted by food. Listeriosis is a disease with a wide spectrum of severity that ranges from self-limiting febrile gastroenteritis to severe invasive disease with frequent involvement of the central nervous system. It predominantly affects people with some degree of cellular immunosuppression. It has a predilection for pregnant women, in whom it does not tend to produce severe disease, but is associated with severe obstetric complications and high rates of neonatal morbidity and mortality. C. diphtheriae is the causal agent of cutaneous or respiratory tract diphtheria, with potential cardiac or neurological complications mediated by the diphtheria toxin. The rest of the Corynebacterium species have traditionally been considered saprobionts, although various species have been described as the causal agents of opportunistic infections in recent decades. B. anthracis produces cutaneous, respiratory, or gastrointestinal anthrax, according to the spores’ route of entry. The spores are capable of germinating and multiplying, generating the toxin that is responsible for the disease. It is considered a potential bioterrorism agent for its high degree of lethality.

Targeting ZFP64/GAL-1 axis promotes therapeutic effect of nab-paclitaxel and reverses immunosuppressive microenvironment in gastric cancer

BackgroundChemoresistance is a main obstacle in gastric cancer (GC) treatment, but its molecular mechanism still needs to be elucidated. Here, we aim to reveal the underlying mechanisms of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) resistance in GC.MethodsWe performed RNA sequencing (RNA-seq) on samples from patients who were resistant or sensitive to nab-paclitaxel, and identified Zinc Finger Protein 64 (ZFP64) as critical for nab-paclitaxel resistance in GC. CCK8, flow cytometry, TUNEL staining, sphere formation assays were performed to investigate the effects of ZFP64 in vitro, while subcutaneous tumor formation models were established in nude mice or humanized mice to evaluate the biological roles of ZFP64 in vivo. Chromatin immunoprecipitation sequencing (CHIP-seq) and double-luciferase reporter gene assay were conducted to reveal the underlying mechanism of ZFP64.ResultsZFP64 overexpression was linked with aggressive phenotypes, nab-paclitaxel resistance and served as an independent prognostic factor in GC. As a transcription factor, ZFP64 directly binds to Galectin-1 (GAL-1) promoter and promoted GAL-1 transcription, thus inducing stem-cell like phenotypes and immunosuppressive microenvironment in GC. Importantly, compared to treatment with nab-paclitaxel alone, nab-paclitaxel plus GAL-1 blockade significantly enhanced the anti-tumor effect in mouse models, particularly in humanized mice.ConclusionsOur data support a pivotal role for ZFP64 in GC progression by simultaneously promoting cellular chemotherapy resistance and tumor immunosuppression. Treatment with the combination of nab-paclitaxel and a GAL-1 inhibitor might benefit a subgroup of GC patients.

Effect of polycyclic aromatic hydrocarbons on immunity

Nearly a quarter of the total number of deaths in the world are caused by unhealthy living or working environments. Therefore, we consider it significant to introduce the effect of a widely distributed component of air/water/food-source contaminants, polycyclic aromatic hydrocarbons (PAHs), on the human body, especially on immunity in this review. PAHs are a large class of organic compounds containing two or more benzene rings. PAH exposure could occur in most people through breath, smoke, food, and direct skin contact, resulting in both cellular immunosuppression and humoral immunosuppression. PAHs usually lead to the exacerbation of autoimmune diseases by regulating the balance of T helper cell 17 and regulatory T cells, and promoting type 2 immunity. However, the receptor of PAHs, aryl hydrocarbon receptor (AhR), appears to exhibit duality in the immune response, which seems to explain some seemingly opposite experimental results. In addition, PAH exposure was also able to exacerbate allergic reactions and regulate monocytes to a certain extent. The specific regulation mechanisms of immune system include the assistance of AhR, the activation of the CYP-ROS axis, the recruitment of intracellular calcium, and some epigenetic mechanisms. This review aims to summarize our current understanding on the impact of PAHs in the immune system and some related diseases such as cancer, autoimmune diseases (rheumatoid arthritis, type 1 diabetes, multiple sclerosis, and systemic lupus erythematosus), and allergic diseases (asthma and atopic dermatitis). Finally, we also propose future research directions for the prevention or treatment on environmental induced diseases.

Nanotransferrin-Based Programmable Catalysis Mediates Three-Pronged Induction of Oxidative Stress to Enhance Cancer Immunotherapy.

Current oxidative stress amplifying strategies for immunogenic cell death (ICD) promotion are mainly restricted to immune tolerance induced by adaptive cellular antioxidation, limited tumor-selectivity, and tumoral immunosuppression. Herein, a facile and efficient scenario of genetically engineering transferrin-expressing cell membrane nanovesicle encapsulated IR820-dihydroartemisinin nanomedicine (Tf@IR820-DHA) was developed to boost a-PD-L1-mediated immune checkpoint blocking (ICB) via synergetic triple stimuli-activated oxidative stress-associated ICD. We demonstrate that the engineered transferrin of Tf@IR820-DHA has excellent tumor targeting and Fe(III)-loading properties and thus delivered Fe(III) and IR820-DHA nanoparticles (NPs) to the lesion location effectively. We found that the self-carrying Fe(III)-mediated programmable catalysis of DHA and glutathione (GSH) depletion generated plenty of reactive oxygen species (ROS). Moreover, DHA also acted as an immunomodulator to decrease the number of T regulatory cells, thereby remodeling the tumor immune microenvironment and achieving double T cell activation. Furthermore, the IR820 molecule served as a competent sonosensitizer to produce ROS under ultrasound activation and guide precise immunotherapy via fluorescent/photoacoustic (FL/PA) imaging. Through its three-pronged delivery of stimuli-activated oxidative stress (DHA-induced chemodynamic therapy, catalysis-conferred GSH depletion, and IR820-mediated sonodynamic therapy), Tf@IR820-DHA caused high levels of targeted ICD. This significantly increased the proportions of IFN-γ-secreting T cells (CD4+ T and CD8+ T) and enhanced a-PD-L1-mediated ICB against primary and distant tumors, which represents a promising approach for cancer nanoimmunotherapy.

Normalization of the Immune Microenvironment during Lenalidomide Maintenance Is Associated with Sustained MRD Negativity in Patients with Multiple Myeloma

Normalization of the Immune Microenvironment during Lenalidomide Maintenance Is Associated with Sustained MRD Negativity in Patients with Multiple Myeloma

KDM1A Promotes Immunosuppression in Hepatocellular Carcinoma by Regulating PD-L1 through Demethylating MEF2D.

Background Immune checkpoint inhibitor therapy targeting antiprogrammed cell death-1 (anti-PD-1) or its ligand (anti-PD-L1) is effective in the treatment of some hepatocellular carcinomas (HCC). Hence, further identification of biological targets related to PD-L1 regulation in HCC is beneficial to improve the clinical efficacy of immunotherapy. Some HCC cells express lysine-specific demethylase 1A (KDM1A), which is implicated in the reduced survival time of patients. Here, we studied whether the level of PD-L1 and the immunosuppression are regulated by KDM1A and its miRNA in HCC cells. Methods In the present study, we studied clinical data from The Cancer Genome Atlas (TCGA) database. We performed qPCR and western blotting assays to measure the expression level of genes of interest. PD-L1 expression was also analyzed by FACS. Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 was used to generate gene knockout cells to investigate the relationships of genes of interest. We also developed a reporter gene assay (RGA) to explore the changes in T cell-induced antitumor immunity relative to PD-L1 expression in HCC cells. The binding between proteins and promoters or miRNAs and their target genes was explored by luciferase reporter assays. Results The results showed that PD-L1 and KDM1A were increased in HCC patients and cells, and KDM1A promoted the expression of PD-L1 in HCC cells. Our findings showed that the enhancement of PD-L1 expression was not attributed to mitochondrial dysfunction caused by increases in KDM1A in HCC cells. Furthermore, we observed a lower level of MEF2D methylation in HCC cells than in normal human liver cells. Demethylated MEF2D could bind to the promoter of PD-L1 and activate its expression, while KDM1A interacted with MEF2D and acted as a demethylase to reduce its methylation. Moreover, a new miRNA, miR-329-3p, targeting KDM1A was found to regulate the PD-L1 expression profile in HCC cells. In the xenograft model, the tumors treated with miR-329-3p showed growth inhibition. Conclusions Mechanistically, miR-329-3p inhibits tumor cellular immunosuppression and reinforces the response of tumor cells to T cell-induced cytotoxic effect by targeting KDM1A mRNA and downregulating its expression, which contributed to MEF2D demethylation and activation of PD-L1 expression.