Search results for: immune dysregulation

Authors: Pampita Chakraborty, Sukumar Mukherjee

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People with diabetes mellitus are more susceptible to developing infections, as high blood sugar levels can weaken the patient's immune system defences. People with diabetes are more adversely affected when they get an infection than someone without the disease, because you have weakened immune defences in diabetes. People who have minimally elevated blood sugar levels experience worse outcomes with infections. Diabetic patients in hospitals do not necessarily have a higher mortality rate due to infections, but they do face longer hospitalisation and recovery times. A study was done in a tertiary care unit in eastern India. Patients with type 2 diabetes mellitus infection were recruited in the study. A total of 520 cases of Type 2 Diabetes Mellitus were recorded out of which 200 infectious cases was included in the study. All subjects underwent detailed history & clinical examination. Microbiological samples were collected from respective site of the infection for microbial culture and antibiotic sensitivity test. Out of the 200 infectious cases urinary tract infection(UTI) was found in majority of the cases followed by diabetic foot ulcer (DFU), respiratory tract infection(RTI) and sepsis. It was observed that Escherichia coli was the most commonest pathogen isolated from UTI cases and Staphylococcus aureus was predominant in foot ulcers followed by other organisms. Klebsiella pneumonia was the major organism isolated from RTI and Enterobacter aerogenes was commonly observed in patients with sepsis. Isolated bacteria showed differential sensitivity pattern against commonly used antibiotics. The majority of the isolates were resistant to several antibiotics that are usually prescribed on an empirical basis. These observations are important, especially for patient management and the development of antibiotic treatment guidelines. It is recommended that diabetic patients receive pneumococcal and influenza vaccine annually to reduce morbidity and mortality. Appropriate usage of antibiotics based on local antibiogram pattern can certainly help the clinician in reducing the burden of infections.

Keywords: antimicrobial resistance, diabetic foot ulcer, respiratory tract infection, urinary tract infection

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Authors: Veronika Zivicova, Petr Broz, Zdenek Fik, Alzbeta Mifkova, Jan Plzak, Zdenek Cada, Herbert Kaltner, Jana Fialova Kucerova, Hans-Joachim Gabius, Karel Smetana Jr.

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The possibility to determine genome-wide expression profiles of cells and tissues opens a new level of analysis in the quest to define dysregulation in malignancy and thus identify new tumor markers. Toward this long-term aim, we here address two issues on this level for head and neck cancer specimen: i) defining profiles in different regions, i.e. the tumor, the transition zone and normal control and ii) comparing complete data sets for seven individual patients. Special focus in the flanking immunohistochemical part is given to adhesion/growth-regulatory galectins that upregulate chemo- and cytokine expression in an NF-κB-dependent manner, to these regulators and to markers of differentiation, i.e. keratins. The detailed listing of up- and down-regulations, also available in printed form (1), not only served to unveil new candidates for testing as marker but also let the impact of the tumor in the transition zone become apparent. The extent of interindividual variation raises a strong cautionary note on assuming uniformity of regulatory events, to be noted when considering therapeutic implications. Thus, a combination of test targets (and a network analysis for galectins and their downstream effectors) is (are) advised prior to reaching conclusions on further perspectives.

Keywords: galectins, genome scale sequencing, squamous cell carcinoma, transition zone

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Authors: Ava Faridi, Pouya Faridi, Aleksandr Kakinen, Ibrahim Javed, Thomas P. Davis, Pu Chun Ke

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Human islet amyloid polypeptide (IAPP) is a hormone associated with glycemic control and type 2 diabetes. Biophysically, the chirality of IAPP fibrils has been little explored with respect to the aggregation and toxicity of the peptide. Biochemically, it remains unclear as for how protein expression in pancreatic beta cells may be altered by cell exposure to the peptide, and how such changes may be mitigated by nanoparticle inhibitors for IAPP aggregation. In this study, we first demonstrated the elimination of the IAPP nucleation phase and shortening of its elongation phase by silica nanoribbons. This accelerated IAPP fibrillization translated to reduced toxicity, especially for the right-handed silica nanoribbons, as revealed by cell viability, helium ion microscopy, as well as zebrafish embryo survival, developmental and behavioral assays. We then examined the proteomes of βTC6 pancreatic beta cells exposed to the three main aggregation states of monomeric, oligomeric and amyloid fibrillar IAPP, and compared that with cellular protein expression modulated by graphene quantum dots (GQDs). A total of 29 proteins were significantly regulated by different forms of IAPP, and the majority of these proteins were nucleotide-binding proteins. A regulatory capacity of GQDs against aberrant protein expression was confirmed. These studies have demonstrated the great potential of employing nanomaterials targeting the mesoscopic enantioselectivity and protein expression dysregulation in pancreatic beta cells.

Keywords: graphene quantum dots, IAPP, silica nanoribbons, protein expression, toxicity

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Authors: Sajewicz-Krukowska Joanna, Domańska-Blicharz Katarzyna, Tarasiuk Karolina, Marzec-Kotarska Barbara

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Astroviral infections pose a significant problem in the poultry industry, leading to multiple adverse effects such as decreased egg production, breeding disorders, poor weight gain, and even increased mortality. Commonly observed chicken astrovirus (CAstV) was recently reported to be responsible for "white chicks syndrome" associated with increased embryo/chick mortality. The CAstV-mediated pathogenesis in chicken occurs due to complex interactions between the infectious pathogen and the immune system. Many aspects of CAstV-chicken interactions remain unclear, and there is no information available regarding gene expression changes in the chicken's spleen in response to CAstV infection. We aimed to investigate the molecular background triggered by CAstV infection. Ten 21-day-old SPF White Leghorn chickens were divided into two groups of 5 birds each. One group was inoculated with CAstV, and the other was used as the negative control. On 4th dpi, spleen samples were collected and immediately frozen at -70°C for RNA isolation. We analysed transcriptional profiles of the chickens' spleens at the 4th day following infection using RNA-seq to establish differentially expressed genes (DEGs). The RNA-seq findings were verified by quantitative real-time PCR (qRT-PCR). A total of 31959 transcripts were identified in response to CAstV infection. Eventually 45 DEGs (p-value<0.05; Log2Foldchange>1)were recognized in the spleen after CAstV infection (26 upregulated DEGs and 19 downregulated DEGs). qRT-PCR performed on 4 genes (IFIT5, OASL, RASD1, DDX60) confirmed RNAseq results. Top differentially expressed genes belonged to novel putative IFN-induced CAstV restriction factors. Most of the DEGs were associated with RIG-I–like signalling pathway or, more generally, with an innate antiviral response(upregulated: BLEC3, CMPK2, IFIT5, OASL, DDX60, IFI6, and downregulated: SPIK5, SELENOP, HSPA2, TMEM158, RASD1, YWHAB). The study provided a global analysis of host transcriptional changes that occur during CAstV infection in vivo and proved the cell cycle in the spleen and immune signalling in chickens were predominantly affected upon CAstV infection.

Keywords: chicken astrovirus, CastV, RNA-seq, transcriptome, spleen

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Authors: Mahbuba Rahman, Sabri Boughorbel, Scott Presnell, Charlie Quinn, Darawan Rinchai, Damien Chaussabel, Nico Marr

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Collections of large-scale datasets made available in public repositories can be used to identify and fill gaps in biomedical knowledge. But first, these data need to be made readily accessible to researchers for analysis and interpretation. Here a collection of transcriptome datasets was made available to investigate the functional programming of human hematopoietic cells in early life. Thirty two datasets were retrieved from the NCBI Gene Expression Omnibus (GEO) and loaded in a custom, interactive web application called the Gene Expression browser (GXB), designed for visualization and query of integrated large-scale data. Multiple sample groupings and gene rank lists were created based on the study design and variables in each dataset. Web links to customized graphical views can be generated by users and subsequently be used to graphically present data in manuscripts for publication. The GXB tool also enables browsing of a single gene across datasets, which can provide information on the role of a given molecule across biological systems. The dataset collection is available online. As a proof-of-principle, one of the datasets (GSE25087) was re-analyzed to identify genes that are differentially expressed by regulatory T cells in early life. Re-analysis of this dataset and a cross-study comparison using multiple other datasets in the above mentioned collection revealed that PMCH, a gene encoding a precursor of melanin-concentrating hormone (MCH), a cyclic neuropeptide, is highly expressed in a variety of other hematopoietic cell types, including neonatal erythroid cells as well as plasmacytoid dendritic cells upon viral infection. Our findings suggest an as yet unrecognized role of MCH in immune regulation, thereby highlighting the unique potential of the curated dataset collection and systems biology approach to generate new hypotheses which can be tested in future mechanistic studies.

Keywords: early-life, GEO datasets, PMCH, interactive query, systems biology

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Authors: Don Anushka Sandaruwan Elvitigala, P. D. S. U. Wickramasinghe, Jehee Lee

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Cystatins are a large superfamily of proteins which act as reversible inhibitors of cysteine proteases. Papain proteases and cysteine cathepsins are predominant substrates of cystatins. Cystatin superfamily can be further clustered into three groups as Stefins, Cystatins, and Kininogens. Among them, stefines are also known as family 1 cystatins which harbors cystatin Bs and cystatin As. In this study, a homologue of family one cystatins more close to cystatin Bs was identified from Korean black rockfish (Sebastes schlegeli) using a prior constructed cDNA (complementary deoxyribonucleic acid) database and designated as RfCyt1. The full-length cDNA of RfCyt1 consisted of 573 bp, with a coding region of 294 bp. It comprised a 5´-untranslated region (UTR) of 55 bp, and 3´-UTR of 263 bp. The coding sequence encodes a polypeptide consisting of 97 amino acids with a predicted molecular weight of 11kDa and theoretical isoelectric point of 6.3. The RfCyt1 shared homology with other teleosts and vertebrate species and consisted conserved features of cystatin family signature including single cystatin-like domain, cysteine protease inhibitory signature of pentapeptide (QXVXG) consensus sequence and N-terminal two conserved neighboring glycine (⁸GG⁹) residues. As expected, phylogenetic reconstruction developed using the neighbor-joining method showed that RfCyt1 is clustered with the cystatin family 1 members, in which more closely with its teleostan orthologues. An SYBR Green qPCR (quantitative polymerase chain reaction) assay was performed to quantify the RfCytB transcripts in different tissues in healthy and immune stimulated fish. RfCyt1 was ubiquitously expressed in all tissue types of healthy animals with gill and spleen being the highest. Temporal expression of RfCyt1 displayed significant up-regulation upon infection with Aeromonas salmonicida. Recombinantly expressed RfCyt1 showed concentration-dependent papain inhibitory activity. Collectively these findings evidence for detectable protease inhibitory and immunity relevant roles of RfCyt1 in Sebastes schlegeli.

Keywords: Sebastes schlegeli, family 1 cystatin, immune stimulation, expressional modulation

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Authors: Jianming Cai

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Exposure to ionizing radiation causes severe damage to human body and an safe and effective radioprotector is urgently required for alleviating radiation damage. In 2008, flagellin, an agonist of TLR5, was found to exert radioprotective effects on radiation injury through activating NF-kB signaling pathway. From then, the radioprotective effects of TLR ligands has shed new lights on radiation protection. CpG-ODN is an unmethylated oligonucleotide which activates TLR9 signaling pathway. In this study, we demonstrated that CpG-ODN has therapeutic effects on radiation injuries induced by γ ray and 12C6+ heavy ion particles. Our data showed that CpG-ODN increased the survival rate of mice after whole body irradiation and increased the number of leukocytes as well as the bone marrow cells. CpG-ODN also alleviated radiation damage on intestinal crypt through regulating apoptosis signaling pathway including bcl2, bax, and caspase 3 etc. By using a radiation-induced pulmonary fibrosis model, we found that CpG-ODN could alleviate structural damage, within 20 week after whole–thorax 15Gy irradiation. In this model, Th1/Th2 imbalance induced by irradiation was also reversed by CpG-ODN. We also found that TGFβ-Smad signaling pathway was regulated by CpG-ODN, which accounts for the therapeutic effects of CpG-ODN in radiation-induced pulmonary injury. On another hand, for high LET radiation protection, we investigated protective effects of CpG-ODN against 12C6+ heavy ion irradiation and found that after CpG-ODN treatment, the apoptosis and cell cycle arrest induced by 12C6+ irradiation was reduced. CpG-ODN also reduced the expression of Bax and caspase 3, while increased the level of bcl2. Then we detected the effect of CpG-ODN on heavy ion induced immune dysfunction. Our data showed that CpG-ODN increased the survival rate of mice and also the leukocytes after 12C6+ irradiation. Besides, the structural damage of immune organ such as thymus and spleen was also alleviated by CpG-ODN treatment. In conclusion, we found that TLR9 ligand, CpG-ODN reduced radiation injuries in response to γ ray and 12C6+ heavy ion irradiation. On one hand, CpG-ODN inhibited the activation of apoptosis induced by radiation through regulating bcl2, bax and caspase 3. On another hand, through activating TLR9, CpG-ODN recruit MyD88-IRAK-TRAF6 complex, activating TAK1, IRF5 and NF-kB pathway, and thus alleviates radiation damage. This study provides novel insights into protection and therapy of radiation damages.

Keywords: TLR9, CpG-ODN, radiation injury, high LET radiation

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Authors: Annabel Burnley, Michelle St. Clair, Charlotte Dack, Yvonne Wren

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Children with Developmental Language Disorder (DLD) are well documented to experience social and emotional difficulties. Despite this, there is little consensus as to how these difficulties manifest, without which the ability to develop prevention initiatives is limited. An online survey was completed by 107 parents of either child with DLD (‘DLD sample’; n=57), or typically developing children (‘typical sample’; n=50), all aged 6-12 years old. Psychosocial symptom measures were used, alongside 11 psychosocial statements generated from previous qualitative work. Qualitative interviews were then held to understand the manifestation of key difficulties in more depth (n=4). The DLD sample scored significantly higher on all psychosocial statements than the typical sample. Experiencing anxiety (80.7%), requiring routine and sameness (75.4%) and struggling to regulate their emotions (75.4%) were the most common difficulties for a majority of children with DLD. For this DLD sample, family communication and coping styles were found not to contribute to the manifestation of these difficulties. Two separate mediation models were run to understand the role of other psychosocial difficulties in the manifestation of (1) anxiety and (2) social frustration. ‘Intolerance of uncertainty was found to strongly mediate the relationship between DLD diagnosis and symptoms of anxiety. Emotion regulation was found to moderately mediate the relationship between DLD diagnosis and social frustration. Parents appear to cope well with their children’s complex psychosocial needs, but further external intervention is needed. Intervention focussing on intolerance of uncertainty and emotion dysregulation may help the management of anxiety and social frustration. Further research is needed to understand the children’s routined behaviors.

Keywords: psychosocial difficulties, developmental language disorder, specific language impairment, parent, anxiety

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Authors: Khalid Mahmoud Gaafar

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In human diets , ω-6 and ω-3 are important essential fatty acids for immunity and health. However, considerable alteration in dietary patterns and contents has resulted in change of the consumption of such fatty acids ,with subsequent increase in the consumption of ω-6 fatty acids and a marked decrease in the consumption of ω-3 fatty acids. This dietary alteration has led to an imbalance in the ratio for ω-6/ω-3, which at 20:1 now differs considerably from the original ratio (1:1). Therefore, dietary supplements such as eggs and meat enriched with omega 3 are necessary to increase the consumption of ω-3 to meet the recommended need for ω-3. Foods that supply ω-6 fatty acids include soybean, palm , sunflower, and rapeseed oils, whereas foods that supply ω-3 fatty acids such as linseed and fish oils. Lin seed oils contain Alpha – linolenic acid (ALA), which can be converted to DHA and EPA in the birds body, with linseed oil containing more than 50% ALA. On the other hand, high doses of omega 6 sources in the diet may have deleterious effects on humans. Maintaining an optimum ratio of ω-3 and ω-6fatty acids not only improves performance but also prevents these health risks. The ratio of n-6:ω-3 fatty acids also plays an important role in the immune response, production performance of broilers and designing meat enriched with ω-3 polyunsaturated fatty acids (PUFAs). Birds of three experimental groups fed on basal starter (0-2nd weeks), grower (3rd -4th weeks) and finisher (5th week) rations. The first is control group fed during the grower-finisher periods on basic diet with two replicate (one fed on basic diet contain vegetable oil and the other don’t) without any additives. The three experimental groups (T1 – T2 –T3) fed during the grower- finisher periods on diets free from vegetable oils and contain of 5% of extruded mixture of soybean and linseed (60%:40%). The second (T2) and third (T3) experimental groups supplemented with vitamin B12 and enzyme mixture. The first experimental groups don’t receive vitamins or enzymes. The obtained results showed a significant increased growth performance, immune response, highest antioxidant activity and serum HDL with lowest serum LDL and triglycerides levels in all experimental groups compared with control group, which was highly significant in group fed on vitamin B6.

Keywords: omega fatty acids, broiler, feeding, human health, growth performance, immunity

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Authors: Zaralyn Bernardo, Dante Boac, Annabelle Del Rosario

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Professional individuals who are in a primary role to impart learning with the new generation are alarmingly tend to have a vast decrease in their workforce due to stress at work. Thus, the study used mixed method research design to explore the ideal and actual coping patterns of college school teachers, both private and public, using Coping Response Inventory-Adult (CRI-Adult). It was suggested that in order for coping to be effective there must be a congruence or good match between coping efforts and preferred coping style. Results basically provided the same information on sources of teacher stress. However, workload and low salary were more likely heightened, for public and private school, respectively. There is also a significant difference between the ideal and actual coping style of college school teachers. Though the public school teachers leaned towards problem-focused as their ideal way of coping, both public and private teachers are somewhat inclined to use emotion-focused coping in actual situation. Results of FGD identified the factors that contribute to the incongruence or mismatch in their preferred style of coping and actual efforts to cope. Identified factors based on thematic analysis (TA) are clustered into themes such as affectivity and rehearsal of the preferred coping responses, sensitivity to pressure impairs coping efficacy, seeking for social acceptance and approval, indefinite appraisal of perceived stress, emotional dysregulation, and impulsivity, immediate desire to terminate negative emotion and adversity. Most of the factors somewhat provide partial elucidation on the engagement of the respondents on emotion-focused coping.

Keywords: coping responses subtypes, appraisal, teacher stress, ideal and actual coping

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Authors: Ashleigh Williams

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Micro- and nanoplastics’ (MNLPs) omnipresence and ecological accumulation is evident when surveying recent environmental impact studies. For example, in 2014 it was estimated that at least 52.3 trillion plastic microparticles are floating at sea, and scientists have even found plastics present remote Arctic ice and snow (5,6). Plastics have even found their way into precipitation, with more than 1000 tons of microplastic rain precipitating onto the Western United States in 2020. Even more recent studies evaluating the chemical safety of reusable plastic bottles found that hundreds of chemicals leached into the control liquid in the bottle (ddH2O, ph = 7) during a 24-hour time period. A consequence of the increased abundance in plastic waste in the air, land, and water every year is the bioaccumulation of MNLPs in ecosystems and trophic niches of the animal food chain, which could potentially cause increased direct and indirect exposure of humans to MNLPs via inhalation, ingestion, and dermal contact. Though the detrimental, toxic effects of MNLPs have been established in marine biota, much less is known about the potentially hazardous health effects of chronic MNLP ingestion in humans. Recent data indicate that long-term exposure to MNLPs could cause possible inflammatory and dysbiotic effects. However, toxicity seems to be largely dose-, as well as size-dependent. In addition, the transcytotic uptake of MNLPs through the intestinal epithelia in humans remain relatively unknown. To this point, the goal of the current study was to investigate the mechanisms of micro- and nanoplastic uptake and transcytosis of Polystyrene (PE) in human stem-cell derived, physiologically relevant in vitro intestinal model systems, and to compare the relative effect of particle size (30 nm, 100 nm, 500 nm and 1 µm), and concentration (0 µg/mL, 250 µg/mL, 500 µg/mL, 1000 µg/mL) on polystyrene MNLP uptake, transcytosis and intestinal epithelial model integrity. Observational and quantitative data obtained from confocal microscopy, immunostaining, transepithelial electrical resistance (TEER) measurements, cryosectioning, and ELISA cytokine assays of the proinflammatory cytokines Interleukin-6 and Interleukin-8 were used to evaluate the localization and transcytosis of polystyrene MNPs and its impact on epithelial integrity in human-derived intestinal in vitro model systems. The effect of Microfold (M) cell induction on polystyrene micro- and nanoparticle (MNP) uptake, transcytosis, and potential inflammation was also assessed and compared to samples grown under standard conditions. Microfold (M) cells, link the human intestinal system to the immune system and are the primary cells in the epithelium responsible for sampling and transporting foreign matter of interest from the lumen of the gut to underlying immune cells. Given the uptake capabilities of Microfold cells to interact both specifically and nonspecific to abiotic and biotic materials, it was expected that M- cell induced in vitro samples would have increased binding, localization, and potentially transcytosis of Polystyrene MNLPs across the epithelial barrier. Experimental results of this study would not only help in the evaluation of the plastic toxicity, but would allow for more detailed modeling of gut inflammation and the intestinal immune system.

Keywords: nanoplastics, enteroids, intestinal barrier, tissue engineering, microfold (M) cells

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Authors: Shujun Xie, Shirong Zhang, Shenglin Ma

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Background: Chronic inflammation might lead to many malignancies, and inadequate resolution could play a crucial role in tumor invasion, progression, and metastases. A randomised, double-blind, placebo-controlled trial shows that IL-1β inhibition with canakinumab could reduce incident lung cancer and lung cancer mortality in patients with atherosclerosis. The process and secretion of proinflammatory cytokine IL-1β are controlled by the inflammasome. Here we showed the correlation of the innate immune system and afatinib, a tyrosine kinase inhibitor targeting epidermal growth factor receptor (EGFR) in non-small cell lung cancer. Methods: Murine Bone marrow derived macrophages (BMDMs), peritoneal macrophages (PMs) and THP-1 were used to check the effect of afatinib on the activation of NLRP3 inflammasome. The assembly of NLRP3 inflammasome was check by co-immunoprecipitation of NLRP3 and apoptosis-associated speck-like protein containing CARD (ASC), disuccinimidyl suberate (DSS)-cross link of ASC. Lipopolysaccharide (LPS)-induced sepsis and Alum-induced peritonitis were conducted to confirm that afatinib could inhibit the activation of NLRP3 in vivo. Peripheral blood mononuclear cells (PBMCs) from non-small cell lung cancer (NSCLC) patients before or after taking afatinib were used to check that afatinib inhibits inflammation in NSCLC therapy. Results: Our data showed that afatinib could inhibit the secretion of IL-1β in a dose-dependent manner in macrophage. Moreover, afatinib could inhibit the maturation of IL-1β and caspase-1 without affecting the precursors of IL-1β and caspase-1. Next, we found that afatinib could block the assembly of NLRP3 inflammasome and the ASC speck by blocking the interaction of the sensor protein NLRP3 and the adaptor protein ASC. We also found that afatinib was able to alleviate the LPS-induced sepsis in vivo. Conclusion: Our study found that afatinib could inhibit the activation of NLRP3 inflammasome in macrophage, providing new evidence that afatinib could target the innate immune system to control chronic inflammation. These investigations will provide significant experimental evidence in afatinib as therapeutic drug for non-small cell lung cancer or other tumors and NLRP3-related diseases and will explore new targets for afatinib.

Keywords: inflammasome, afatinib, inflammation, tyrosine kinase inhibitor

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Authors: Jessica P. Fiorotti, Maria C. Freitas, Caio J. B. Coutinho-Rodrigues, Mariana G. Camargo, Emily S. Mesquita, Amanda R. C. Corval, Ricardo O. B. Bitencourt, Allan F. Marciano, Diva D. Spadacci-Morena, Patricia S. Golo, Isabele C. Angelo, Vania R. E. P. Bittencourt

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The bovine tick, Rhipicephalus microplus, is an arthropod of great importance in veterinary medicine leading to anemia, weight loss, animals' leather depreciation and also acting as a vector of many pathogens. In this way, the parasitism causes a loss of 3.24 billion dollars per year in Brazil. Knowingly, entomopathogenic fungi act as natural controller of some arthropods, acting mainly by active penetration through the cuticle. However, it can also act on the hemolymph and through the production of mycotoxins. Hemocytes are responsible for the cellular immune response and participate in the processes of phagocytosis, nodulation and encapsulation and may undergo changes when challenged by pathogens. The aim of the present study was to evaluate changes in R. microplus hemocytes after inoculation of Metarhizium robertsii using transmission electron microscopy. The isolate ARSEF 2575 and 200 engorged R. microplus females were used. The groups were divided into control, in which the females were inoculated with 5 μL of sterile distilled water solution and 0.1% Tween 80, and a group inoculated with 5 μL of fungal suspension at the concentration of 10⁷ conidia mL⁻¹. The experiment was performed in duplicate and each group contained 50 females. Twenty-four hours after fungal inoculation, hemolymph was collected through the cuticle dorsal surface perforation of the tick females. After collection, the hemolymph samples were centrifuged at 500 x g for 3 minutes at 4 °C, the plasma was discarded and the hemocyte pellet was resuspended in 50 μl PBS. The suspension material was fixed in 2% glutaraldehyde in Millonig buffer for three hours. After fixation, the material was centrifuged at 500 x g for 3 minutes, the supernatant was discarded and the cells were resuspended in a wash solution. Subsequently, the cells were post-fixed with 1% osmium tetroxide in phosphate buffer for one hour at room temperature and dehydrated in increasing concentrations of ethanol, and then embedded in Epon resin. The ultrathin sections were examined under the LEO EM 906E transmission electron microscopy at 80kV. The ultrastructural results revealed that.in control group, the cells were considered intact, in which the granulocytes were observed with granules of different electrodensities, intact mitochondria and cytoplasm without vacuolization. In addition, granulocytes showed plasma membrane projections similar to pseudopodia. Plasmatocytes presented as irregularly shaped cells, with the eccentric nucleus, agranular cytoplasm and some cells presented pseudopodia. Nevertheless, in the group exposed to the fungus, most of the cells presented in degeneration. The granulocytes found had fewer granules in the cytoplasm and more vacuoles. Plasmatocytes, after treatment, presented many vacuoles also in the cytoplasm and the lysosomes presented great amount of electrodense material in their interior. Thus, the results suggest that the fungus has a depressant action in the immune system of the tick, not only by the cell degranulation, but also suggesting that this leads to morphological changes in the hemocytes and may even trigger processes such as phagocytosis.

Keywords: bovine tick, cellular defense, entomopathogenic fungi, immune response

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Authors: Philip Friedlander, John Rutledge, Jason Suh

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Inhibition of programmed death-1 (PD-1) or its ligand PD-L1 confers therapeutic efficacy in a wide range of solid tumor malignancies. Primary or acquired resistance can develop through activation of immunosuppressive immune cells such as tumor-associated macrophages. The renin angiotensin system (RAS) systemically regulates fluid and sodium hemodynamics, but components are expressed on and regulate the activity of immune cells, particularly of myeloid lineage. We hypothesized that inhibition of RAS would improve the efficacy of PD-1/PD-L-1 treatment. A retrospective analysis was performed through a chart review of patients with solid metastatic malignancies treated with a PD-1/PD-L1 inhibitor between 1/2013 and 6/2019 at Valley Hospital, a community hospital in New Jersey, USA. Efficacy was determined by medical oncologist documentation of clinical benefit in visit notes and by the duration of time on immunotherapy treatment. The primary endpoint was the determination of efficacy differences in patients treated with an inhibitor of RAS ( ace inhibitor, ACEi, or angiotensin blocker, ARB) compared to patients not treated with these inhibitors. To control for broader antihypertensive effects, efficacy as a function of treatment with beta blockers was assessed. 173 patients treated with PD-1/PD-L-1 inhibitors were identified of whom 52 were also treated with an ACEi or ARB. Chi-square testing revealed a statistically significant relationship between being on an ACEi or ARB and efficacy to PD-1/PD-L-1 therapy (p=0.001). No statistically significant relationship was seen between patients taking or not taking beta blocker antihypertensives (p= 0.33). Kaplan-Meier analysis showed statistically significant improvement in the duration of therapy favoring patients concomitantly treated with ACEi or ARB compared to patients not exposed to antihypertensives and to those treated with beta blockers. Logistic regression analysis revealed that age, gender, and cancer type did not have significant effects on the odds of experiencing clinical benefit (p=0.74, p=0.75, and p=0.81, respectively). We conclude that retrospective analysis of the treatment of patients with solid metastatic tumors with anti-PD-1/PD-L1 in a community setting demonstrates greater clinical benefit in the context of concomitant ACEi or ARB inhibition, irrespective of gender or age. This data supports the development of prospective assessment through randomized clinical trials.

Keywords: angiotensin, cancer, immunotherapy, PD-1, efficacy

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Authors: Akterono Budiyati, Gita Kusumo, Teguh Putra, Fritzie Rexana, Antonius Kurniawan, Aru Sudoyo, Ahmad Utomo, Andi Utama

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The presence of the programmed death ligand-1 (PD-L1) has been used in multiple clinical trials and approved as biomarker for selecting patients more likely to respond to immune checkpoint inhibitors. However, the expression of PD-L1 is regulated in different ways, which leads to a different significance of its presence. Positive PD-L1 within tumors may result from two mechanisms, induced PD-L1 expression by T-cell presence or genetic mechanism that lead to constitutive PD-L1 expression. Amplification of PD-L1 genes was found as one of genetic mechanism which causes an increase in PD-L1 expression. In case of colorectal cancer (CRC), targeting immune checkpoint inhibitor has been recommended for patients with microsatellite instable (MSI). Although the correlation between PD-L1 expression and MSI status has been widely studied, so far the precise mechanism of PD-L1 gene activation in CRC patients, particularly in MSI population have yet to be clarified. In this present study we have profiled 61 archived formalin fixed paraffin embedded CRC specimens of patients from Medistra Hospital, Jakarta admitted in 2010 - 2016. Immunohistochemistry was performed to measure expression of PD-L1 in tumor cells as well as MSI status using antibodies against PD-L1 and MMR (MLH1, MSH2, PMS2 and MSH6), respectively. PD-L1 expression was measured on tumor cells with cut off of 1% whereas loss of nuclear MMR protein expressions in tumor cells but not in normal or stromal cells indicated presence of MSI. Subset of PD-L1 positive patients was then assessed for copy number variations (CNVs) using single Tube TaqMan Copy Number Assays Gene CD247PD-L1. We also observed KRAS mutation to profile possible genetic mechanism leading to the presence or absence of PD-L1 expression. Analysis of 61 CRC patients revealed 15 patients (24%) expressed PD-L1 on their tumor cell membranes. The prevalence of surface membrane PD-L1 was significantly higher in patients with MSI (87%; 7/8) compared to patients with microsatellite stable (MSS) (15%; 8/53) (P=0.001). Although amplification of PD-L1 gene was not found among PD-L1 positive patients, low-level amplification of PD-L1 gene was commonly observed in MSS patients (75%; 6/8) than in MSI patients (43%; 3/7). Additionally, we found 26% of CRC patients harbored KRAS mutations (16/61), so far the distribution of KRAS status did not correlate with PD-L1 expression. Our data suggest genetic mechanism through amplification of PD-L1 seems not to be the mechanism underlying upregulation of PD-L1 expression in CRC patients. However, further studies are warranted to confirm the results.

Keywords: colorectal cancer, gene amplification, microsatellite instable, programmed death ligand-1

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Authors: Mustafa M. Donma, Orkide Donma

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A growing list of cancers might be influenced by obesity. Obesity is associated with an increased risk for the occurrence and development of some cancers. Inflammation can lead to cancer. It is one of the characteristic features of cancer and plays a critical role in cancer development. C-reactive protein (CRP) is under evaluation related to the new and simple prognostic factors in patients with metastatic renal cell cancer. Obesity can predict and promote systemic inflammation in healthy adults. BMI is correlated with hs-CRP. In this study, SII index and CRP values were evaluated in children with normal BMI and those within the range of different obesity grades to detect the tendency towards cancer in pediatric obesity. A total of one hundred and ninety-four children; thirty-five children with normal BMI, twenty overweight (OW), forty-seven obese (OB) and ninety-two morbid obese (MO) participated in the study. Age- and sex-matched groups were constituted using BMI-for age percentiles. Informed consent was obtained. Ethical Committee approval was taken. Weight, height, waist circumference (C), hip C, head C and neck C of the children were measured. The complete blood count test was performed. C-reactive protein analysis was performed. Statistical analyses were performed using SPSS. The degree for statistical significance was p≤0.05. SII index values were progressively increasing starting from normal weight (NW) to MO children. There is a statistically significant difference between NW and OB as well as MO children. No significant difference was observed between NW and OW children, however, a correlation was observed between NW and OW children. MO constitutes the only group, which exhibited a statistically significant correlation between SII index and CRP. Obesity-related bladder, kidney, cervical, liver, colorectal, endometrial cancers are still being investigated. Obesity, characterized as a chronic low-grade inflammation, is a crucial risk factor for colon cancer. Elevated childhood BMI values may be indicative of processes leading to cancer, initiated early in life. Prevention of childhood adiposity may decrease the cancer incidence in adults. To authors’ best knowledge, this study is the first to introduce SII index values during obesity of varying degrees of severity. It is suggested that this index seems to affect all stages of obesity with an increasing tendency and may point out the concomitant status of obesity and cancer starting from very early periods of life.

Keywords: children, C-reactive protein, systemic immune-inflammation index, obesity

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Authors: Michael Daly

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Background/Aims: The interplay of childhood self-control and early life social background in predicting adult health is currently unclear. We drew on rich data from two large nationally representative cohort studies to test whether individual differences in childhood self-control may: (i) buffer the health impact of social disadvantage, (ii) act as a mediating pathway underlying the emergence of health disparities, or (iii) compensate for the health consequences of socioeconomic disadvantage across the lifespan. Methods: We examined data from over 25,000 participants from the British Cohort Study (BCS) and the National Child Development Study (NCDS). Child self-control was teacher-rated at age 10 in the BCS and ages 7/11 in the NCDS. The Early life social disadvantage was indexed using measures of parental education, occupational prestige, and housing characteristics (i.e. housing tenure, home crowding). A range of health outcomes was examined: the presence of chronic conditions, whether illnesses were limiting, physiological dysregulation (gauged by clinical indicators), mortality, and perceptions of pain, psychological distress, and general health. Results: Childhood self-control and social disadvantage predicted each measure of adult health, with similar strength on average. An examination of mediating factors showed that adult smoking, obesity, and socioeconomic status explained the majority of these linkages. There was no systematic evidence that self-control moderated the health consequences of early social disadvantage and limited evidence that self-control acted as a key pathway from disadvantage to later health. Conclusions: Childhood self-control predicts adult health and may compensate for early life social disadvantage by shaping adult health behaviour and social status.

Keywords: personality and health, social disadvantage, health psychology, life-course development

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Authors: Filip Franciszek Karuga, Szymon Turkiewicz, Marta Ditmer, Marcin Sochal, Piotr Białasiewicz, Agata Gabryelska

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Circadian rhythm, an internal coordinator of physiological processes is composed of a set of semi-autonomous clocks. Clocks are regulated through the expression of circadian clock genes which form feedback loops, creating an oscillator. The primary loop consists of activators: CLOCK, BMAL1 and repressors: CRY, PER. CLOCK can be substituted by the Neuronal PAS Domain Protein 2 (NPAS2). Orphan nuclear receptor (REV-ERB-α) is a component of the secondary major loop, modulating the expression of BMAL1. Circadian clocks might be disrupted by the obstructive sleep apnea (OSA), which has also been associated with type II diabetes mellitus (DM2). Interestingly, studies suggest that dysregulation of NPAS2 and REV-ERB-α might contribute to the pathophysiology of DM2 as well. The goal of our study was to examine the role of NPAS2 and REV-ERB-α in DM2 in OSA patients. After examination of the clinical data, all participants underwent polysomnography (PSG) to assess their apnea-hypopnea index (AHI). Based on the acquired data participants were assigned to one of 3 groups: OSA (AHI>30, no DM2; n=17 for NPAS2 and 34 for REV-ERB-α), DM2 (AHI>30 + DM2; n=7 for NPAS2 and 15 for REV-ERB-α) and control group (AHI<5, no DM2; n=16 for NPAS2 and 31 for REV-ERB-α). ELISA immunoassay was performed to assess the serum protein level of REV-ERB-α and NPAS2. The only statistically significant difference between groups was observed in NPAS2 protein level (p=0.037). Post-hoc analysis showed significant differences between the OSA and the control group (p=0.017). AHI and NPAS2 level was significantly correlated (r=-0.478, p=0.002) in all groups. A significant correlation was observed between the REV-ERB-α level and sleep efficiency (r=0.617, p=0.005) as well as sleep maintenance efficiency (r=0.645, p=0.003) in the OSA group. We conclude, that NPAS2 is associated with OSA severity and might contribute to metabolic sequelae of this disease. REV-ERB-α on the other hand can influence sleep continuity and efficiency.

Keywords: OSA, diabetes mellitus, endocrinology, chronobiology

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Authors: Aminul Islam

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The issue of aging is now an emerging aspect of all over the world. Both the rural and urban societies of our country are not immune from this problem. This study mainly explored the influence of wealth on the enjoyment of role and status of the elderly in rural Bangladesh. It is based on empirical findings from the four villages of Gopalnagar union of Dhunat upazila of Bogra district. The study depicted that wealth has much influence regarding the enjoyment of role and status. Mixed approach has been given priority in this study. Survey, observation, case study and life history methods and focus group discussion technique have also been used in this study. Data have been collected from both primary and secondary sources. Simple random sampling procedure has also been followed in this study.

Keywords: wealth, role status, elderly

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Authors: Jung–Min Yang

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In this paper, fault recovery for parallel interconnected asynchronous sequential machines is studied. An adversarial input can infiltrate into one of two submachines comprising parallel composition of the considered asynchronous sequential machine, causing an unauthorized state transition. The control objective is to elucidate the condition for the existence of a corrective controller that makes the closed-loop system immune against any occurrence of adversarial inputs. In particular, an efficient existence condition is presented that does not need the complete modeling of the interconnected asynchronous sequential machine.

Keywords: asynchronous sequential machines, parallel composi-tion, corrective control, fault tolerance

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Authors: Bajraktarevic Adnan, Djukic Branka, Sporisevic Lutvo, Krdzalic Zecevic Belma, Uzicanin Sajra, Hadzimuratovic Admir, Hadzimuratovic Hadzipasic Emina, Abduzaimovic Alisa, Kustric Amer, Suljevic Ismet, Serafi Ismail, Tahmiscija Indira, Khatib Hakam, Semic Jusufagic Aida, Haas Helmut, Vladicic Aleksandra, Aplenc Richard, Kadic Deovic Aida

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Introduction: Joubert syndrome has an autosomal recessive pattern of inheritance. It is referred as the brain malfunctioning and caused due to the underdevelopment of the cerebellar vermis. Associated conditions involving the eye, the kidney, and ocular disease are well described. Aims: Research helps us better understand this diseases, Joubert syndrome and can lead to advances in diagnosis and treatment. Methods: Different several conditions have been described in which the molar tooth sign and characteristics of Joubert syndrome in ten different places in the world. Carrier testing and diagnosis are available if one of these gene mutations has been identified in an affected family member. Results: Authors have described eleven cases during twenty years of Joubert syndrome. It is a clinically and genetically heterogeneous group of disorders characterized by hypoplasia of the cerebellar vermis with the characteristic neuroradiologic molar tooth sign, and accompanying neurologic symptoms, including dysregulation of breathing pattern and developmental delay. We made confirmation of diagnosis in twin sisters with Joubert syndrome with renal anomalies. Ocular symptoms have existed in seven cases (63.64%) from total eleven. Eleven cases were different sex, five boys (45.45%) and six girls (54.44%). Conclusions: Joubert syndrome is inherited as an autosomal recessive genetic disorder with several features of the disease.

Keywords: Joubert syndrome, cerebellooculorenal syndrome, autosomal recessive genetic disorder (ARGD), children

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Authors: Shahla Afshar Paiman, Sedigheh Madani, Zahra Hosseininezhad

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Introduction: The most common causes of appendix luminal obstruction are fecaliths and lymphoid follicle hyperplasia. Appendicitis is a very rare Gastrointestinal complication of varicella zosterand it is mostly observed in immune-compromised patient. Case presentation: Here we reported a case of varicella zoster-related perforated appendicitis with synchronous encephalopathy as a first presentation of chickenpox in a 10-year-old boy. He had no history of immunodeficiency or predisposing factors and his diagnosis is confirmed by both serological lab tests and abdominal fluid (peritoneal secretion) PCR. Conclusion: Varicella zoster could cause appendicitis as first presentation, along with other critical complications look likes encephalopathy.

Keywords: Varicella zoster, appendicitis, encephalitis, children

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Authors: Martha Berg, Megan Ramaiya, Andi Schmidt, Susanna Sharma, Brandon Kohrt

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Nepali adolescents report tension and negative emotion due to perceived expectations of both academic and social achievement. These societal goals, which are internalized through early-life socialization, drive the development of self-regulatory processes such as emotion regulation. Emotion dysregulation is linked with adverse psychological outcomes such as depression, self-harm, and suicide, which are public health concerns for organizations working with Nepali adolescents. This study examined the relation among socialization, internalized cultural goals, and emotion regulation to inform interventions for reducing depression and suicide in this population. Participants included 102 students in grades 7 through 9 in a post-earthquake school setting in rural Kathmandu valley. All participants completed a tablet-based battery of quantitative measures, comprising transculturally adapted assessments of emotion regulation, depression, and self-harm/suicide ideation and behavior. Qualitative measures included two focus groups and semi-structured interviews with 22 students and 3 parents. A notable proportion of the sample reported depression symptoms in the past 2 weeks (68%), lifetime self-harm ideation (28%), and lifetime suicide attempts (13%). Students who lived with their nuclear family reported lower levels of difficulty than those who lived with more distant relatives (z=2.16, p=.03), which suggests a link between family environment and adolescent emotion regulation, potentially mediated by socialization and internalization of cultural goals. These findings call for further research into the aspects of nuclear versus extended family environments that shape the development of emotion regulation.

Keywords: adolescent mental health, emotion regulation, Nepal, socialization

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Authors: S. Buloyan, V. Mamikonyan, H. Hakobyan, H. Harutyunyan, H. Gasparyan

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The liver is the strongest regenerating organ of the organism, and even with 2/3 surgically removed, it can regenerate completely. Hence, liver cirrhosis may only develop when the regenerating system is off. We present the results of a comparative study of structural and functional characteristics of rat liver tissue under the conditions of toxic liver cirrhosis development, induced by carbon tetrachloride, and its prevention/treatment by natural compounds with antioxidant and immune stimulating action. Studies were made on Wister rats, weighing 120~140 g. Grape seeds extracts, separately and in combination with well known anticirrhotic drug ursodeoxycholic acid (ursodiol) have demonstrated effectiveness in prevention of liver cirrhosis development and its treatment.

Keywords: carbon tetrachloride, GSE, liver cirrhosis, prevention, treatment

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Authors: Marina Kljaković-Gašpić Batinjan, Tea Petrović, Frano Vučković, Irzal Hadžibegović, Barbara Radovani, Ivana Jurin, Lovorka Đerek, Eva Huljev, Alemka Markotić, Ivica Lukšić, Irena Trbojević-Akmačić, Gordan Lauc, Ivan Gudelj, Rok Čivljak

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Immunoglobulin G has essential role in defense against infectious diseases, but its role cannot be fully recognized without understanding of changes in its N-glycans attached to the Fc domain. We analyzed and compared total IgG glycome in plasma samples of patients with influenza, patients with COVID-19 and healthy controls. We found similarities in IgG glycosylation changes in COVID-19 survivors and influenza patients that could be the consequence of adequate immune response to enveloped viruses, while observed changes in deceased COVID-19 patients may indicate its deviation.

Keywords: COVID-19, glycosylation, immunoglobulin G, influenza, pneumonia, viral infection

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Authors: Valeria T. Dilcheva, Svetlozara L. Petkova, Ivelin Vladov

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Trichinellosis is a food-borne parasitic disease caused by nematodes of the genus Trichinella which are zoonotic parasites with cosmopolitan distribution and major socio-economic importance. Human infection is acquired through consumption of undercooked meat from domestic or wild animal. Penetration of Trichinella larvae into striated skeletal muscle cells results in ultrastructural and metabolic changes. Migration of larvae causes the typical symptoms and signs of the disease. The severity of the symptoms depends on the number of ingested Trichinella larvae and the immune response of the host. Eosinophilia is present, with few exceptions, in most cases of human trichinellosis, inasmuch as it is the earliest and most important host response. Even in human asymptomatic cases, increases in eosinophilia of up to 15% have been observed. Eosinophilia appears at an early stage of infection between the second and fifth weeks of infection. By 2005 it was considered that only two species of Trichinella genus were found in the country. After routine trichinelloscopy procedure disseminated single muscle larvae in samples of wild boars and badger were PCR-identified as T. pseudospiralis. The study aimed to observed hematological changes occurring during experimentally induced infection with Trichinella spiralis, T. britovi and T. pseudospiralis in mice. We performed hematological blood profile, tracking 15 blood indicators. In statistical analysis made by Two-way ANOVA, there were significant differences of HGB, MCHC, PLT, Lymph%, Gran% in all three types of trichinellosis compared to control animals. Capsule-forming T. spiralis showed statistically significant differences in HGB, MCHC, Lymph% and PLT compared to the other two species. Non capsule-forming T. pseudospiralis showed statistically significant differences in Lymph%, Gran% relative to the control and in Gran% relative to T. spiralis. It appears rather substantial the process of capsule formation for prolonged immune response and retention of high content of percentage of lymphocytes(Lymph%) and low of granulocyte(Gran%) in T. pseudospiralis, which is contrary to studies for T. spiralis and eosinophilia. Studies and analyzes of some specific blood profile parameters can provide additional data in favor of early diagnosis and adequate treatment as well as provide a better understanding of acute and chronic trichinosis.

Keywords: hematological test, T. britovi, T. spiralis, T. pseudospiralis

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Authors: Emma Plante, Charles Ekwunwa, Diego Illanes

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Introduction: Serum Sickness-Like Reaction (SSLR) is an inflammatory immune response characterized by a rash, polyarthralgias, and fever. SSLR usually occurs in response to a new medication (most commonly antibiotics, anticonvulsants, or antiinflammatory agents) and is believed to involve the formation of drug-specific immune complexes. Here we present a case of a 16-year-old female patient who developed an SSLR in response to the D-mannose-containing over-the-counter supplement, Uqora, used to promote bladder health. Methodology: The methodology for this study included a thorough literature search for other cases of SSLR associated with D-Mannose containing products. Data collection was performed through a review of the patient’s medical record, including history, physical examination, relevant laboratory results, and treatment plan. Findings: A 16-year-old female with a history of overactive bladder and anemia presented with a diffuse urticarial rash, headaches, joint pain, and swelling for three days. Her medications included oral contraceptive pills, iron, mirabegron, UQora, and a probiotic. Physical examination revealed a diffuse urticarial rash, and her musculoskeletal exam revealed swelling and tenderness in her wrists. Her CBC, basic metabolic panel, liver function panel, lyme titers, and urinalysis were all within normal limits. The patient was referred to an allergist, who diagnosed her with SSLR. All medications were discontinued, and she was treated with a 7-day course of prednisone and cetirizine. Her symptoms resolved, and her medications were slowly resumed sequentially over several months. However, UQora triggered a recurrence of her symptoms, and it was identified as the culprit medication. Consequently, UQora was permanently discontinued, and the patient has remained symptom-free. Conclusion: This case report describes the first documented case of SSLR caused by UQora (active ingredient D-mannose). D-Mannose is a monosaccharide found in many plants and fruits, and it is commonly used to prevent urinary tract infections. While the clinical features and timeline, in this case, were typical of SSLR, UQora as the trigger was highly unusual. Clinicians should be aware of the diverse triggers of SSLR and the importance of prompt identification and management to enhance patient safety. It is possible D-mannose was not the trigger, and further research is necessary to better understand the potential therapeutic applications of D-mannose, as well as the potential risks and interactions.

Keywords: serum sickness-like reaction, d-mannose, hypersensitivity reaction, urticaria

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Authors: Abbas Pourreza

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MicroRNAs (miRNAs) are small single-stranded non-coding RNAs. They are almost 18-25 nucleotides long and very conservative through evolution. They are involved in adjusting the expression of numerous genes due to the existence of a complementary region, generally in the 3' untranslated regions (UTR) of target genes, against particular mRNAs in the cell. Also, miRNAs have been proven to be involved in cell development, differentiation, proliferation, and apoptosis. More than 2000 miRNAs have been recognized in human cells, and these miRNAs adjust approximately one-third of all genes in human cells. Dysregulation of miRNA originated from abnormal DNA methylation patterns of the locus, cause to down-regulated or overexpression of miRNAs, and it may affect tumor formation or development of it. Breast cancer (BC) is the most commonly identified cancer, the most prevalent cancer (23%), and the second-leading (14%) mortality in all types of cancer in females. BC can be classified based on the status (+/−) of the hormone receptors, including estrogen receptor (ER), progesterone receptor (PR), and the Receptor tyrosine-protein kinase erbB-2 (ERBB2 or HER2). Currently, there are four main molecular subtypes of BC: luminal A, approximately 50–60 % of BCs; luminal B, 10–20 %; HER2 positive, 15–20 %, and 10–20 % considered Basal (triple-negative breast cancer (TNBC)) subtype. Aberrant expression of miR-145, miR-21, miR-10b, miR-125a, and miR-206 was detected by Stem-loop real-time RT-PCR in BC cases. Breast tumor formation and development may result from down-regulation of a tumor suppressor miRNA such as miR-145, miR-125a, and miR-206 and/or overexpression of an oncogenic miRNA such as miR-21 and miR-10b. MiR-125a, miR-206, miR-145, miR-21, and miR-10b are hugely predicted to be new tumor markers for the diagnosis and prognosis of BC. MiR-21 and miR-125a could play a part in the treatment of HER-2-positive breast cancer cells, while miR-145 and miR-206 could speed up the evolution of cure techniques for TNBC. To conclude, miRNAs will be presented as hopeful molecules to be used in the primary diagnosis, prognosis, and treatment of BC and battle as opposed to its developed drug resistance.

Keywords: breast cancer, HER2 positive, miRNA, TNBC

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Authors: Mohammad Asadpour

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Cryptosporidium spp. is zoonotic pathogens transmissible from a variety of animals to humans and is a considerable public health concern. Calves have been identified in numerous reports as a major source of environmental contamination with this pathogen. Parasite has a different species that are the cases of zoonotic disease in immunodeficient people and neonatal calves. Cryptosporidium oocysts are extremely resistant to chlorine and other physical cases that commonly used in drinking water. Reproduction of resistant oocytes is a way for this monoxenous parasite to remain in the environment. Cryptosporidium parvum is the most important species that has human and cattle genotypes. Cryptosporidium is one of the most important causes of diarrhea in neonatal calves and also, one of the four causes of diarrhea symptoms in pre-weaned calves. Because of the incompetent immune system in calves, Cryptosporidium infection is the cause of a lot of problems in raising farms.

Keywords: Cryptosporidium spp, dairy calves, importance, veterinary medicine

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Authors: Shraddha Rane, Richard Warren, Stephen Eyre

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L-23 is a pro-inflammatory molecule that signals T cells to release cytokines such as IL-17A and IL-22. Psoriasis is driven by a dysregulated immune response, within which IL-23 is now thought to play a key role. Genome-wide association studies (GWAS) have identified a number of genetic risk loci that support the involvement of IL-23 signalling in psoriasis; in particular a robust susceptibility locus at a gene encoding a subunit of the IL-23 receptor (IL23R) (Stuart et al., 2015; Tsoi et al., 2012). The lead psoriasis-associated SNP rs9988642 is located approximately 500 bp downstream of IL23R but is in tight linkage disequilibrium (LD) with a missense SNP rs11209026 (R381Q) within IL23R (r2 = 0.85). The minor (G) allele of rs11209026 is present in approximately 7% of the population and is protective for psoriasis and several other autoimmune diseases including IBD, ankylosing spondylitis, RA and asthma. The psoriasis-associated missense SNP R381Q causes an arginine to glutamine substitution in a region of the IL23R protein between the transmembrane domain and the putative JAK2 binding site in the cytoplasmic portion. This substitution is expected to affect the receptor’s surface localisation or signalling ability, rather than IL23R expression. Recent studies have also identified a psoriatic arthritis (PsA)-specific signal at IL23R; thought to be independent from the psoriasis association (Bowes et al., 2015; Budu-Aggrey et al., 2016). The lead PsA-associated SNP rs12044149 is intronic to IL23R and is in LD with likely causal SNPs intersecting promoter and enhancer marks in memory CD8+ T cells (Budu-Aggrey et al., 2016). It is therefore likely that the PsA-specific SNPs affect IL23R function via a different mechanism compared with the psoriasis-specific SNPs. It could be hypothesised that the risk allele for PsA located within the IL23R promoter causes an increase IL23R expression, relative to the protective allele. An increased expression of IL23R might then lead to an exaggerated immune response. The independent genetic signals identified for psoriasis and PsA in this locus indicate that different mechanisms underlie these two conditions; although likely both affecting the function of IL23R. It is very important to further characterise these mechanisms in order to better understand how the IL-23 receptor and its downstream signalling is affected in both diseases. This will help to determine how psoriasis and PsA patients might differentially respond to therapies, particularly IL-23 biologics. To investigate this further we have developed an in vitro model using CD4 T cells which express either wild type IL23R and IL12Rβ1 or mutant IL23R (R381Q) and IL12Rβ1. Model expressing different isotypes of IL23R is also underway to investigate the effects on IL23R expression. We propose to further investigate the variants for Ps and PsA and characterise key intracellular processes related to the variants.

Keywords: IL23R, psoriasis, psoriatic arthritis, SNP

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