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Background: Sharing of injecting paraphernalia is known to contribute to hepatitis C virus (HCV) transmission amongst people who inject drugs. Objectives: In this paper, we identify the variables correlated with paraphernalia sharing among male drug injectors in Kermanshah city, western Iran. Methods: We enrolled 606 male drug injectors using snowball sampling in a cross-sectional study. Serological testing for HCV, HIV and HBV infections were performed after the completion of a bio-behavioral questionnaire. To identify variables associated with paraphernalia sharing, logistic regression analysis was completed. Results: The respondents were aged 18–65 years (mean±SD age of 36.7 ± 8.5). Approximately half of those surveyed (55.3% 335 individuals) reported sharing of injecting paraphernalia in the month prior to interview. Serological testing showed 54.8% (CI 50.8–58.7%), 6.4% (4.4–8.3%) and 2.9% (1.6–4.3%) positive result for HCV antibody, HIV antibody and HBs-Antigen, respectively. Being unemployed P <.001, single P <.001, having a history of drug overdose P <.001, having a previous positive HCV test P <.001, less than weekly attendance to needle/syringe programs P <.001and alcohol consumption P <.001 were all significant in the final model. Conclusions: With over half the participants reporting injecting paraphernalia sharing, providing more accessible harm reduction programs together with HCV testing and treatment programs may help to reduce the transmission of HCV among networks of drug injectors in Kermanshah city. [ABSTRACT FROM AUTHOR]

Allergic contact dermatitis (ACD) is a delayed-type hypersensitivity (DTH) reaction induced by repeated contact with sensitizers. The ability of a chemical to act as a sensitizer has most frequently been tested in animals. As the use of animals for these purposes is gradually and globally being phased out, there is a need for reliable in vitro surrogate assays. Currently proposed in vitro assays are designed to test four key events of the adverse outcome pathway (AOP) involving covalent modification of self-proteins by sensitizers (haptenation) and presentation of new antigens (hapten/carrier complexes) to the immune system. There appears to be imperfect alignment of in vitro assays with clinical and/or animal data, suggesting possibly additional mechanisms of ACD development. Indeed, studies on allergies to small drugs, small chemical-induced HLA-peptide exchange for vaccination purposes and cosmetic ingredient-induced exposure of autoantigens suggest a possibility of DTH response promotion by hapten/carrier-independent mechanisms. Therefore, there is a need for additional appropriate in vitro assays, in order to achieve maximal concordance between clinical and/or animal data and in vitro assays. In this paper, we will review evidence supporting the idea of diverse mechanisms of ACD development. We will also discuss the impact of these multiple mechanisms, on the AOP and on the in vitro assays that should be used for allergen detection. We will propose alloreactivity-like reactions, aided by computer modeling and biochemical tests of compound-HLA binding, as additional tools for better prediction of DTH reactions, resulting from exposure to ingredients in cosmetic products. The combination of the proposed tests, along with the existing assays, should further enhance animal-free assessment of sensitizing potential of individual chemicals. [ABSTRACT FROM AUTHOR]

The paper describes the use of frequentist and Bayesian shared-parameter joint models of longitudinal measurements of prostate-specific antigen (PSA) and the risk of prostate cancer (PCa). The motivating dataset corresponds to the screening arm of the Spanish branch of the European Randomized Screening for Prostate Cancer study. The results show that PSA is highly associated with the risk of being diagnosed with PCa and that there is an age-varying effect of PSA on PCa risk. Both the frequentist and Bayesian paradigms produced very close parameter estimates and subsequent 95% confidence and credibility intervals. Dynamic estimations of disease-free probabilities obtained using Bayesian inference highlight the potential of joint models to guide personalized risk-based screening strategies. [ABSTRACT FROM PUBLISHER]

We recently identified a novel role for podosomes in antigen sampling. Podosomes are dynamic cellular structures that consist of point-like concentrations of actin surrounded by integrins and adaptor proteins such as vinculin and talin. Podosomes establish cellular contact with the extracellular matrix (ECM) and facilitate cell migration via ECM degradation. In our recent paper, we studied podosomes of human dendritic cells (DCs), major antigen presenting cells (APC) that take-up, process, and present foreign antigen to naive T-cells. We employed gelatin-impregnated porous polycarbonate filters to demonstrate that the mechanosensitive podosomes of DCs selectively localize to regions of low-physical resistance such as the filter pores. After degradation of the gelatin, podosomes increasingly protrude into the lumen of these pores. These protrusive podosome-derived structures contain several endocytic and early endosomal markers such as clathrin, Rab5, and VAMP3, and, surprisingly, also contain C-type lectins, a type of pathogen recognition receptors (PRRs). Finally, we performed functional uptake experiments to demonstrate that these PRRs facilitate uptake of antigen from the opposite side of the filter. Our data provide mechanistic insight in how dendritic cells sample for antigen across epithelial barriers for instance from the lumen of the lung and gut. [ABSTRACT FROM PUBLISHER]

Toxoplasma gondii (T.gondii) is a widespread protozoan with significant economic losses and public health importance. But so far, the protective effect of reported DNA-based vaccines fluctuates widely, and no study has demonstrated complete protection. This review provides an inclusive summary of T. gondii DNA vaccine antigens, adjuvants, and some other parameters. A total of 140 articles from 2000 to 2021 were collected from five databases. By contrasting the outcomes of acute and chronic challenges, we aimed to investigate and identify viable immunological strategies for optimum protection. Furthermore, we evaluated and discussed the impact of several parameters on challenge outcomes in the hopes of developing some recommendations to assist better future horizontal comparisons among research. In the coming five years of research, the exploration of vaccine cocktails combining invasion antigens and metabolic antigens with genetic adjuvants or novel DNA delivery methods may offer us desirable protection against this multiple stage of life parasite. In addition to finding a better immune strategy, developing better in silico prediction methods, solving problems posed by variables in practical applications, and gaining a more profound knowledge of T.gondii-host molecular interaction is also crucial towards a successful vaccine. [ABSTRACT FROM AUTHOR]

A plethora of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) diagnostic tests are available, each with different performance specifications, detection methods, and targets. This narrative review aims to summarize the diagnostic technologies available and how they are best selected to tackle SARS-CoV-2 infection as the pandemic evolves. Seven key settings have been identified where diagnostic tests are being deployed: symptomatic individuals presenting for diagnostic testing and/or treatment of COVID-19 symptoms; asymptomatic individuals accessing healthcare for planned non-COVID-19-related reasons; patients needing to access emergency care (symptom status unknown); patients being discharged from healthcare following hospitalization for COVID-19; healthy individuals in both single event settings (e.g. airports, restaurants, hotels, concerts, and sporting events) and repeat access settings (e.g. workplaces, schools, and universities); and vaccinated individuals. While molecular diagnostics remain central to SARS-CoV-2 testing strategies, we have offered some discussion on the considerations for when other tools and technologies may be useful, when centralized/point-of-care testing is appropriate, and how the various additional diagnostics can be deployed in differently resourced settings. As the pandemic evolves, molecular testing remains important for definitive diagnosis, but increasingly widespread point-of-care testing is essential to the re-opening of society. [ABSTRACT FROM AUTHOR]

Cancer patients, including breast cancer patients, live in a hypercoagulable state. Chemo- and hormone- therapy used in the treatment of breast cancer increases the risk of thrombosis. Due to differences in health care services between developed and developing countries, the survival rate of women with breast cancer in developing countries is low. Consequently, ethnomedicines are used and their efficacy as potential alternatives are being scientifically explored. The seed oils of Kigelia africana, Ximenia caffra and Mimusops zeyheri have anti-proliferative effects on hormone-dependent (MCF-7) and cytotoxic effects on hormone-independent (MDA-MB-231) breast cancer cells. In this study, we determined if these seed oils reduce the thrombogenic ability of breast cancer cells by measuring the platelet surface expression of the activation-specific antigens CD62P and CD63. MDA-MB-231 and MCF-7 cells were pretreated with the seed oils before being exposed to whole blood of human female volunteers. An increase in CD62P and CD63 expression following whole blood exposure to untreated breast cancer cells was observed. Treated MDA-MB-231 cells reduced CD62P and CD63 expression while treated MCF-7 cells increased CD62P and decreased CD63 expression. Kigelia africana, Ximenia caffra and Mimusops zeyheri seed oils are able to reduce the thrombogenic ability of MDA-MB-231 breast cancer cells. [ABSTRACT FROM AUTHOR]

Fasciola hepatica is an important pathogen that causes liver fluke disease in definitive hosts such as livestock animals and humans. Various excretory/secretory products have been used in serological diagnosis and vaccination studies targeting fasciolosis. There are no commercial vaccines against fasciolosis yet. Bioinformatic analysis based on computational methods have lower cost and provide faster output compared to conventional vaccine antigen discovery techniques. The aim of this study was to predict B- and T-cell specific epitopes of four excretory/secretory antigens (Kunitz-type serine protease inhibitor, cathepsin L1, helminth defense molecule, and glutathione S-transferase) of Fasciola hepatica and to construct a multiepitope vaccine candidate against fasciolosis. Initially, nonallergic and the highest antigenic B- and T- cell epitopes were selected and then, physico-chemical parameters, secondary and tertiary structures of designed multiepitope vaccine candidate were predicted. Tertiary structure was refined and validated using online bioinformatic tools. Linear and discontinuous B-cell epitopes and disulfide bonds were determined. Finally, molecular docking analysis for MHC-I and MHC-II receptors was performed. This multi-epitope vaccine candidate antigen, with high immunological properties, can be considered as a promising vaccine candidate for animal experiments and wet lab studies. [ABSTRACT FROM AUTHOR]

The acceptance of ABO-incompatible (ABOi) liver grafts will expand the donor pool for a patient in urgent need for a liver transplantation (LT). Here we report our results with emergency ABOi DD (deceased donor) LT using rituximab and antigen specific immunoadsorption. 2009 to 2019 we performed 20 ABOi DD LTs (adults n = 17, children n = 3) for patients in urgent need for a LT. Immunosuppression consisted of rituximab (n = 20) and basiliximab (n = 15) or anti-thymocyte globuline (n = 4), intravenous immunoglobulin (IVIG; n = 6), tacrolimus, prednisolone and mycophenolate mofetil. Fifteen patients were treated with IA (n = 14) or both IA and plasmapheresis (PP; n = 1) pre-transplant and 18 patients were treated with IA (n = 15) or both IA and PP (n = 3) post-transplant. The median pre-transplant MELD- score was 40 (range 18–40). Patient and graft survival and complications were compared to a 1:4 case matched control group of ABO-identical or compatible (ABOid/c) DDLT. The 1-, 3- and 5-year patient and graft survival rates were 85, 85 and 78% for the ABOi recipients and not significantly different compared to ABOid/c controls. Only one ABOi patient developed antibody-mediated rejection. Patient and graft survival after emergency ABOi DDLT using rituximab and immunoadorption was equal to ABOid/DDLT. ABOi DD LT was a successful approach to expand the donor pool for patients in urgent need for a liver graft. [ABSTRACT FROM AUTHOR]

The co-reactivity of the Plasmodium histidine-rich protein 2 (HRP2) and lactate dehydrogenase (pLDH) in malaria rapid diagnosis tests (mRDTs) as a potential indicator of high parasitemia linked to Plasmodium falciparum was evaluated in the reported study from Cameroon. The samples were screened for malaria using both mRDTs (SD bioline HRP2/pLDH), light microscopy and further confirmed by Plasmodium species-specific PCR assay. Of the 483 patients enrolled, 161 (33.3%) showed a reactive mRDTs amongst which 70 patients were positive by both microscopy and mRDTs with 30.0% (21/70) positive for HRP2 alone, while 70.0% (49/70) showed a dual reaction to HRP2 and pLDH parasite antigens. P. falciparum parasitemia was found to be significantly high among patients with both reactive antigens, (p < 0.0001) suggesting that mRDTs reactivity is influenced by parasite load which could be used as a diagnostic marker for therapeutic management of patients with high parasitemia in field conditions. [ABSTRACT FROM AUTHOR]

Antigen testing for SARS-CoV-2 is considered to be less sensitive than the standard reference method – real-time PCR (RT-PCR). It has been suggested that many patients with positive RT-PCR 'missed' by antigen testing might be non-infectious. In a real-world high-throughput setting for asymptomatic or mildly symptomatic patients, 494 patients were tested using RT-PCR as well as a single lateral flow antigen test (Ecotest, AssureTech, China). Where the results differed, virus viability was evaluated by cell culture. The test parameters were calculated with RT-PCR and RT-PCR adjusted on viability as reference standards. The overall sensitivity of the used antigen test related to the RT-PCR only was 76.2%, specificity was 97.3%. However, 36 out of 39 patients 'missed' by the antigen test contained no viable virus. After adjusting on that, the sensitivity grew to 97.7% and, more importantly for disease control purposes, the negative predictive value reached 99.2%. We propose that viability testing should be always performed when evaluating a new antigen test. A well-chosen and validated antigen test provides excellent results in identifying patients who are shedding viable virus (although some caveats still remain) in the real-world high-throughput setting of asymptomatic or mildly symptomatic individuals. [ABSTRACT FROM AUTHOR]

Listeria monocytogenes is one of the most invasive foodborne pathogens and is responsible for numerous outbreaks worldwide. Most of the methods to detect this bacterium in food require selective enrichment using traditional bacterial culture techniques that can be time-consuming and labour-intensive. Moreover, molecular methods are expensive and need specific technical knowledge. In contrast, immunological approaches are faster, simpler, and user-friendly alternatives and have been developed for the detection of L. monocytogenes in food, environmental, and clinical samples. These techniques are dependent on the constitutive expression of L. monocytogenes antigens and the specificity of the antibodies used. Here, updated knowledge on pathogenesis and the key immunogenic virulence determinants of L. monocytogenes that are used for the generation of monoclonal and polyclonal antibodies for the serological assay development are summarised. In addition, immunological approaches based on enzyme-linked immunosorbent assay, immunofluorescence, lateral flow immunochromatographic assays, and immunosensors with relevant improvements are highlighted. Though the sensitivity and specificity of the assays were improved significantly, methods still face many challenges that require further validation before use. [ABSTRACT FROM AUTHOR]

Antibody-virus coevolution in HIV infection: paths for HIV vaccine development. HIV, sublingual vaccine, mucosal immunity, IgA, sublingual system delivery Keywords: HIV; sublingual vaccine; mucosal immunity; IgA; sublingual system delivery EN HIV sublingual vaccine mucosal immunity IgA sublingual system delivery 1047 1050 4 09/15/21 20210901 NES 210901 Even if human correlates of HIV-1 protection still remain unknown, animal data and some HIV-1 cohort studies suggest that an effective vaccine against HIV-1 will require the induction of a multifunctional immune response. The use of gp41-specific Fab-IgAs derived from HIV-1 highly exposed but persistently seronegative individuals also highlighted the role of CHI domain of IgA in the protection against sexually acquired HIV-1 [[6]]. [Extracted from the article]

Keywords: COVID-19; vaccines; S protein; neutralizing antibodies; two proline substitutions EN COVID-19 vaccines S protein neutralizing antibodies two proline substitutions 769 772 4 09/04/21 20210701 NES 210701 The spike protein of SARS-CoV-2 is the first target identified by researchers on COVID-19 vaccines. Consequently, an efficient way of enhancing the effectiveness of S protein vaccines is by stabilizing the pre-fusion conformation of the S protein. Moreover, T cells targeting the S protein have been identified in SARS-CoV, MERS-CoV, and SARS-CoV-2. Some studies reported that the S-2P expression in the Ad26 vaccine from Janssen induces high levels of nAbs and is safer than the other native S protein vaccines in NHPs [[19]]. [Extracted from the article]

Chemorefractory ovarian cancer has limited therapeutic options. Hence, new types of treatment including neoantigen-specific immunotherapy need to be investigated. Neoantigens represent promising targets for personalized cancer immunotherapy. We here describe the clinical and immunological effects of a neoantigen peptide-loaded DC-based immunotherapy in a patient with recurrent and chemoresistant ovarian cancer. A 71-year-old female patient with chemorefractory ovarian cancer and malignant ascites received intranodal vaccination of DCs loaded with four neoantigen peptides that were predicted by our immunogenomic pipeline. Following four rounds of vaccinations with this therapy, CA-125 levels were remarkably declined and tumor cells in the ascites were also decreased. Concordantly, the tumor-related symptoms such as respiratory discomfort improved without any adverse reactions. The reactivity against one HLA-A2402-restricted neoantigen peptide derived from a mutated PPM1 F protein was detected in lymphocytes from peripheral blood by IFN-γ ELISPOT assay. Furthermore, the neoantigen (PPM1 F mutant)-specific TCRs were detected in the tumor-infiltrating T lymphocytes post-vaccination. Our results showed that vaccination with intranodal injection of neoantigen peptide-loaded DCs may have clinical and immunological impacts on cancer treatment. [ABSTRACT FROM AUTHOR]

Introduction: Locally advanced cutaneous squamous cell carcinoma (lacSCC) is rare. Approximately one-fourth of the cases are observed among immunocompromised patients, in particular in solid organ transplant recipients (OTRs). LacSCC has a very poor prognosis. Surgery with or without radiotherapy remains the golden standard of treatment for cSCC. However, in advanced cases, there is a medical need for alternative treatment options. Classic systemic treatments include chemotherapy and/or EGFR inhibitors. Recently the effectiveness of programmed cell death protein-1 (PD-1) inhibitors has been demonstrated for lacSCC. Cemiplimab is a recombinant IgG4 human monoclonal antibody against the PD-1 protein for the intravenous treatment of lacSCC.Areas Covered: The principal studies evaluating the efficacy and safety of cemiplimab for lacSCC are presented.Expert Opinion: Cemiplimab is the first anti-PD-1 antibody that was FDA (2018) and EMA (2019) approved as a systemic treatment for lacSCC and/or metastatic cSCC when curative surgery or radiotherapy is no longer amenable. For this situation, experts currently recommend cemiplimab as a first-line systemic alternative. As cemiplimab therapy is potentially associated with a risk of organ graft rejection, pros and cons should be evaluated for every individual OTR patient with lacSCC. [ABSTRACT FROM AUTHOR]

HEV-Ag ELISA assay is a reliable diagnostic test in resource-limited areas. HEV genotype 1 (HEV-1) infections are either self-limited or progress to fulminant hepatic failure (FHF) and death if anti-HEV therapy is delayed. Limited data is available about the diagnostic utility of HEV Ag on HEV-1 infections. Herein we aimed to study the kinetics of HEV Ag during HEV-1 infections at different stages, i.e., acute HEV infection, recovery, and progression to FHF. Also, we evaluated the diagnostic utility of this marker to predict the outcomes of HEV-1 infections. Plasma of acute hepatitis E (AHE) patients were assessed for HEV RNA by RT-qPCR, HEV Ag, and anti-HEV IgM by ELISA. The kinetics of HEV Ag was monitored at different time points; acute phase of infection, recovery, FHF stage, and post-recovery. Our results showed that the level of HEV Ag was elevated in AHE patients with a significantly higher level in FHF patients than recovered patients. We identified a plasma HEV Ag threshold that can differentiate between self-limiting infection and FHF progression with 100% sensitivity and 88.89% specificity. HEV Ag and HEV RNA have similar kinetics during the acute phase and self-limiting infection. In the FHF stage, HEV Ag and anti-HEV IgM have similar patterns of kinetics which could be the cause of liver damage. In conclusion, the HEV Ag assay can be used as a biomarker for predicting the consequences of HEV-1 infections which could be diagnostically useful for taking the appropriate measures to reduce the complications, especially for high-risk groups. [ABSTRACT FROM AUTHOR]

We recently described a protein O-glycosylation pathway conserved in all species of the Burkholderia genus that results in the synthesis and incorporation of a trisaccharide glycan to membrane-exported proteins. Here, we exploited this system to construct and evaluate a diagnostic tool for glanders. Burkholderia mallei, the causative agent of glanders, is a highly infectious and fatal zoonotic pathogen that infects horses, mules, donkeys, and occasionally humans. A highly sensitive and specific diagnostic tool is crucial for the control, elimination, and eradication of B. mallei infections. We constructed plasmids carrying synthetic genes encoding a modified, previously unannotated Burkholderia glycoprotein containing three glycosylation sequons fused to the cholera toxin B-subunit. The resulting proteins were glycosylated in the B. cenocepacia K56-2 parental strain, but not in glycosylation-deficient mutants, as determined by SDS-PAGE and fluorescent lectin blots. One of these glycopro- teins was used as an antigen in ELISA and western blots to screen a panel of serum samples collected from glanders-infected and healthy horses, which were previously investigated by complement fixation test and indirect ELISA based on a semi-purified fraction of B. mallei. We show that ELISA and western blot assays based on our glycoprotein antigen provide 100% specificity, with a sensitivity greater than 88%. The glycoprotein antigen was recognized by serum samples collected from patients infected with B. pseudomallei, B. mallei, B. multivorans, and B. cenocepacia. Our results indicate that protein O-glycosylation in Burkholderia can be exploited as a biomarker for diagnosis of Burkholderia-associated infections. [ABSTRACT FROM AUTHOR]

Vaccine-induced monoclonal antibodies targeting circumsporozoite protein prevent Plasmodium falciparum infection. Given that several peptide vaccines contain disordered epitopes, we should implement more studies to understand the nature of IDRs and their potential for designing vaccines. However, using a mixture of ordered and disordered epitopes in a peptide vaccine construct may modulate the recognition of disordered epitopes by antibodies. Keywords: Intrinsically disordered regions (IDRS); drug targets; protein; vaccine design EN Intrinsically disordered regions (IDRS) drug targets protein vaccine design 1 3 3 01/20/22 20220101 NES 220101 A comprehensive insight into how each part of a protein work can result in a better understanding of its role in cells and biological activities. [Extracted from the article]

Three of the most assessed biomarkers in the screening of biological samples for gastric cancer are carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and serum protein p53 (p53). Protoporphyrin IX immobilized in different nitrogen-doped graphene materials was used as the recognition molecule for the simultaneous determination of CEA, CA19-9, and p53 in various biological samples: whole blood, saliva, urine, and tissue samples. The proposed stochastic microsensors used as the recognition molecule protoporphyrin IX were reliable for the simultaneous determination of CEA, CA19-9, and p53 due to their high sensitivities and low limits of determination. The wide linear concentration ranges made possible the determination of the biomarkers in different stages of gastric cancer, from the earliest to the latest stages. [ABSTRACT FROM AUTHOR]

Hypersensitivity pneumonitis (HP) is an interstitial lung disease (ILD) caused by the inhalation of antigens. Antigen-specific IgG antibodies (sIgG) are used as biomarkers of exposure when diagnosing HP, but little is known about the longitudinal relation between antibody levels and risk of HP or other ILD. In a follow-up design, we explored the relationship between sIgG antibodies against Aspergillus fumigatus and the diagnosis of HP in 647 subjects suspected of HP. We showed that IgG levels above the reference value resulted in a hazard ratio of 9.5 for subsequent HP. Our findings support a relationship between high levels of sIgG against A. fumigatus and risk of HP. [ABSTRACT FROM AUTHOR]

Salivary proteins specific antibodies have been shown to be useful biomarkers of exposure to sand fly bites. This study aimed to investigate the level, duration, and dynamics of the human immune response against the SGL of Phlebotomus sergenti Parrot, 1917 (Diptera: Psychodidae), and to assess the immunoreactivity of human sera with SGL components in an endemic area of anthroponotic cutaneous leishmaniasis (ACL) in Iran. The study was carried out in 2-phase; longitudinal and cross-sectional. Sand flies were collected monthly from indoors and outdoors. In the longitudinal study, sera from healthy volunteers were collected monthly, and in the cross-sectional study, sera from healthy volunteers and patients with ACL lesion/s, were collected for immunoassay studies. The level of anti-P. sergenti saliva IgG was detected using the ELISA. Immunoreactivity of individual human sera with saliva components was also assessed by western blotting. Phlebotomus sergenti was the predominant sand fly species in the study area. The maximum and minimum percentages of IgG responses were seen in October (66%) and March (29%), respectively. Additionally, the cross-sectional study showed that 59.3% of the healthy volunteers and 80% of the patients were IgG positive. The antibody response against P. sergenti salivary gland was high during the sand fly active season and declined by the end of the activity of the vectors. Antibody response against the SGL components of P. sergenti was transient and individual-specific. Some individuals shared a strong reaction against certain individual antigens, which could be considered as vector exposure markers for further investigation. ELISA: Enzyme-Linked Immunosorbent Assay; SDS PAGE: Sodium Dodecyl Sulfate–Polyacrylamide Gel Electrophoresis; SGL: Salivary Gland Lysate; ACL: Anthroponotic Cutaneous Leishmaniasis; PBS: Phosphate Buffered Saline; BCA: Bicinchoninic Acid; PBS-T: Phosphate Buffered Saline Tween; FBS: Fetal Bovine Serum; HRP: Horseradish Peroxidase; TMB: 3,3′,5,5′-Tetramethylbenzidine; PVDF: Polyvinylidene Difluoride; SGA: Salivary Gland Antigens; OD: Optical Density; KDa: Kilodalton; VL: Visceral Leishmaniasis; CL: Cutaneous Leishmaniasis; SGs: Salivary glands The antibody response was transient to P. sergenti salivary gland antigens, and some individuals shared a strong reaction toward some proteins of SGL. [ABSTRACT FROM AUTHOR]

Brucellosis is the most dreadful disease among bovines, although breed differences have been observed in prevalence of disease, worldwide. In present study, antibody response and relative expression of proinflammatory cytokines was compared in Bos indicus (zebu) and Bos taurus × Bos indicus (crossbred) cattle vaccinated by live attenuated Brucella abortus S19 antigen. Six female calves (4–6 months age) of both groups were vaccinated with B.abortus S19 strain. Blood samples were collected before vaccination (0d) and 7th (7d), 14th (14d) and 28th (28d) days after vaccination. Indirect ELISA showed high (p <.05) anti-Brucella antibody level after vaccination; with no significant difference between the groups. During Real-time expression, IFNγ, TNFα, IL6 and IL10 genes initially showed down regulation followed by upregulation in both the groups; however, the trend was much prominent in crossbreds. The expressions of IFNγ, TNFα and IL6, proinflammatory molecules important for initial containment of the Brucella were significantly (p <.01) higher in crossbred. The study showed that the Sahiwal cattle were less responsive to B.abortus S19 antigen than crossbreds, indicating its lower sensitivity to the Brucella, comparatively. In contrary, higher expression of the proinflammatory molecules in crossbreds could be important for containment of the organism during initial stage of infection. [ABSTRACT FROM AUTHOR]

Introduction: Autoimmune retinopathy (AR) is a sight-threating retinal disorder that is mediated by autoantibodies (AAbs) against retinal proteins. The visual paraneoplastic syndromes, including cancer-associated retinopathy (CAR) and melanoma-associated retinopathy (MAR), are mediated by anti-retinal AAbs. A number of immunochemical techniques have been used to detect serum anti-retinal autoantibodies in patients to help with autoimmune diagnosis. Area covered: We review techniques used for serum autoantibody evaluation in patients with suspected autoimmune retinopathy. Expert opinion: Detection of serum AAbs has served as the standard diagnostic tool for autoimmune retinopathies and for management of retinal disorders. An identification of anti-retinal autoantibody or multiple autoantibodies can be useful for not only for diagnosis of autoimmune retinopathies but also for management of retinal disorders. We propose that the line-blotting technique used in conjunction with immunohistochemistry are the best and most reliable assays for detection of serum anti-retinal AAb in the context of clinical history and findings. Clinician should recognize that the majority of antigenic targets identified to date in retinal autoimmunity are ubiquitously expressed proteins (e.g. enolase), which may be difficult to reconcile with the specific patterns of retinal damage observed in CAR, MAR, or AR. [ABSTRACT FROM AUTHOR]

Although AML-M3 (APL) and HLA-DR negative non-APL are characterized by negative HLA-DR antigen, they are different entities with similar morphology in some cases. The aim of this study is the precise, differential diagnosis of APL from HLA-DR negative non-APL by flow cytometry to narrow the diagnosis window. Bone marrow or blood samples of 580 AML patients were analyzed, and flow cytometry and molecular analysis were performed for the diagnosis of blood disorders. In 105 HLA-DR negative AML patients, expression of HLA-DR, CD33, CD117, CD11b, CD64, CD34, CD9 and myeloperoxidase staining pattern were evaluated. Fifty-six patients were diagnosed with APL, and 49 patients were diagnosed with HLA-DR negative non-APL. The APL blasts expressed CD33, CD117, CD64, and CD9 in 100%, 80.3%, 94.6%, and 100% of the cases, respectively. HLA-DR negative non-APL blasts expressed CD33, CD117, CD64 and CD9 in 75.5%, 59.1%, 32.6%, and 73.4% of the cases, respectively. APL cells were negative for HLA-DR, CD11b, and CD34 in 96.4%, 94.6%, and 91.0%, respectively. Blasts in HLA-DR negative non M3-AML were negative for CD11b, CD117, and CD34 in 77.5%, 40.9%, and 22.4%, respectively. We also investigated myeloperoxidase (MPO) staining pattern and found strong diffuse reaction in APL cells while HLA-DR negative non-APL cells showed focal positive reaction. In all of the APL patients, except for one, PML/RARA translocation was positive, and in another case with HLA-DR negative non-APL, PML/RARA and other translocations were not detected. The six-panel combination profile rapidly and specifically identifies APL from other HLA-DR negative AML. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICPIs) are novel drugs in the field of oncology however carry the risk of immune-related dermatologic, gastrointestinal, and endocrine side effects which can be fatal. These new innovative immunoregulatory drugs have intertwined the fields of oncology and endocrinology. CTLA-4 and PD-1 are co-inhibitory receptors on T cells that turn the T cell 'off' when binding to receptors on APCs. Tumor cells can also carry receptors for CTLA- and PD-1. By rendering T cells inactive, tumor cells can evade immune attack. Antibodies that bind to CTLA-4 and PD-1 lead to T cell activation and destruction of both tumor and normal host cells. ICPIs have been used in a variety of malignancies including melanoma, kidney cancer, and non-small cell lung cancer. A unique underrecognized side effect of the autoimmune response is hypophysitis leading to central adrenal insufficiency which can be fatal. Additional immune-related adverse events (irAEs) include hypothyroidism, hyperthyroidism, diabetes, and hypoparathyroidism. [ABSTRACT FROM AUTHOR]

CD8+T cells are important in protective immunity against intracellular pathogens and tumors. In chronic infections or cancer, CD8+T cells are constantly exposed to antigens and inflammatory signals. Such excessive and constitutive signals lead to the deterioration of T cell function, called 'exhaustion'. Exhausted T cells are characterized by low proliferation in response to antigen stimulation, progressive loss of effector function (cytokine production and killing function), expression of multiple inhibitory receptors such as PD-1, Tim3, and LAG3, and metabolic alterations from oxidative phosphorylation to glycolysis. These dysfunctions are associated with altered transcriptional programs and epigenetic regulations and recent studies suggested that NR4a and TOX transcription factors are deeply involved in exhaustion phenotypes. However, an increase the early memory T cells including stem cell memory T (TSCM) cells is critical for T cell persistence and efficient tumor killing especially for adoptive cancer immunotherapy such as CAR-T cell therapy. An increasing amount of evidence supports the therapeutic potential of targeting exhausted T cells and TSCM cells. We have begun to understand the molecular mechanisms of T cell exhaustion and early memory formation, and the clinical application of converting exhausted T cells to rejuvenated early memory T cells is the goal of our study. [ABSTRACT FROM AUTHOR]

Introduction: The new category of chimeric antigen receptor T - cell raised hopes for a more effective treatment of large B cell lymphoma and acute lymphoblastic leukemia. Nevertheless, their soaring acquisition costs will stretch the fiscal capacity of the health systems worldwide. To this direction, the scope of this study is to provide a systematic review of their economic evaluations. Areas covered: A systematic review of the economic evaluations of tisagenlecleucel and axicabtagene was performed. Expert opinion: The available data indicate that these products demonstrate a potentially favorable cost-effectiveness ratio. Nevertheless, their budget impact is of overriding importance and it should be incorporated in any economic evaluation. Moreover, more affirmative clinical data are imperative in order to mitigate uncertainty. [ABSTRACT FROM AUTHOR]

Although differential expression of ABO antigens on platelets is related to recipients' platelet recovery and neonatal alloimmune thrombocytopenia in ABO-incompatible transfusion and pregnancy, the expression of ABO antigens on platelets in normal and variant ABO blood group individuals is rarely reported. Here, we analyzed the expression of ABO antigens on platelets in a cohort of 515 individuals with normal and variant ABO. The variants were also genotyped for ABO and/or FUT1 loci to distinguish inherited or acquired ABO variants. The results showed that ABO antigens expression on individual platelets was relatively stable during the storage period in vitro. The frequency of low-, moderate-, and high-expression phenotype in normal individual was 59.6%, 35.5%, and 4.9%, respectively. The platelets from para-Bombay and most inherited ABO subgroups express very low levels of ABO antigens, but the acquired ABO variants and the B3 subgroup express normal or abnormally high levels of ABO antigens on platelets. The data extend the information of antigens expression on platelets, which may help to improve the strategy of platelets transfusion. [ABSTRACT FROM AUTHOR]

The intracellular peptide pump TAP feeds antigenic peptides for loading onto HLA class I molecules, and its down-modulation is a frequent immune evasion mechanism in human cancers. Two recent papers describe which 'hidden' antigens we might exploit to target these escaped cancer variants by CD8 T cells. These unTAPped peptides are now ready for clinical testing. [ABSTRACT FROM AUTHOR]

Objective: The exact aetiology of obsessive-compulsive disorder (OCD) is unknown, although there is evidence to suggest a gene–environment interaction model. Several lines of evidence support a possible role of the immune system in this model. Methods: The present study explores the allele variability in HLA genes of class II (HLA-DRB1, HLA-DQB1) in a sample of 144 early-onset OCD compared with reference samples of general population in the same geographical area. Results: None of the 39 alleles identified (allele frequency >1%) showed significant differences between OCD and reference populations. Pooling the different alleles that comprised HLA-DR4 (including DRB1*04:01, DRB1*04:04 and DRB1*04:05 alleles) we observed a significantly higher frequency (X21 = 5.53, P = 0.018; OR = 1.64, 95% CI 1.08–2.48) of these alleles in the early-onset OCD sample (10.8%) than in the reference population (6.8%). Conclusions: Taking into account the role of HLA class II genes in the central nervous system, the results presented here support a role of the immune system in the pathophysiological model of OCD. [ABSTRACT FROM AUTHOR]

Introduction: Membranous nephropathy (MN) is the most common cause of a nephrotic syndrome in Caucasian adults. The identification of target antigens in MN in the last decade has had a major impact on the clinical approach to these patients. Areas covered: Since the discoveries in animal models in the 1980s that circulating autoantibodies induce disease upon in situ binding to glomerular podocytes, many attempts have been undertaken to define the human antigens responsible for disease induction. Only in 2009 was Phospholipase A2 Receptor 1 described as the major antigen responsible for MN onset in about 70% of patients. Subsequently, in 2014, Thrombospondin Type-1 Domain-Containing 7A was identified as a second antigen, accounting for 2-3% of patients with MN. The knowledge of the role of these antibodies in MN has improved the diagnosis and management of patients and helped to better define the need for immunosuppressive treatment. Expert commentary: These discoveries over the last 10 years in the discipline of nephrology have clearly shown the improvements a better understanding of disease pathogenesis can bring for patient care. [ABSTRACT FROM AUTHOR]

Purpose: We investigated the expression of the proinflammatory and proangiogenic factor osteoprotegerin (OPG) and its ligands, receptor activator of nuclear factor-κB ligand (RANKL), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and the receptor RANK in proliferative diabetic retinopathy (PDR).Materials and Methods: Vitreous samples from PDR and nondiabetic control patients and epiretinal membranes from PDR patients were studied by enzyme-linked immunosorbent assay, immunohistochemistry, and Western blot analysis.Results: Vascular endothelial growth factor, OPG, and soluble RANK levels in vitreous samples from PDR patients were significantly higher than that in nondiabetic controls. Soluble TRAIL levels were significantly lower in PDR patients than that in nondiabetic control, whereas soluble RANKL levels did not differ significantly. RANKL, RANK, and TRAIL were expressed in vascular endothelial cells, myofibroblasts, and CD45-expressing leukocytes in PDR epiretinal membranes.Conclusions: Dysregulated expression of OPG/RANKL/RANK pathway and TRAIL might be related to inflammation and angiogenesis in PDR. [ABSTRACT FROM AUTHOR]

Introduction: T-cell checkpoint inhibition as a cancer treatment approach has been the main breakthrough in cancer treatment during the last years. Since the approval of the first commercial CTLA-4 antibody ipilimumab in 2011 for the treatment of melanoma, research and drug development in this field has accelerated massively. In 2014, the US Food and Drug Administration (FDA) approved the first PD-1 targeting agent, namely pembrolizumab, shortly followed by nivolumab. Areas covered: Nivolumab is a fully human immunoglobulin G4 anti-PD-1 monoclonal antibody which is approved for multiple advanced malignancies, including melanoma, non-small cell lung cancer, renal cell cancer, Hodgkin's lymphoma, squamous head and neck cancer, and urothelial carcinoma. In September 2017, nivolumab was approved by the FDA for liver cancer as a second line treatment after failure of sorafenib based on the data of the multi-cohort phase 1/2 trial CheckMate-040. This article reviews the concept of immunotherapy in liver cancer with focus on nivolumab. Expert commentary: Immunotherapy in hepatocellular carcinoma is safe and is a new treatment option for patients with advanced stage disease besides sorafenib and regorafenib in the US. Randomized phase III trials of nivolumab, pembrolizumab, atezolizumab, durvalumab and tislelizumab as mono- or combination-therapy are ongoing. [ABSTRACT FROM AUTHOR]

Introduction: Highly sensitized patients awaiting a kidney transplant accrue on the transplant waiting list. The breadth of HLA antibodies in this subpopulation of patients precludes receiving a compatible organ offer through regular allocation within an acceptable time-frame. Areas covered: Several alternative options to receive a transplant exist for these patients, including additional priority in regular allocation, special programs based on allocation through acceptable antigens, kidney paired donation programs, desensitization protocols, or a combination of the latter two. In this review, these options and their outcomes are discussed as well as some possibilities to further enhance transplantation of this disadvantaged group of patients. Expert commentary: For highly sensitized patients, special attention is required, for which several strategies may apply. A step-wise approach may be the optimal strategy to facilitate successful transplantation of highly sensitized patients. [ABSTRACT FROM AUTHOR]

Household dust contains an array of constituents, including house dust mites (HDM) and the HDM allergen, Der p 1, which can cause sensitivities such as asthma and eczema. Vacuuming can help alleviate symptoms, yet little is understood about cleaning behaviour in different households. This pilot study investigated the contents of dust from four household types (students; over 65 s; and families with and without pets). This was then related to cleaning behaviours and perceptions of cleanliness. Our investigation found that HDMs and Der p 1 were present in all households and sampling locations, including participants’ cars. The median Der p 1 was greatest in the living room, though results varied. Demographic group was a determinant for the number of human and pet hairs present in dust. Surprisingly, vacuuming was the most disliked task overall. This information requires consideration when developing cleaning products and advising individuals with dust-related health issues. [ABSTRACT FROM AUTHOR]

Plasma biomarkers are useful tools in the diagnosis and prognosis of heart failure (HF). In the last decade, numerous studies have aimed to identify novel HF biomarkers that would provide superior and/or additional diagnostic, prognostic, or stratification utility. Although numerous biomarkers have been identified, their implementation in clinical practice has so far remained largely unsuccessful. Whereas cardiac-specific biomarkers, including natriuretic peptides (ANP and BNP) and high sensitivity troponins (hsTn), are widely used in clinical practice, other biomarkers have not yet proven their utility. Galectin-3 (Gal-3) and soluble suppression of tumorigenicity 2 (sST2) are the only novel HF biomarkers that are included in the ACC/AHA HF guidelines, but their clinical utility still needs to be demonstrated. In this review, we will describe natriuretic peptides, hsTn, and novel HF biomarkers, including Gal-3, sST2, human epididymis protein 4 (HE4), insulin-like growth factor-binding protein 7 (IGFBP-7), heart fatty acid-binding protein (H-FABP), soluble CD146 (sCD146), interleukin-6 (IL-6), growth differentiation factor 15 (GDF-15), procalcitonin (PCT), adrenomedullin (ADM), microRNAs (miRNAs), and metabolites like 5-oxoproline. We will discuss the biology of these HF biomarkers and conclude that most of them are markers of general pathological processes like fibrosis, cell death, and inflammation, and are not cardiac- or HF-specific. These characteristics explain to a large degree why it has been difficult to relate these biomarkers to a single disease. We propose that, in addition to clinical investigations, it will be pivotal to perform comprehensive preclinical biomarker investigations in animal models of HF in order to fully reveal the potential of these novel HF biomarkers. [ABSTRACT FROM AUTHOR]

Introduction: The therapeutic categories of tyrosine kinase inhibitors of vascular endothelial growth factor receptors, mammalian target of rapamycin inhibitors and programmed death-1 inhibitors have transformed the treatment of metastatic renal cell cancer. Nevertheless, this comes at an increased cost, in tandem with similar fiscal pressures in the broader oncology sector, which may jeopardize the sustainability of health systems.Areas Covered: To this direction, the economic evaluation of these agents is essential for rational and efficient decision-making and resource allocation process. The aim of this study is to glean, assess and present an outline of the available cost-effectiveness studies of these agents in the management of metastatic renal cell cancer.Expert Commentary: We concluded that the results of the economic evaluations are pertinent, apart from the product under evaluation, to the country setting as well. [ABSTRACT FROM AUTHOR]

Purpose: To identify autoantigens in autoimmune retinopathy patients by phage immunoprecipitation sequencing (PhIP-Seq), a new technique for autoantigen discovery.Methods: PhIP-Seq was used to sequence putative autoantibodies in plasma from 11 patients with autoimmune retinopathy and eight controls. We compared the autoantibodies' molecular weights with those of proteins detected by Western blot.Results: Several autoantigens were found in cases and not detected in the controls. Autoantigens RTN3, PRPF6, TRPC6, and B3GNT8, four proteins expressed in the retina, were detected in plasma as autoantibodies from one patient each and no controls. Only one patient had an autoantibody, B3GNT8 (43.4 kDa), within a similar weight range as that detected by antiretinal antibody Western blot (42 kDa). Autoantibody POLR3A, which has a well-characterized role in scleroderma, was detected in two cases and no controls.Conclusion: PhIP-Seq detected autoantigens that are expressed in the retina as well as scleroderma-related autoantigens in autoimmune retinopathy patients. [ABSTRACT FROM AUTHOR]

Objective:Congenital prothrombin deficiency is one of the rarest clotting disorders. It is commonly subdivided in Type I defects or cases of ‘true’ prothrombin deficiency characterized by a concomitant decrease in FII activity and antigen and in Type II or dysprothrombinemias, in which FII activity is low but FII antigen is normal or near normal. A bleeding tendency, often a severe one, is the hallmark of the two-defects even though the bleeding is usually less severe in the Type 2 defects or dysprothrombinemias. Patients and Methods:An extensive search of published cases of prothrombin deficiency was carried out in Pubmed and Scopus. The search started in 2012, after the publication of the first family with dysprothrombinemia and venous thrombosis. A few additional families were found. Results:Recent studies have demonstrated that the Type 2 defects are heterogeneous. Several heterozygous mutations involving the Arg596 residue of exon 14 have been demonstrated not be associated with a bleeding tendency but, surprisingly, with venous thromboses. Mutations in close areas of prothrombin have failed to show the same pattern. Conclusions:These observations have required a reclassification of prothrombin defects. To the Type I and Type II defects, a Type III has to be added characterized by the absence of bleeding and the presence of venous thrombosis. It is not clear yet if this special variant of Type II defect is limited to the Arg596 mutations or if other residues may be involved. [ABSTRACT FROM AUTHOR]

The soluble transcobalamin receptor (sCD320) is present in cerebrospinal fluid and correlates with the dementia-related biomarkers phospho-tau and total-tau. Here we present data on the relation of sCD320 to Alzheimer’s disease and scores of cognitive tests. Lumbar cerebrospinal fluid samples from 42 pathologically-confirmed cases of Alzheimer’s disease and 25 non-demented controls were analyzed for sCD320 employing an in-house ELISA. The participants’ cognitive functions were tested using the Cambridge Cognition Examination (CAMCOG) and the Mini-Mental State Examination (MMSE). There was no significant difference in the median CSF sCD320 concentration between patients and controls. The median (2.5–97.5 percentiles) sCD320 for all participants (n = 67) was 15 (3–29) pmol/L. We observed a non-linear correlation between sCD320 and cognitive scores. Spearman’s correlation between sCD320 and total CAMCOG scores was 0.627 (n = 16,p = .009) for CAMCOG scores ≤27, and −0.293 (n = 39,p = .071) for CAMCOG scores ≥68. Spearman’s correlation between sCD320 and both the low (≤9) and high (≥16) total MMSE scores was 0.274, −0.363 (n = 18, 44),p = .272, .016, respectively. In conclusion, sCD320 cannot be employed as a biomarker for differentiating Alzheimer dementia patients from controls. Further studies are warranted to explore the non-linear correlations between sCD320 and scores of cognitive function. [ABSTRACT FROM PUBLISHER]

The enzyme-linked immunosorbent assay (ELISA) is extensively used for measurement of proteins utilized for various research and diagnostic purposes in the biological disciplines. However, it is a labor-intensive and lengthy procedure due to a number of incubation and washing steps required for performing the assay. The ELISA procedure in the current study has been simplified through the simultaneous addition of antigen and detection antibody and elimination of washing steps. This resulted in a decreased time required to perform the procedure and without affecting assay capability. This approach offers the possibility of increasing ELISA productivity in low throughput laboratories without the need for alternative analytical platforms which would require significant assay redevelopment and capital expense. [ABSTRACT FROM AUTHOR]

Objective: We study the phenotype and genotype of a novel gene mutation of factor II (FII) that leads to dysprothrombinemia, and do the meta-analysis to illuminate its molecular pathogenesis. It will further contribute to our comprehension of the pathogenesis of this type of disease. Methods: The prothrombin time (PT), activated partial thromboplastin time (APTT) and the activities of other factors were determined by the one-stage clotting method. The prothrombin antigen was measured with enzyme-linked immunosorbent assay (ELISA). Function of the mutant protein was evaluated by thrombin generation tests. Potential mutations in exons, exon–intron boundaries and 5', 3' untranslated sequences of prothrombin gene were screened by polymerase chain reaction and direct sequencing. Suspected mutations were confirmed by reverse sequencing. The structure change of this protein was analyzed by model and bioinformatics analyses. Results: Phenotypic analysis revealed that the proband had an obviously prolonged PT, APTT, reduced prothrombin activity but normal antigen levels. The other tests were normal. Sequencing analysis detected a homozygous g.26329T>G in the catalytic domain resulting in p.Tyr510Asp. His parents and uncle were heterozygous for this mutation. The thrombin generation test showed that the mutant protein had obstacles in thrombin generation. Bioinformatics and model analyses illuminated that the mutation will be probably damaging and perturbing the structure of Na+-binding site, which will affect the activation of prothrombin. Conclusion: This was the first report of such a mutation in the position which was associated with dysprothrombinemia. [ABSTRACT FROM AUTHOR]

Introduction: In the last years, a spectacular development of immunotherapeutic agents aimed at the PD-1/PD-L1 axis has taken place. This development of these checkpoint inhibitors has greatly influenced our approach to the treatment of lung cancer in first and second line. The limited toxicity profile and the ability to treat for prolonged periods, even in smokers, is a welcome expansion of the therapeutic arsenal of the oncologist. Areas covered: This review highlights the results of recent clinical trials on pembrolizumab for the treatment of non-small cell lung cancer. The authors discuss both first and second line treatment with pembrolizumab as monotherapy and in combination therapies. Additionally, implications of the PD-L1 immunohistochemistry assay with the 22C3 antibody and its use in clinical practice and trials is discussed. Expert commentary: A higher overall response, overall survival and a moderate toxicity profile is observed with the use of pembrolizumab, compared to chemotherapy, in both first and second line. These promising results have already translated into the registration of pembrolizumab in first and second line in patients with a high expression of PD-L1. However, as PD-L1 staining does not sufficiently discriminate responders from non-responders for all checkpoint inhibitors, there still is a need for a better predictive biomarker. [ABSTRACT FROM AUTHOR]

There is increasing evidence for a direct relationship between the vascular system and non-alcoholic fatty liver disease (NAFLD). The aim of this study was to investigate endocan and adhesion molecules such as P-selectin derived from the endothelium and platelets in obese children and adolescents with NAFLD. One hundred obese patients and 40 lean controls were enrolled. The obese subjects were divided into two subgroups based on the presence or absence of fatty liver. Blood samples were assayed for endocan, P-selectin, platelet-derived growth factor (PDGF), intercellular cell adhesion molecule (ICAM)-1, and vascular cell adhesion molecule (VCAM)-1. Obese patients with NAFLD presented higher ALT and insulin levels, as well as more profound dyslipidemia when compared with their counterparts without NAFLD. Serum levels of high-sensitivity C-reactive protein, VCAM-1 and ICAM-1 were found increased in both obese groups, regardless of NAFLD. In obese subjects with NAFLD, decreased P-selectin levels (51.6 ± 4.14 ng/mL) were detected as compared with the obese (72.3 ± 4.23) and control (74.2 ± 6.97) subjects. Furthermore, circulating P-selectin levels were closely associated with endocan levels (r = 0.852,p < 0.001). Childhood obesity leads to vascular inflammation and therefore may cause a predisposition to atherosclerosis at an early age. The possible outcome of decreased P-selectin levels with NAFLD development must be further investigated. [ABSTRACT FROM PUBLISHER]

Extracellular vesicles (EVs) are small, membrane-bound particles released by all cell types, including abundant release by platelets. EVs are a topic of increasing interest in the academic and clinical community due to their increasingly recognised and diverse role in normal biology as well as in disease. However, typical analysis methods to characterise EVs released by cultured cells or isolated from whole blood or other body fluids are restricted to bulk analysis of all EVs in a sample. In this review, we discuss the motivation for analysis of individual EVs, as well as discuss three emerging methods for physical and chemical characterisation of individual EVs: nanoparticle tracking analysis, tunable resistive pulse sensing and Raman spectroscopy. We give brief descriptions of the working principles of each technique, along with a review noting the benefits and limitations of each method as applied to detection of single EVs. [ABSTRACT FROM AUTHOR]

Background: The most crucial clinical problem of Eosinophilic Otitis Media (EOM) is sensorineural hearing loss. A previous report revealed that repeated antigen stimulation of middle ear causes eosinophilic inflammation not only in the middle ear but also in the inner ear. Objective: The purpose of the present study was to elucidate the mechanism of eosinophil infiltration to the inner ear in the animal model of EOM. Methods: Continuous OVA stimulation to the middle ear of guinea pigs was performed for 7 days, 14 days, and 28 days. Histological observation was made for eosinophil infiltration and morphological change of the inner ear. Immunostaining for eotaxin and RANTES was performed to study immunoreactivity of those chemokines. Results: In the 7-day stimulation side, a few eosinophils were found in the scala tympani, without obvious morphological damage of the inner ear. Moreover, immunoreactivity of both eotaxin and RANTES was significantly higher in the OVA stimulation sides than control sides. For both eotaxin and RANTES, the number of immunopositive cells was significantly increased in the 14-day stimulation side over the 7-day stimulation side. Conclusions: Eotaxin and RANTES seem to play some important roles for the eosinophil infiltration in the middle and inner ear of model animal of EOM. [ABSTRACT FROM AUTHOR]

The aim of the study was to investigate the combined impact of the genetic heterogeneity of the glycoproteins Ia (GpIa) and IIIa (GpIIIa) and the platelet-endothelial cell adhesion molecule-1 (PECAM-1) and P-Selectin genes on IVF embryo transfer implantation failures (IVF-ET failures). Sixty nulligravida women with previous IVF-ET failures and 60 fertile controls were genotyped for the GpIa-C807T, GpIIIa-PlA1/PA2, PECAM-1-C373G (Leu125Val) and P-Selectin-A37674C (Thr715Pro) polymorphisms by pyrosequencing. Compared with wild-type combined homozygotes, carriers of combinations of risk alleles in two gene loci were at significantly increased risk for IVF-ET failure, whereas carriers of the combination of GpIa-807T, GpIIIa-PlA2 and PECAM-1-373G alleles had OR = 52.50 (95%CI: 4.05–680.95,p < .001). The area under the receiver-operating characteristic curve (AUC) based on the number of polymorphisms and the number of risk alleles per subject was 75.4% (95%CI: 66.7%–82.8%,p < .001) and 72.5% (95%CI: 63.6%–80.3%,p < .001), respectively. The OR per polymorphism and risk allele increase was 4.26 (95%CI: 2.15–8.41,p < .001) and 2.85 (95%CI: 1.71–4.76,p < .001), respectively. The above associations were more robust among younger women. The combined analysis of these polymorphisms revealed strong association of combined carriers with IVF-ET failures especially for younger women and provided a genetic risk score with good diagnostic accuracy in the prediction of IVF-ET failures. [ABSTRACT FROM PUBLISHER]

Introduction: Adoptive therapy with chimeric antigen receptor (CAR) T cells redirected towards CD19 produces remissions of B cell malignancies, however, it also eradicates healthy B cells sharing the target antigen. Such ‘on-target off-tumor’ toxicity raises serious safety concerns when the target antigen is also expressed by tissue stem cells, with the risk of lasting tissue destruction. Areas covered: We discuss CAR T cell targeting of activation antigens versus lineage associated antigens on the basis of recent experimental and animal data and the literature in the field. Expert commentary: Targeting an activation associated antigen which is transiently expressed by stem cells seems to be safe, like CAR T cells targeting CD30 spare CD30+hematopoietic stem and progenitor cells while eliminating CD30+lymphoma cells, whereas targeting lineage associated antigens which increase in expression during cell maturation, like folate receptor-β and CD123, is of risk to destruct tissue stem cells. [ABSTRACT FROM AUTHOR]

Purpose: To examine antigen-stimulated cytokine production by Behçet disease patients (BD) before and after infliximab infusion.Methods: PBMCs were obtained before and after infliximab infusion in BD patients with or without recurrent uveitis during at least 1 year of infliximab therapy, and from healthy subjects. PBMCs were cultured with IRBP, and Th-related cytokines in cultures were measured.Results: Levels of IL-4, IL-6, IL-10 IL-17A, IL-17F, IL-31, IFN-γ, and TNFα were higher in BD before infliximab infusion than in healthy subjects, and these levels were the highest in BD with recurrent uveitis. After infliximab infusion, these cytokine levels were reduced to a greater extent in BD without recurrent uveitis than in BD with recurrence.Conclusions: Th-related cytokines produced by IRBP-stimulated PBMCs were elevated in BD, and infliximab infusion suppressed these cytokines to a greater extent in BD without recurrent uveitis than in those with recurrence. [ABSTRACT FROM AUTHOR]