Neutrophil generation from hematopoietic progenitor cells and induced pluripotent stem cells (iPSCs): potential applications.

Neutrophils are the most frequent immune cell type in peripheral blood, performing an essential role against pathogens. People with neutrophil deficiencies are susceptible to deadly infections, highlighting the importance of generating these cells in host immunity. Neutrophils can be generated from hematopoietic progenitor cells (HPCs) and embryonic stem cells (ESCs) using a cocktail of cytokines. In addition, induced pluripotent stem cells (iPSCs) can be differentiated into various functional cell types, including neutrophils. iPSCs can be derived from differentiated cells, such as skin and blood cells, by reprogramming them to a pluripotent state. Neutrophil generation from iPSCs involves a multistep process that can be performed through feeder cell-dependent and feeder cell-independent manners. Various cytokines and growth factors, in particular, stem cell facto, IL-3, thrombopoietin and granulocyte colony-stimulating factor (G-CSF), are used in both methods, especially, G-CSF which induces the final differentiation of neutrophils in the granulocyte lineage. iPSC-derived neutrophils have been used as a valuable tool for studying rare genetic disorders affecting neutrophils. The iPSC-derived neutrophils can also be used for disease modeling, infection research and drug discovery. However, several challenges must be overcome before iPSC-derived neutrophils can be used therapeutically in transplantation medicine. This review provides an overview of the commonly employed protocols for generating neutrophils from HPCs, ESCs and iPSCs and discusses the potential applications of the generated cells in research and medicine.

Prevalence of mental disorders among middle-aged population of primary healthcare centers in Northeastern Iran.

BACKGROUND: Primary healthcare centers (PHCs) serve as the cornerstone of accessible medical services in society, playing a crucial role in screening, detecting, and treating various health issues. This study aimed to investigate the prevalence of psychiatric disorders in middle-aged individuals who refer to PHCs and the potential of PHCs in diagnosing mental disorders. METHODS: This cross-sectional study was implemented at PHCs under the supervision of Mashhad University of Medical Sciences (MUMS) in northeast Iran in 2018. The enrolled subjects were middle-aged adults who had electronic medical records in SINA, an integrated health management system, and the electronic medical records of MUMS. The prevalence of psychiatric disorders by type and their relationship with demographic information was evaluated by a Chi-square test using SPSS 22. RESULTS: This study involved 218,341 middle-aged participants. Prevalence of psychiatric disorders was 8.59%, and depression (53.72%) and anxiety (42.02%) were the most common psychiatric disorders in both males and females. The prevalence of mental disorders was significantly higher in females than in males (88.18% vs. 18.81%; P < 0.0001). Indeed, a significant higher prevalence of depression, anxiety, somatoform, childhood psychiatric disorder, and bipolar disorders was observed in females compared to males (P < 0.05). In addition, individuals between the age of 45-60 years, and those from rural areas showed more prevalence of mental disorders than others, but these differences were not significant. CONCLUSIONS: Considering the previous studies in Iran, the prevalence of mental disorders among patients presenting to PHCs was noticeably lower than expected rates. It seems probable that this huge difference is due to poor screening and detection of mental illness in PHCs of MUMS. It is recommended that health policymakers pursue specific measures to make PHCs more helpful for people with mental health problems in the community.

Aberrant expression of SOCS impairs the anti-leishmanial immune response.

Establishing a balance between Th1 and Th2 subsets and M1- and M2-type macrophages is essential for the control of Leishmania infection. The suppressors of cytokine secretion (SOCS) proteins, particularly SOCS1 and SOCS3, play a significant role in regulating cytokine-triggered signaling pathways, thereby impacting the macrophage-and effector T-cell mediated antileishmanial immune response. In addition to the pro-inflammatory cytokines, Leishmania-derived lipophosphoglycan (LPG) and CpG-DNA interact with TLR2 and TLR9 to trigger SOCS expression. The aberrant levels of SOCS1 and SOCS3 expression in Leishmania-infected macrophages impair macrophage-T-cell interaction perturbing the balance in macrophage subsets polarization. This hinders macrophage apoptosis and macrophage-mediated leishmanicidal activity, both support the establishment of infection and parasite replication. Furthermore, aberrant SOCS3 levels in T-cells disrupt Th1 differentiation and aid in parasite replication, lesion development, and pathological immune responses. Strategically, selective modulation of SOCS expression and function in immune effector cells may reduce parasite survival and prevent disease progression.

Differential roles of regulatory T cells in Alzheimer's disease.

Regulatory T (Treg) cells interact with a variety of resident cells and infiltrated immune cells in the central nervous system (CNS) to modulate neuroinflammation and neurodegeneration. Extracellular amyloid-ß (Aß) peptide deposition and secondary persistent inflammation due to activation of microglia, astrocytes, and infiltrated immune cells contribute to Alzheimer's disease (AD)-related neurodegeneration. The majority of evidence supports the neuroprotective effects of Treg cells in AD. In the early stages of AD, appropriate Treg cell activity is required for the induction of microglia and astrocyte phagocytic activity in order to clear A deposits and prevent neuroinflammation. Such neuroprotective impacts were in part attributed to the ability of Treg cells to suppress deleterious and/or boost beneficial functions of microglia/astrocytes. In the later stages of AD, an effective Treg cell activity needs to prevent neurotoxicity and neurodegeneration. Treg cells can exert preventive effects on Th1-, and Th17 cell-related pathologic responses, whilst potentiating Th2-mediated protective activity. The impaired Treg cell-related immunomodulatory mechanisms have been described in AD patients and in related animal models which can contribute to the onset and progression of AD. This review aimed to provide a comprehensive figure regarding the role of Treg cells in AD while highlighting potential therapeutic approaches.

Aberrant expression of suppressor of cytokine signaling (SOCS) molecules contributes to the development of allergic diseases.

Suppressor of cytokine signalling (SOCS) proteins bind to certain cytokine receptors, Janus kinases and signalling molecules to regulate signalling pathways, thus controlling immune and inflammatory responses. Dysregulated expression of various types of SOCS molecules was indicated in multiple types of allergic diseases. SOCS1, SOCS2, SOCS3, SOCS5, and cytokine-inducible SH2 domain protein (CISH) can differentially exert anti-allergic impacts through different mechanisms, such as suppressing Th2 cell development and activation, reducing eosinophilia, decreasing IgE production, repressing production of pro-allergic chemokines, promoting Treg cell differentiation and activation, suppressing Th17 cell differentiation and activation, increasing anti-allergic Th1 responses, inhibiting M2 macrophage polarization, modulating survival and development of mast cells, reducing pro-allergic activity of keratinocytes, and suppressing pulmonary fibrosis. Although some anti-allergic effects were attributed to SOCS3, it can perform pro-allergic impacts through several pathways, such as promoting Th2 cell development and activation, supporting eosinophilia, boosting pro-allergic activity of eosinophils, increasing IgE production, enhancing the expression of the pro-allergic chemokine receptor, reducing Treg cell differentiation, increasing pro-allergic Th9 responses, as well as supporting mucus secretion and collagen deposition. In this review, we discuss the contrasting roles of SOCS proteins in contexts of allergic disorders to provide new insights regarding the pathophysiology of these diseases and possibly explore SOCS proteins as potential therapeutic targets for alleviating allergies.

[99m Tc] Tc-MDP bone SPECT/CT diagnosing unstable slipped capital femoral epiphysis with secondary AVN in a patient with misleading knee pain.

Bone scan is highly sensitive whole-body imaging with relative low radiation in patients with non-localized skeletal symptoms. Patient is 12-year-old boy with Down syndrome, suffering recent claudication and exacerbated left knee pain unable to walk even with crutches. Three-dimensional Single photon emission computed tomography/Computed tomography (SPECT/CT) detected left slipped capital femoral epiphysis (SCFE) and secondary Avascular necrosis (AVN).

Inflammatory responses during trichomoniasis: The role of Toll-like receptors and inflammasomes.

Toll-like receptors (TLRs) and inflammasomes belong to the pattern recognition receptors (PRRs) of innate immunity identifying conserved compounds produced by pathogens or discharged by injured cells. Different cell subsets in the human urogenital system, such as epithelial cells and infiltrating leukocytes, express different kinds of TLRs (such as TLR2, TLR3, TLR4, TLR5 and TLR9) as well as inflammasomes (such as NLRP3, NLRC4 and AIM2). Various types of the Trichomonas vaginalis-derived components such as glycosyl-phosphatidylinositol (GPI), T. vaginalis virus (TVV), Lipophosphoglycan (LPG) and flagellin can be recognized by TLR2, TLR3, TLR4 and TLR5, respectively, leading to the production of proinflammatory cytokines and chemokines in the cervicovaginal mucosa. The T. vaginalis-induced inflammasomes can lead to pyroptosis as well as the release of IL-1ß and IL-18 promoting innate and adaptive immune responses. The PRR-mediated responses to T. vaginalis may contribute to the induction of protective immune responses, local inflammation, promotion of co-infections, or even the development of malignancies, for example, prostate cancer. The protective or pathogenic roles of the TLRs and inflammasomes during trichomoniasis are highlighted in this review. A better understanding of PRR-mediated responses provides invaluable insights to develop effective immunotherapeutic strategies against T. vaginalis infection.

Apelin receptor antagonist boosts dendritic cell vaccine efficacy in controlling angiogenic, metastatic and apoptotic-related factors in 4T1 breast tumor-bearing mice.

Apelin/APJ axis plays a critical role in cancer progression, thus its targeting inhibits tumor growth. However, blocking of Apelin/APJ axis in combination with immunotherapeutic approaches may be more effective. This study aimed to investigate the effects of APJ antagonist ML221 in combination with a DC vaccine on angiogenic, metastatic and apoptotic-related factors in a breast cancer (BC) model. Four groups of female BALB/c mice with 4T1-induced BC were treated with PBS, APJ antagonist ML221, DC vaccine, and "ML221 + DC vaccine". After completion of the treatment, the mice were sacrificed and the serum levels of IL-9 and IL-35 as well as the mRNA expression of angiogenesis (including VEGF, FGF-2, and TGF-ß), metastasis (including MMP-2, MMP-9, CXCR4) and apoptosis-related markers (Bcl-2, Bax, Caspase-3) in tumor tissues were determined using ELISA and real-time PCR, respectively. Angiogenesis was also evaluated by co-immunostaining of tumor tissues with CD31 and DAPI. Primary tumor metastasis to the liver was analyzed using hematoxylin-eosin staining. The efficiency of combination therapy with "ML221 + DC vaccine" was remarkably higher than single therapies in preventing liver metastasis compared to the control group. In comparison with the control group, combination therapy could significantly reduce the expression of MMP-2, MMP-9, CXCR4, VEGF, FGF-2, and TGF-ß in tumor tissues (P < 0.05). It also decreased the serum level of IL-9 and IL-35 compared with the control group (P < 0.0001). Moreover, vascular density and vessel diameter were significantly reduced in the combination therapy group compared with the control group (P < 0.0001). Overall, our findings demonstrate that combination therapy using a blocker of the apelin/APJ axis and DC vaccine can be considered a promising therapeutic program in cancers.

Interferon-γ-Treated Mesenchymal Stem Cells Modulate the T Cell-Related Chemokines and Chemokine Receptors in an Animal Model of Experimental Autoimmune Encephalomyelitis.

BACKGROUND: Mesenchymal stem cells (MSCs) modulate immune responses, and their immunomodulatory potential can be enhanced using inflammatory cytokines. Here, the modulatory effects of IFN-γ-licensed MSCs on expression of T cell-related chemokines and chemokine receptors were evaluated using an experimental autoimmune encephalomyelitis (EAE) model. MATERIAL AND METHODS: EAE was induced in 3 groups of C57bl/6 mice and then treated with PBS, MSCs and IFN-γ-treated MSCs. The EAE manifestations were registered daily and finally, the brain and spinal cords were isolated for histopathological and gene expression studies. RESULTS: The clinical scores were lowered in MSCs and IFN-γ-licensed MSCs groups, however, mice treated with IFN-γ-licensed MSCs exhibited lower clinical scores than MSCs-treated mice. Leukocyte infiltration into the brain was reduced after treatment with MSCs or IFN-γ-licensed MSCs compared to untreated group (P<0.05 and P<0.01, respectively). In comparison with untreated EAE mice, treatment with MSCs reduced CCL20 expression (P<0.001) and decreased CXCR3 and CCR6 expression (P<0.02 and P<0.04, respectively). In comparison with untreated EAE mice, treatment with IFN-γ-licensed MSCs reduced CXCL10, CCL17 and CCL20 expression (P<0.05, P<0.05, and P<0.001, respectively) as well as decreased CXCR3 and CCR6 expression (P<0.002 and P<0.02, respectively), whilst promoting expression of CCL22 and its receptor CCR4 (P<0.0001 and P<0.02, respectively). In comparison with MSC-treated group, mice treated with IFN-γ-licensed MSCs exhibited lower CXCL10 and CCR6 expression (P<0.002 and P<0.01, respectively), whereas greater expression of CCL22 and CCR4 (P<0.0001 and P<0.01, respectively). CONCLUSION: Priming the MSC with IFN-γ can be an efficient approach to enhance the immunomodulatory potential of MSCs.

Contribution of survivin to the immune system, allergies and autoimmune diseases.

In addition to malignancies, survivin (a member of the apoptosis inhibitor family) has been implicated in the pathogenesis of inflammatory disorders, including autoimmune and allergic diseases. Survivin is constantly expressed in the proliferating hematopoietic progenitor cells, and it is re-expressed in the mature cells of the innate and adaptive immunity, upon activation. Survivin enhances the expression of co-stimulatory molecules and MHC class II molecules in dendritic cells, and promotes the lifespan of macrophages, neutrophils, and eosinophils, while suppressing natural killer (NK) cell activity. Survivin has been implicated in T cell maturation, T cell expansion, effector CD4+ T cell differentiation, maintenance of memory CD4+ T and CD8+ T cells, as well as antibody production. Upregulated expression of survivin was indicated in the T cells as well as various samples collected from allergic patients. Survivin can contribute to the pathogenesis of allergic diseases via the promotion of the Th2 polarization, promoting IL-4 expression, compromising activation-induced cell death (AICD) in Th2 cells, and preventing apoptosis of eosinophils, as well as, amplification of eosinophilia. Moreover, survivin can interfere with clonal deletion of autoreactive T and B cells, as well as suppress Treg cell development and activity supporting the development of autoimmune diseases. This review discusses the role of survivin in immunity, allergy and autoimmunity as well as provides evidence that survivin may be considered as a novel therapeutic target for the treatment of allergic and autoimmune diseases.

Development and exacerbation of autoimmune hemolytic anemia following COVID-19 vaccination: A systematic review.

Autoimmune hemolytic anemia (AIHA) is caused by the production of autoantibodies against RBCs. COVID-19 vaccines can reduce the risk of severe disease, however, various adverse effects such as AIHA were observed following vaccination. This review aimed to assess the relationship of AIHA and COVID-19 vaccination using the PRISMA guidelines. Among 18 cases included in this review, new post-vaccination AIHA development was reported in 11 patients (7 women and 4 men) with a median age of 67.0 years. In 7 of 11 and 3 of 11 cases, the onset of symptoms occurred after first and second vaccine dose with median times of 7 and 14 days, respectively. In 1 of 11 cases, the AIHA occurred on Day 17 after booster vaccination. Ten of 11 and 1 of 11 AIHA patients received mRNA- and vector-based vaccine, respectively. After vaccination, 9 of 11, 1 of 11, and 1 of 11 AIHA patients developed warm IgG, cold IgM, and mixed autoantibodies against RBCs, respectively. Significant AIHA exacerbation was reported in seven patients (four women and three men) with a median age of 73.0 years. In 4 of 7 and 2 of 7 exacerbated AIHA cases, the onset of symptoms occurred after first and second vaccine dose with median times of 7 and 3 days, respectively. In 1 of 7 exacerbated AIHA cases, the onset of symptoms was observed on Day 2 after booster vaccination. All exacerbated AIHA cases received mRNA-based vaccines; 3 of 7 and 4 of 7 exacerbated AIHA cases developed IgG and IgM against RBCs, respectively. This review provides a comprehensive explanation regarding the AIHA development and exacerbation after COVID-19 vaccination.

SARS-CoV-2 Infection: A Possible Risk Factor for Incidence and Recurrence of Cancers.

COVID-19 and malignancy can affect the susceptibility of one another. Clinically recovered COVID-19 individuals display immune abnormalities that persist several months after discharge. The lymphopenia-related immunosuppression, functional exhaustion of cytotoxic lymphocytes (such as CD8+ cytotoxic T-cells and natural killer cells), hyperinflammatory responses, oxidative stress, downregulation of interferon response, development of the myeloid-derived suppressor cells, downregulation of tumor suppressor proteins and perhaps reactivation of the latent oncogenic viruses may directly and/or indirectly play a role in the cancer development and recurrence in severe COVID-19 patients. SARS-CoV-2-infected malignant patients may be at higher risk of death of their cancer than SARS-CoV-2-uninfected patients with the same cancers. On the other side, the patients with some types of cancers may be more vulnerable to SARS-CoV-2 infection compared with the non-cancerous individuals, due to their immunocompromised state resulted from malignancy, chemotherapy, and other concomitant abnormalities as well as perhaps greater expression of angiotensin-converting enzyme 2. SARS-CoV-2-infected cancerous patients are unable to produce an effective anti-virus immune response and may exhibit more severe forms of COVID-19. This review described the possible impacts of SARS-CoV-2 infection on cancer development and recurrence, and the potential cancer impacts on COVID-19 development, while the possible interventions are highlighted.

MicroRNA-383: A tumor suppressor miRNA in human cancer.

Downregulated expression of anti-tumor miR-383 has been found in many kinds of cancer. MiR-383 family members can directly target the 3'-untranslated region (3'-UTR) of the mRNA of some pro-tumor genes to attenuate several cancer-related processes, including cell proliferation, invasion, migration, angiogenesis, immunosuppression, epithelial-mesenchymal transition, glycolysis, chemoresistance, and the development of cancer stem cells, whilst promoting apoptosis. Functionally, miR-383 operates as a tumor inhibitor miRNA in many types of cancer, including breast cancer, hepatocellular carcinoma, gastric cancer, pancreatic cancer, colorectal cancer, esophageal cancer, lung cancer, head and neck cancer, glioma, medulloblastoma, melanoma, prostate cancer, cervical cancer, oral squamous cell carcinoma, thyroid cancer, and B-cell lymphoma. Both pro-tumor and anti-tumor effects have been attributed to miR-383 in ovarian cancer. However, only the pro-tumor effects of miR-383 were reported in cholangiocarcinoma. The restoration of miR-383 expression could be considered a possible treatment for cancer. This review discusses the anti-tumor effects of miR-383 in human cancers, emphasizing their downstream target genes and potential treatment approaches.

Bidirectional cytokine-microRNA control: A novel immunoregulatory framework in leishmaniasis.

As effector innate immune cells and as a host to the protozoan parasite Leishmania, macrophages play a dual role in antileishmanial immunoregulation. The 2 key players in this immunoregulation are the macrophage-expressed microRNAs (miRNAs) and the macrophage-secreted cytokines. miRNAs, as small noncoding RNAs, play vital roles in macrophage functions including cytokines and chemokines production. In the reverse direction, Leishmania-regulated cytokines alter miRNAs expression to regulate the antileishmanial functions of macrophages. The miRNA patterns vary with the time and stage of infection. The cytokine-regulated macrophage miRNAs not only help parasite elimination or persistence but also regulate cytokine production from macrophages. Based on these observations, we propose a novel immunoregulatory framework as a scientific rationale for antileishmanial therapy.

Interplays between non-coding RNAs and chemokines in digestive system cancers.

Within tumors, chemokines and their cognate receptors are expressed by infiltrated leukocytes, cancerous cells, and related cells of stroma, like tumor-associated fibroblasts and tumor-associated macrophages. In malignancies, the altered expression of chemokines/chemokine receptors governs leukocyte infiltration and activation, epithelial-mesenchymal transition (EMT), cancer cell proliferation, angiogenesis, and metastasis. Non-coding RNAs (ncRNAs) contribute to multiple physiological and pathophysiological processes. Some miRNAs can exert anti-tumorigenic activity in digestive system malignancies by repressing the expression of tumor-promoting chemokines/chemokine receptors or by upregulating tumor-suppressing chemokines/chemokine receptors. However, many miRNAs exert pro-tumorigenic activity by suppressing the expression of chemokines/chemokine receptors or by upregulating tumor-promoting chemokines/chemokine receptors. LncRNA and circRNAs also exert pro- and anti-tumorigenic effects by targeting downstream miRNAs influencing the expression of tumor-promoting and tumor-suppressor chemokines/chemokine receptors. On the other side, some chemokines influence the expression of ncRNAs affecting tumor formation. The current review explains the communications between ncRNAs and chemokines/chemokine receptors in certain digestive system malignancies, such as gastric, colorectal, and pancreatic cancers and hepatocellular carcinoma to gain better insights into their basic crosstalk as well as possible therapeutic modalities.

Cimetidine and Ibuprofen Modulate T Cell Responses in a Mouse Model of Breast Cancer.

Cimetidine and ibuprofen exhibit immunomodulatory effects as an antagonist of histamine H2 receptor, and a cyclooxygenase inhibitor, respectively. Here, the effects of cimetidine and ibuprofen on some effector T cell-related parameters were investigated using a breast cancer (BC) model. BC was established in Balb/c mice using the 4T1 cell line. On day 10 after tumor induction, the BC-bearing mice were classified into four groups and treated with PBS, cimetidine (20 mg/kg), ibuprofen (20 mg/kg) or a combination of "cimetidine + ibuprofen" via intraperitoneal injection (daily from days 11 to 30). The mice were sacrificed on day 31 and the frequency of splenic Th1 and Treg cells, plasma IFN-γ and TGF-ß levels, and intra-tumoral T-bet, GATA3, FOXP3 and RORγt expressions were detected using flowcytometry, ELISA and real-time-PCR, respectively. In untreated cancerous mice, the percentage of splenic Th1 cells and plasma IFN-γ levels were lower (P<0.003 and P<0.01, respectively), whereas the percentage of splenic Treg cells and plasma TGF-ß levels were higher than in healthy mice (P<0.04 and P<0.005, respectively). Treatment of BC-bearing mice with cimetidine, ibuprofen or both drugs promoted the frequency of Th1 cells (P<0.05, P<0.007 and P<0.005, respectively) as well as IFN-γ levels (P<0.004, P<0.0001 and P<0.03, respectively), while reduced the frequencies of Treg cells (P<0.02, P<0.03 and P<0.01, respectively), TGF-ß levels (P<0.006, P<0.02 and P<0.002, respectively), intra-tumoral expression of FOXP3 (P<0.006, P<0.005 and P<0.005, respectively), and intra-tumoral expression of RORγt (P<0.04, P<0.03 and P<0.05, respectively) compared with untreated BC mice. The "cimetidine + ibuprofen"-treated mice displayed greater T-bet expression than the un-treated mice (P<0.006). Cimetidine and/or ibuprofen-treated BC-bearing mice exhibited reduced intra-tumoral expression of GATA3 compared with the untreated BC mice, but the differences were not significant. Cimetidine and ibuprofen correct some effector T cell-related parameters in cancerous mice. Immunotherapeutic potentials cimetidine and ibuprofen in cancers need investigations.

Investigation of the effect of IFN-γ/TNF-α-treated mesenchymal stem cells on Th9- and Treg cell-related parameters in a mouse model of ovalbumin-induced allergic asthma.

OBJECTIVE: Th9- and regulatory T (Treg) cells exert pro- and anti-allergic activity, respectively. Mesenchymal stem cell (MSC)-related immunomodulatory impacts can be enhanced by inflammatory cytokines. Here, the modulatory effects of IFN-γ/TNF-α-induced MSCs on Th9- and Treg cell-related parameters were investigated using an asthma model. METHODS: Allergic asthma was induced in BALB/c mice using sensitized and challenging with ovalbumin (OVA). The asthmatic groups were treated intraperitoneally with PBS, MSCs, IFN-γ-induced MSCs, TNF-α-induced MSCs and 'IFN-γ + TNF-α'-induced MSCs before the challenge phase. The mice were sacrificed 24 h after challenge. The serum IL-9 and IL-35 levels, as well as gene expression of IL-9, PU.1, IL-35-EBI3, and FOXP3 in the lung tissues were assessed using ELISA and real time-PCR, respectively. RESULTS: The differences of Th9 and Treg-related parameters were not significant between untreated asthmatic mice and those treated with non-induced MSCs. In comparison with untreated asthmatic group, treatment with IFN-γ-induced MSCs significantly reduced serum IL-9 levels, reduced lung expression of IL-9 and PU.1, while increasing serum IL-35 levels as well as lung expression of FOXP3; treatment with TNF-α-induced MSCs significantly reduced serum IL-9 levels as well as lung expression of IL-9, and treatment with 'IFN-γ + TNF-α'-induced MSCs, significantly modulated all investigated Th9 and Treg-related parameters. In comparison to mice treated with non-induced MSCs, serum IL-9 levels were remarkably decreased in mice treated with IFN-γ-induced and 'IFN-γ + TNF-α'-induced MSCs. CONCLUSIONS: IFN-γ-and 'IFN-γ + TNF-α' treated MSCs exerted almost comparable impacts, but were more efficient than TNF-α-exposed MSCs. Thus, IFN-γ alone can be sufficient to promote immunomodulatory effects of MSCs.

Reduced Expression of Natural Killer Cell-Related Activating Receptors by Peripheral Blood Mononuclear Cells from Patients with Breast Cancer and Their Improvement by Zoledronic Acid.

BACKGROUND/AIM: Natural killer (NK) cell receptors affect the NK cell-mediated elimination of malignant cells. In this experimental study the effect of Zoledronic acid (ZOL) was investigated on the expression of NK activating- (NKP46 and NKG2D) and inhibitory (KIR2DL1) receptors by Phytohaemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMCs) from breast cancer (BC) patients. MATERIALS AND METHODS: Peripheral blood mononuclear cell-extracted RNA from thirty breast cancer women and twenty-five healthy subjects was analyzed for gene expression of NKP46, NKG2D and KIR2DL1 using real time-PCR. Then, the PBMCs from BC patients were cultured in the presence of PHA with 5 µg/ml, 10 or 20 µg/ml of ZOL for 32 hours and expression of the aforementioned receptors was determined. RESULTS: Expression of NKP46, NKG2D and NKP46/KIR2DL1 ratio in BC women were lower than healthy group (P<0.01, P<0.04 and P<0.05, respectively). NKP46 expression was up-regulated by PHA-stimulated PBMCs treated with 10 µg/ml and 20 µg/ml of ZOL compared with PHA-stimulated cultures (P<0.01 and P<0.05, respectively). NKG2D expression remarkably increased by PHA-stimulated cultures treated with 5 µg/ml, 10 µg/ml and 20 µg/ml of ZOL compared with PHA-stimulated cultures (P<0.05 and P<0.02 and P<0.04, respectively). CONCLUSION: Expression of NK cell-related activating receptors decreased in BC patients. ZOL can improve the expression of NK activating receptors.

The expression of PD-1 and its ligands increases in Leishmania infection and its blockade reduces the parasite burden.

The expression of programmed cell death protein-1 (PD-1) and its ligands- PD-L1 and PD-L2- on T cells and macrophages', respectively, increases in Leishmania infection. The PD-1/PD-L1 interaction induces T cell anergy, T cell apoptosis and exhaustion, diversion of T cells toward TH2 and T-reg cells but inhibits M1 macrophage activities by suppression of nitric oxide (NO) and reactive oxygen species (ROS) production. These changes exacerbate Leishmania infection. As PD-L1-deficient, but not PD-L2-deficient, mice were protected againstL. mexicanainfection, differential roles have been proposed for PD-L1 and PD-L2 in mouse models of leishmaniasis. Blockade of PD-1/PD-L1 interaction in various in vitro and Leishmania-infected mouse, hamster and dog models enhanced IFN-γ and NO production, reduced IL-10 and TGF-ß generation, promoted T cell proliferation and reduced parasite burden. Therefore, PD-1/PD-L1 blockade is being considered as a potential therapeutic strategy to restore protective immunity during leishmaniasis, particularly, in drug-resistant cases.

Comparison of the effects of remifentanil and dexmedetomidine on surgeon satisfaction with surgical field visualization and intraoperative bleeding during rhinoplasty.

OBJECTIVE: We aimed to compare the effect of dexmedetomidine with remifentanil on hemodynamic stability, surgical field quality, and surgeon satisfaction during rhinoplasty. METHODS AND MATERIALS: In this double-blind randomized controlled-trial, 60 participants scheduled for rhinoplasty at the Mother and Child Hospital, Shiraz, Iran, was randomely divided into the dexmedetomidine group (IV infusion of 1 µg/kg dexmedetomidine over 20 min before induction of anesthesia then 0.6 µg/kg/hr. dexmedetomidine from the time of induction until the end of the operation) or in the the remifentanil group (an infusion rate of 0.25 µg/kg/min from the time of anesthesia induction until the end of the operation). Bleeding volume, surgeon satisfaction, postoperative pain (visual analog scale (VAS)), Level of sedation (Richmond Agitation Sedation Scale (RASS)), Patient satisfaction, Vital signs & recovery, and the Aldrete Score (used to discharge the patients from recovery) were measured for all participants. RESULTS: The patients in the dexmedetomidine group had less bleeding (p = 0.047) and shorter time to return of respiration, extubation, and the postoperative recovery time (p < 0.001). The surgeon satisfaction was higher in the dexmedetomidine group (p < 0.001). Patient satisfaction was significantly different between the two groups (p < 0.001). VAS scores, intaking paracetamol, and RASS score were significantly lower in the remifentanil group (p < 0.001). SBP, DBP, MAP, and heart rate were lower in dexmedetomidine group. CONCLUSION: Dexmedetomidine was associated with relatively stable hemodynamics, leading to decreased intraoperative bleeding, recovery time, and greater surgeon satisfaction and the level of consciousness in the recovery ward. However, painlessness and patient satisfaction were greater with the use of remifentanil. TRIAL REGISTRATION: IRCT20141009019470N112 .