Search results for: therapeutic embolization

Authors: Michio Kurosu

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Alterations in glycosylation not only directly impact cell growth and survival but also facilitate tumor-induced immunomodulation and eventual metastasis. Identification of cell type-specific glycoconjugates (tumor markers) has led to the discovery of new assay systems for certain cancers via immunodetection reagents. N- and O-linked glycans are the most abundant forms of glycoproteins. Recent studies of cancer immunotherapy are based on the immunogenicity of truncated O-glycan chains (e.g., Tn, sTn, T, and sLea/x). The prevalence of N-linked glycan changes in the development of tumor cells is known; however, therapeutic antibodies against N-glycans have not yet been developed. This is due to the lack of specificity of N-linked glycans between normal/healthy and cancer cells. Abnormal branching of N-linked glycans has been observed, particularly in solid cancer cells. While the discovery of drug-like glycosyltransferase inhibitors that block the biosynthesis of specific branching has a very low likelihood of success, altered glycosylation levels can be exploited by suppressing N-glycan biosynthesis through the inhibition of dolichyl-phosphate N-acetylglucosaminephosphotransferase1 (DPAGT1) activity. Inhibition of DPAGT1 function leads to changes of O-glycosylation on proteins associated with mitochondria and zinc finger binding proteins (indirect effects). On the basis of dynamic crosstalk between DPAGT1 and Snail/Slung/ZEB1 (a family of transcription factors that promote the repression of the adhesion molecules), we have developed pharmacologically acceptable selective DPAGT1 inhibitors. Tunicamycin kills a wide range of cancer and healthy cells in a non-selective manner. In sharp contrast, our DPAGT1 inhibitors display strong cytostatic effects against 16 solid cancers, which require the overexpression of DPAGT1 in their progression but do not affect the cell viability of healthy cells. The identified DPAGT1 inhibitors possess impressive anti-metastatic ability in various solid cancer cell lines and induce their mitochondrial structural changes, resulting in apoptosis. A prototype DPAGT1 inhibitor, APPB has already been proven to shrink solid tumors (e.g., pancreatic cancers, triple-negative breast cancers) in vivo while suppressing metastases and has strong synergistic effects when combined with current cytotoxic drugs (e.g., paclitaxel). At this conference, our discovery of selective DPAGT1 inhibitors with drug-like properties and proof-of-pharmaceutical concept studies of a novel DPAGT1 inhibitor are presented.

Keywords: DPAGT1 inhibitors, anti-metastatic drugs, natural product based drug designs, cytostatic effects

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Authors: Shao-Ying Wang, Shin-I Shih, Chi-Cheng Wu

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Background: By following to the maturity theory about age, the manifestation of depression in different age groups under occupational stressors still remains unclear. Therefore, the aim of this study was to examine the depression within four main symptoms clusters: cognition, affect, physical complaints and interpersonal difficulty among the different age groups. Additionally, this study also used the stress appraisal theory, through the examination of challenge and hindrance appraisals, the effects of cognitive factors were expected to give therapeutic indication for the future treatment of depression under abusive leadership. Methods (Participants and Procedure): The data were collected in two waves from employees of local companies in Taiwan. The participants (58 males and 167 females) were native Chinese speakers, ranging in age from 20 to 59 years (M= 36.51). Up to 80% educational level of participants were above senior high. The married population was approximately at 43%. Measures; 1. Abusive Leadership: To measure abusive leadership, we used 15-item scale of abusive supervision which anchored on a 7-point Likert-type scale. (α= .96) 2. Depression: We used Taiwanese Depression Scale to measure the 4 clusters (cognition, affect, physical complaints and interpersonal difficulty) of symptoms. Participants responded for depression anchored on a 7-point Likert-type scale (α= .96). 3. Stress Appraisal Scale: To measure challenge and hindrance types of appraisal, participants responded to 33-item measure anchored on a 7-point Likert-type scale. (Challenge appraisal; α= .90; hindrance appraisal α= .87). Results: The results of correlation showed that there was a significant and negative correlation between abusive leadership and age (r = - .21, p < .01). Abusive leadership was positive correlated significantly with hindrance appraisal (r = .52, p < .01) and depression (r = .20, p < .01). The results also showed that hindrance appraisal was correlated to depression positively (r = .36, p < .01). A one-way ANOVA was conducted to compare the effect of lower/middle/order age groups on each cluster of depressive symptoms. The results showed that the effect of age groups on cognition was significant F (2, 157) =3.66, P < .05. Older age group (M=13.43 SD=6.84) reported less cognitive symptoms of depression than the middle (M=16.77 SD=7.49) and lower age (M=16.91 SD=6.97) groups. Besides, the effect of age groups on affect was also significant F (2,157)= 4.09 P < .05. Older age group (M=18.68 SD=8.98) reported less affective symptoms of depression than the middle (M=22.01 SD=7.96) and lower age (M=23.56 SD=7.67) groups. Moreover, the main effect of hindrance appraisal was found F (2, 157) =3.81, P < .05. Older age group (M=9.44 SD=2.89) reported fewer score on hindrance appraisals than the middle (M=11.06 SD=4.02) and lower age (M=9.62 SD=3.17) groups. To conclude, the severity of depression symptoms varies across different age groups. Maturity seems to be the protective factor to depression, accompanying with lower hindrance appraisals.

Keywords: abusive leadership, affective commitment, depression symptoms, psychological well-being

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Authors: Yihenew Simegniew Birhan, Hsieh Chih Tsai

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The recent advancements in synthetic chemistry and nanotechnology fostered the development of different nanocarriers for enhanced intracellular delivery of pharmaceutical agents to tumor cells. Polymeric micelles (PMs), characterized by small size, appreciable drug loading capacity (DLC), better accumulation in tumor tissue via enhanced permeability and retention (EPR) effect, and the ability to avoid detection and subsequent clearance by the mononuclear phagocyte (MNP) system, are convenient to improve the poor solubility, slow absorption and non-selective biodistribution of payloads embedded in their hydrophobic cores and hence, enhance the therapeutic efficacy of chemotherapeutic agents. Recently, redox-responsive polymeric micelles have gained significant attention for the delivery and controlled release of anticancer drugs in tumor cells. In this study, we synthesized redox-responsive diselenide bond containing amphiphilic polymer, Bi(mPEG-PLGA)-Se₂ from mPEG-PLGA, and 3,3'-diselanediyldipropanoic acid (DSeDPA) using DCC/DMAP as coupling agents. The successful synthesis of the copolymers was verified by different spectroscopic techniques. Above the critical micelle concentration, the amphiphilic copolymer, Bi(mPEG-PLGA)-Se₂, self-assembled into stable micelles. The DLS data indicated that the hydrodynamic diameter of the micelles (123.9 ± 0.85 nm) was suitable for extravasation into the tumor cells through the EPR effect. The drug loading content (DLC) and encapsulation efficiency (EE) of DOX-loaded micelles were found to be 6.61 wt% and 54.9%, respectively. The DOX-loaded micelles showed initial burst release accompanied by sustained release trend where 73.94% and 69.54% of encapsulated DOX was released upon treatment with 6mM GSH and 0.1% H₂O₂, respectively. The biocompatible nature of Bi(mPEG-PLGA)-Se₂ copolymer was confirmed by the cell viability study. In addition, the DOX-loaded micelles exhibited significant inhibition against HeLa cells (44.46%), at a maximum dose of 7.5 µg/mL. The fluorescent microscope images of HeLa cells treated with 3 µg/mL (equivalent DOX concentration) revealed efficient internalization and accumulation of DOX-loaded Bi(mPEG-PLGA)-Se₂ micelles in the cytosol of cancer cells. In conclusion, the intelligent, biocompatible, and the redox stimuli-responsive behavior of Bi(mPEG-PLGA)-Se₂ copolymer marked the potential applications of diselenide-linked mPEG-PLGA micelles for the delivery and on-demand release of chemotherapeutic agents in cancer cells.

Keywords: anticancer drug delivery, diselenide bond, polymeric micelles, redox-responsive

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Authors: R. Zhankina, U. Zhanbyrbekuly, A. Tamadon, M. Askarov, R. Sherkhanov, D. Akhmetov, D. Saipiyeva, N. Keulimzhaev

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Male infertility affects about 15% of couples of reproductive age. Approximately 10–15% have azoospermia who have previously been diagnosed with male infertility. Azoospermia is regarded as the absence of spermatozoa in the ejaculate and is found in 10-15% of infertile men. Non-obstructive azoospermia is considered a cause of male infertility that is not amenable to drug therapy. Patients with non-obstructive azoospermia are unable to have their "own" children and have only options for adoption or use of donor sperm. Advances in assisted reproductive technologies such as intracytoplasmic sperm injection in vitro fertilization have significantly changed the management of patients with non-obstructive azoospermia. Advances in biotechnology have increased the options for treating patients with non-obstructive azoospermia. Mesenchymal stem cell therapy has been recognized as a new option for infertility treatment. Material and methods of the study: After obtaining informed consent, 5 patients diagnosed with non-obstructive azoospermia were included in an open, non-randomized study. The age of the patients ranged from 24 to 35 years. The examination was carried out before the start of treatment, which included biochemical blood tests, hormonal profile levels (luteinizing hormone, follicle-stimulating hormone, testosterone, prolactin, inhibin B); tests for tumor markers; genetic research. All studies were carried out in compliance with the requirements of Protocol No. 8 dated 06/09/20, approved by the Local Ethical Commission of NJSC "Astana Medical University". The control examination of patients was carried out after 6 months, by re-taking the program and hormonal profile (testosterone, luteinizing hormone, follicle-stimulating hormone, prolactin, inhibin B). Before micro-TESE of the testis, all 5 patients underwent myeloexfusion in the operating room. During the micro-TESE, autotransplantation of mesenchymal stem cells into the testicular network, previously cultured in a cell technology laboratory for 2 weeks, was performed. Results of the study: in all patients, the levels of total testosterone increased, the level of follicle-stimulating hormone decreased, the levels of luteinizing hormone returned to normal, the level of inhibin B increased. IVF with a positive result; another patient (20%) had spermatogenesis cells. Non-obstructive azoospermia and mesenchymal stem cells Conclusions: The positive results of this work serve as the basis for the application of a new cellular therapeutic approach for the treatment of non-obstructive azoospermia using mesenchymal stem cells.

Keywords: cell therapy, regenerative medicine, male infertility, mesenchymal stem cells

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Authors: Gizaw Mamo Gebeyehu, Marianna Pap, Geza Makkai, Tibor Z. Janosi, Shima Rashidian, Tibor A. Rauch

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Sepsis poses a significant global health threat, necessitating extensive exploration of indicators tied to its pathological mechanisms and multi-organ dysfunction. While murine studies have shed light on sepsis, the intricate cellular and molecular landscape in human sepsis remains enigmatic. Exploring the influence of activated monocyte-derived exosomes in sepsis sheds light on a promising pathway for understanding the intricate cellular and molecular mechanisms involved in this condition in humans. In sepsis, exosome-borne mRNA and miRNA orchestrate immune response gene expression in recipient cells. Yet, the specifics of exosome-mediated cell-to-cell communication, especially how mRNA cargoes modulate gene expression in recipient cells, remain poorly understood. This study aims to elucidate the precise molecular pathways through which exosomal mRNA cargo, particularly MAFB, contributes to the developing sepsis-induced molecular aberrations in liver tissues, employing rigorously defined cell culture conditions. THP-1 cells were treated with LPS to induce changes in exosomal RNA profiles. Exosomes were isolated and characterized using microscopy and mass spectrometry. RNA was extracted from exosomes and sequenced. The most abundant exosomal mRNAs were subjected to GO analysis for functional annotation analysis and KEGG database analysis to identify the involved enriched pathways. PCR (Polymerase Chain Reaction), RNA sequencing, and Western blotting were involved to analyze changes in gene expression, protein levels, and signaling pathways within the liver cells( HepG2) after exposure to exosomal MAFB. This study pinpoints exosomal MAFB as a potential key regulator linked to liver cell damage during sepsis, along with associated genes (miR155HG, H3F3A, and possibly JARD2) forming a crucial molecular pathway contributing to liver cell injury, Together, these elements indicate a vital molecular pathway that plays a significant role in the emergence of liver cell injury during sepsis.. These findings suggest the importance of further research on these components for potential therapeutic interventions in managing acute liver damage in sepsis.

Keywords: sepsis, exososome, exosomal MAFB, LPS-induced THP-1 cells, RNA profiles, sepsis-triggered liver injury

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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: Randa M. T. Mohamed

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Spices have long been used as traditional ingredients in the kitchen for seasoning, coloring, aromatic and food preservative properties. Besides, spices are equally used for therapeutic purposes. The objective of this study was to survey and document the medicinal properties of spices commonly used in the Sudanese kitchen for different food preparations. Also, extracts from reported spices were screened for the presence of secondary metabolites as well as their antioxidant and beta-lactamase inhibitory properties. This study was conducted in the Rekabbya Quartier in Omdurman, Khartoum State, Sudan. Information was collected by carrying out semi-structured interviews. All informants (30) in the present study were women. Spices were purchased from Attareen shop in Omdurman. Essential oils from spices were extracted by hydrodistillation and ethanolic extracts by maceration. Phytochemical screening was performed by thin layer chromatography (TLC). The antioxidant capacity of essential oils and ethanolic extracts was investigated through TLC bioautography. Beta lactamase inhibitory activity was performed by the acidimetric test. Ethnobotany study showed that a total of 16 spices were found to treat 36 ailments belonging to 10 categories. The most frequently claimed medicinal uses were for the digestive system diseases treated by 14 spices and respiratory system diseases treated by 8 spices. Gynaecological problems were treated by 4 spices. Dermatological diseases were cured by 5 spices while infections caused by tapeworms and other microbes causing dysentery were treated by 3 spices. 4 spices were used to treat bad breath, bleeding gum and toothache. Headache, eyes infection, cardiac stimulation and epilepsy were treated by one spice each. Other health problem like fatigue and loss of appetite and low breast milk production were treated by 1, 3 and 2 spices respectively. The majority (69%, 11/16) of spices were exported from different countries like India, China, Indonesia, Ethiopia, Egypt and Nigeria while 31% (5/16) was cultivated in Sudan. Essential oils of all spices were rich in terpenes while ethanolic extracts contained variable classes of secondary metabolites. Both essential oils and ethanolic extracts of all spices exerted considerable antioxidant activity. Only one extract, Syzygium aromaticum, possessed beta lactamase inhibitory activity. In conclusion, this study could contribute in conserving information on traditional medicinal uses of spices in Sudan. Also, the results demonstrated the potential of some of these spices to exert beneficial antimicrobial and antioxidant effect. Detailed phytochemical and biological assays of these spices are recommended.

Keywords: spices, ethnobotany, phytoconstituents, antioxidant, beta lactamase inhibition

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Authors: Beom-Seok Ko, Yoo-Seok Kim, Woo-Sung Lim, Ku-Sang Kim, Hyun-Ah Kim, Jin-Sun Lee, An-Bok Lee, Jin-Gu Bong, Tae-Hyun Kim, Sei-Hyun Ahn

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Background: Breast conserving surgery (BCS) followed by radiation therapy is today standard therapy for early breast cancer. It is safe therapeutic procedure in early breast cancers, because it provides the same level of overall survival as mastectomy. There are a number of different types of incisions used to BCS. Avoiding scars on the breast is women’s desire. Numerous minimal approaches have evolved due to this concern. Periareolar incision is often used when the small tumor relatively close to the nipple. But periareolar incision has a disadvantages include limited exposure of the surgical field. In plastic surgery, various methods such as zigzag incisions have been recommended to achieve satisfactory esthetic results. Periareolar zigzag incision has the advantage of not only good surgical field but also contributed to better surgical scars. The purpose of this study was to evaluate the oncological safety of procedures by studying the status of the surgical margins of the excised tumor specimen and reduces the need for further surgery. Methods: Between January 2016 and September 2016, 148 women with breast cancer underwent BCS or mastectomy by the same surgeon in ASAN medical center. Patients with exclusion criteria were excluded from this study if they had a bilateral breast cancer or underwent resection of the other tumors or taken axillary dissection or performed other incision methods. Periareolar zigzag incision was performed and excision margins of the specimen were identified frozen sections and paraffin-embedded or permanent sections in all patients in this study. We retrospectively analyzed tumor characteristics, the operative time, size of specimen, the distance from the tumor to nipple. Results: A total of 148 patients were reviewed, 72 included in the final analysis, 76 excluded. The mean age of the patients was 52.6 (range 25-19 years), median tumor size was 1.6 cm (range, 0.2-8.8), median tumor distance from the nipple was 4.0 cm (range, 1.0-9.0), median excised specimen sized was 5.1 cm (range, 2.8-15.0), median operation time was 70.0 minute (range, 39-138). All patients were discharged with no sign of infection or skin necrosis. Free resection margin was confirmed by frozen biopsy and permanent biopsy in all samples. There were no patients underwent reoperation. Conclusions: We suggest that periareolar zigzag incision can provide a good surgical field to remove a relatively large tumor and may provide cosmetically good outcomes.

Keywords: periareolar zigzag incision, breast conserving surgery, breast cancer, resection margin

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Authors: Danni Cheng

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Background: Preclinical and epidemiological studies have reported potential protective effects of low-density lipoprotein cholesterol (LDL-C) lowering drugs on head and neck squamous cell cancer (HNSCC) survival, but the causality was not consistent. Genetic variants associated with LDL-C lowering drug targets can predict the effects of their therapeutic inhibition on disease outcomes. Objective: We aimed to evaluate the causal association of genetically proxied cholesterol-lowering drug targets and circulating lipid traits with cancer survival in HNSCC patients stratified by human papillomavirus (HPV) status using two-sample Mendelian randomization (MR) analyses. Method: Single-nucleotide polymorphisms (SNPs) in gene region of LDL-C lowering drug targets (HMGCR, NPC1L1, CETP, PCSK9, and LDLR) associated with LDL-C levels in genome-wide association study (GWAS) from the Global Lipids Genetics Consortium (GLGC) were used to proxy LDL-C lowering drug action. SNPs proxy circulating lipids (LDL-C, HDL-C, total cholesterol, triglycerides, apoprotein A and apoprotein B) were also derived from the GLGC data. Genetic associations of these SNPs and cancer survivals were derived from 1,120 HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) and 2,570 non-HPV-driven HNSCC patients in VOYAGER program. We estimated the causal associations of LDL-C lowering drugs and circulating lipids with HNSCC survival using the inverse-variance weighted method. Results: Genetically proxied HMGCR inhibition was significantly associated with worse overall survival (OS) in non-HPV-drive HNSCC patients (inverse variance-weighted hazard ratio (HR IVW), 2.64[95%CI,1.28-5.43]; P = 0.01) but better OS in HPV-positive OPSCC patients (HR IVW,0.11[95%CI,0.02-0.56]; P = 0.01). Estimates for NPC1L1 were strongly associated with worse OS in both total HNSCC (HR IVW,4.17[95%CI,1.06-16.36]; P = 0.04) and non-HPV-driven HNSCC patients (HR IVW,7.33[95%CI,1.63-32.97]; P = 0.01). A similar result was found that genetically proxied PSCK9 inhibitors were significantly associated with poor OS in non-HPV-driven HNSCC (HR IVW,1.56[95%CI,1.02 to 2.39]). Conclusion: Genetically proxied long-term HMGCR inhibition was significantly associated with decreased OS in non-HPV-driven HNSCC and increased OS in HPV-positive OPSCC. While genetically proxied NPC1L1 and PCSK9 had associations with worse OS in total and non-HPV-driven HNSCC patients. Further research is needed to understand whether these drugs have consistent associations with head and neck tumor outcomes.

Keywords: Mendelian randomization analysis, head and neck cancer, cancer survival, cholesterol, statin

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Authors: Christopher R. Triggle, Hong Ding, Khaled Machaca, Gnanapragasam Arunachalam

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The antidiabetic drug, metformin, has been in clinical use for over 50 years and remains the first choice drug for the treatment of type two diabetes. In addition to its effectiveness as an oral anti-hyperglycaemic drug metformin also possesses vasculoprotective effects that are assumed to be secondary to its ability to reduce insulin resistance and control glycated hemoglobin levels; however, recent data from our laboratory indicate that metformin also has direct vasoprotective effects that are mediated, at least in part, via the anti-ageing gene, SIRT1. Diabetes is a major risk factor for the development of cardiovascular disease (CVD) and it is also well established that tobacco use further enhances the risk of CVD; however, it is not known whether treatment with metformin can offset the negative effects of diabetes and tobacco use on cardiac function. The current study was therefore designed to investigate 1: the effects of hyperglycaemia (HG) either alone or in the presence of elevated fatty acids (palmitate) and nicotine on the protein expression levels of the deacetylase sirtuin 1 (the protein product of SIRT1), anti-apoptotic Bcl-2, pro-apoptotic BIM and the pro-apoptotic, tumour suppressor protein, acetylated p53 in cardiomyocytes. 2: the ability of metformin to prevent the detrimental effects of HG, palmitate and nicotine on cardiomyocyte survival. Cell culture protocols were designed using a rat cardiomyocyte cell line, H9c2, either under normal glycaemic (NG) conditions of 5.5mM glucose, or hyperglycaemic conditions (HG) of 25mM glucose with, or without, added palmitate (250μM) or nicotine (1.0mM) for 24h. Immuno-blotting was used to detect the expression of sirtuin 1, Bcl-2, BIM, acetylated (Ac)-p53, p53 with β-actin used as the reference protein. Exposure to HG, palmitate, or nicotine alone significantly reduced expression of sirtuin1, Bcl-2 and raised the expression levels of acetylated p53 and BIM; however, the combination of HG, palmitate and nicotine had a synergistic effect to significantly suppress the expression levels of sirtuin 1 and Bcl-2, but further enhanced the expression of Ac-p53, and BIM. The inclusion of 1000μM, but not 50μM, metformin in the H9c2 cell culture protocol prevented the effects of HG, palmitate and nicotine on the pro-apoptotic pathways. Collectively these data indicate that metformin, in addition to its anti-hyperglycaemic and vasculoprotective properties, also has direct cardioprotective actions that offset the negative effects of hyerglycaemia, elevated free fatty acids and nicotine on cardiac cell survival. These data are of particular significance for the treatment of patients with diabetes who are also smokers as the inclusion of metformin in their therapeutic treatment plan should help reduce cardiac-related morbidity and mortality.

Keywords: apoptosis, cardiac muscle, diabetes, metformin, nicotine

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Authors: Anjali Roy, Mirza S. Baig

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Atherosclerosis is a chronic inflammatory disease characterized by the formation of lipid rich plaque enriched with necrotic core, modified lipid accumulation, smooth muscle cells, endothelial cells, leucocytes and macrophages. Macrophage foam cells play a critical role in the occurrence and development of inflammatory atherosclerotic plaque. Foam cells are the fat-laden macrophages in the initial stage atherosclerotic lesion formation. Foam cells are an indication of plaque build-up, or atherosclerosis, which is commonly associated with increased risk of heart attack and stroke as a result of arterial narrowing and hardening. The mechanisms that drive atherosclerotic plaque progression remain largely unknown. Dissecting the molecular mechanism involved in process of macrophage foam cell formation will help to develop therapeutic interventions for atherosclerosis. To investigate the mechanism, we studied the role of nitric oxide synthase 1(NOS1)-mediated nitric oxide (NO) on low-density lipoprotein (LDL) uptake by bone marrow derived macrophages (BMDM). Using confocal microscopy, we found that incubation of macrophages with NOS1 inhibitor, TRIM (1-(2-Trifluoromethylphenyl) imidazole) or L-NAME (N omega-nitro-L-arginine methyl ester) prior to LDL treatment significantly reduces the LDL uptake by BMDM. Further, addition of NO donor (DEA NONOate) in NOS1 inhibitor treated macrophages recovers the LDL uptake. Our data strongly suggest that NOS1 derived NO regulates LDL uptake by macrophages and foam cell formation. Moreover, we also checked proinflammatory cytokine mRNA expression through real time PCR in BMDM treated with LDL and copper oxidized LDL (OxLDL) in presences and absences of inhibitor. Normal LDL does not evoke cytokine expression whereas OxLDL induced proinflammatory cytokine expression which significantly reduced in presences of NOS1 inhibitor. Rapid NOS-1-derived NO and its stable derivative formation act as signaling agents for inducible NOS-2 expression in endothelial cells, leading to endothelial vascular wall lining disruption and dysfunctioning. This study highlights the role of NOS1 as critical players of foam cell formation and would reveal much about the key molecular proteins involved in atherosclerosis. Thus, targeting NOS1 would be a useful strategy in reducing LDL uptake by macrophages at early stage of disease and hence dampening the atherosclerosis progression.

Keywords: atherosclerosis, NOS1, inflammation, oxidized LDL

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Authors: Terefe Fuge, George Tsourtos , Emma Miller

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Objectives: Maintaining optimal adherence and viral suppression in people living with HIV (PLWHA) is essential to ensure both preventative and therapeutic benefits of antiretroviral therapy (ART). Prisoners bear a particularly high burden of HIV infection and are highly likely to transmit to others during and after incarceration. However, the level of adherence and viral suppression, as well as its associated factors in incarcerated populations in low-income countries is unknown. This study aimed to determine the prevalence of non-adherence and viral failure, and contributing factors to this amongst prisoners in South Ethiopia. Methods: A prospective cohort study was conducted between June 1, 2019 and July 31, 2020 to compare the level of adherence and viral suppression between incarcerated and non-incarcerated PLWHA. The study involved 74 inmates living with HIV (ILWHA) and 296 non-incarcerated PLWHA. Background information including sociodemographic, socioeconomic, psychosocial, behavioural, and incarceration-related characteristics was collected using a structured questionnaire. Adherence was determined based on participants’ self-report and pharmacy refill records, and plasma viral load measurements which were undertaken within the study period were prospectively extracted to determine viral suppression. Various univariate and multivariate regression models were used to analyse data. Results: Self-reported dose adherence was approximately similar between ILWHA and non-incarcerated PLWHA (81% and 83% respectively), but ILWHA had a significantly higher medication possession ratio (MPR) (89% vs 75%). The prevalence of viral failure (VF) was slightly higher (6%) in ILWHA compared to non-incarcerated PLWHA (4.4%). The overall dose non-adherence (NA) was significantly associated with missing ART appointments, level of satisfaction with ART services, patient’s ability to comply with a specified medication schedule and types of methods used to monitor the schedule. In ILWHA specifically, accessing ART services from a hospital compared to a health centre, an inability to always attend clinic appointments, experience of depression and a lack of social support predicted NA. VF was significantly higher in males, people of age 31-35 years and in those who experienced social stigma, regardless of their incarceration status. Conclusions: This study revealed that HIV-infected prisoners in South Ethiopia were more likely to be non-adherent to doses and so to develop viral failure compared to their non-incarcerated counterparts. A multitude of factors was found to be responsible for this requiring multilevel intervention strategies focusing on the specific needs of prisoners.

Keywords: Adherence , Antiretroviral therapy, Incarceration, South Ethiopia, Viral suppression

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Authors: Hsiang-Ru Lin

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Cholesterol plays an essential role in the regulation of the progression of numerous important diseases including atherosclerosis and Alzheimer disease so the generation of suitable cholesterol-lowering reagents is urgent to develop. Liver X receptor (LXR) is a ligand-activated transcription factor whose natural ligands are cholesterols, oxysterols and glucose. Once being activated, LXR can transactivate the transcription action of various genes including CYP7A1, ABCA1, and SREBP1c, involved in the lipid metabolism, glucose metabolism and inflammatory pathway. Essentially, the upregulation of ABCA1 facilitates cholesterol efflux from the cells and attenuates the production of beta-amyloid (ABeta) 42 in brain so LXR is a promising target to develop the cholesterol-lowering reagents and preventative treatment of Alzheimer disease. Engelhardia roxburghiana is a deciduous tree growing in India, China, and Taiwan. However, its chemical composition is only reported to exhibit antitubercular and anti-inflammatory effects. In this study, four compounds, engelheptanoxides A, C, engelhardiol A, and B isolated from the root of Engelhardia roxburghiana were evaluated for their agonistic activity against LXR by the transient transfection reporter assays in the HepG2 cells. Furthermore, their interactive modes with LXR ligand binding pocket were generated by molecular modeling programs. By using the cell-based biological assays, engelheptanoxides A, C, engelhardiol A, and B showing no cytotoxic effect against the proliferation of HepG2 cells, exerted obvious LXR agonistic effects with similar activity as T0901317, a novel synthetic LXR agonist. Further modeling studies including docking and SAR (structure-activity relationship) showed that these compounds can locate in LXR ligand binding pocket in the similar manner as T0901317. Thus, LXR is one of nuclear receptors targeted by pharmaceutical industry for developing treatments of Alzheimer and atherosclerosis diseases. Importantly, the cell-based assays, together with molecular modeling studies suggesting a plausible binding mode, demonstrate that engelheptanoxides A, C, engelhardiol A, and B function as LXR agonists. This is the first report to demonstrate that the extract of Engelhardia roxburghiana contains LXR agonists. As such, these active components of Engelhardia roxburghiana or subsequent analogs may show important therapeutic effects through selective modulation of the LXR pathway.

Keywords: Liver X receptor (LXR), Engelhardia roxburghiana, CYP7A1, ABCA1, SREBP1c, HepG2 cells

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Authors: Milijana N. Miljkovic, Viktorija M. Dragojevic-Simic, Nemanja K. Rancic, Vesna M. Jacevic, Snezana B. Djordjevic, Momir M. Mikov, Aleksandra M. Kovacevic

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Itraconazole (ITZ) is a weak base and extremely lipophilic compound, with water solubility as a rate-limiting step in its absorption from the gastrointestinal tract. Its absolute bioavailability, about 55%, is maximal when its oral formulation, capsules, are taken immediately after a full meal. Peak plasma concentrations (Cmax) are reached within 2 to 5 hrs after their administration. ITZ undergoes extensive hepatic metabolism by human CYP3A4 isoenzyme and more than 30 different metabolites have been identified. One of the main ones is hydroxyitraconazole (HITZ), in which plasma concentrations are almost twice higher than those of ITZ. Gender differences in drug PK (Pharmacokinetics) have already been recognized, but variations in metabolism are believed to be their major cause. The aim of the study was to investigate the influence of gender on ITZ PK parameters after administration of oral capsule formulation, following 100 mg single dosing in healthy adult volunteers under fed conditions. The single-center, open-label PK study was performed. PK analyses included PK parameters obtained after a single 100 mg dose administration of itraconazole capsules to 48 females and 66 males. Blood samples were collected at pre-dose and up to 72.0 h after administration (1.0, 2.0, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 7.0, 9.0, 12.0, 24.0, 36.0 and 72.0 hrs). The calculated pharmacokinetic parameters, based on the plasma concentrations of itraconazole and hydroxyitraconazole, were Cmax, AUClast, and AUCtot. Plasma concentrations of ITZ and HITZ were determined using a validated liquid chromatographic method with mass spectrometric detection, while pharmacokinetic parameters were estimated using non-compartmental methods. The pharmacokinetic analyses were performed using Kinetica software version 5.0. The mean value of ITZ Cmaxmen was 74.79 ng/ml, and Cmaxwomen was 51.291 ng/ml (independent samples test; p = 0.005). Hydroxyitraconazole had a mean value of Cmaxmen 106.37 ng/ml, and the mean value Cmaxwomen was 70.05 ng/ml. Women had, on average, lower AUClast and Cmax than men. AUClastmen for ITZ was 736.02 ng/mL*h and AUClastwomen was 566.62 ng/mL*h, while AUClastmen for HITZ was 1154.80 was ng/mL*h and AUClastwomen for HITZ was 708.12 ng/mL*h (independent samples test; p = 0.033). The mean values of ITZ AUCtotmen were 884.73 ng/mL*h and AUCtotwomen was 685.10 ng/mL*h. AUCtotmen for HITZ was 1290.41 ng/mL*h, while AUCtotwomen for HIZT was 788.60 ng/mL*h (p < 0.001). The results could point out to lower oral bioavailability of ITZ in women, since values of Cmax, AUClast, and AUCtot of both ITZ and HITZ were significantly lower in women than in men, respectively. The reason may be higher expression and activity of CYP3A4 in women than in men, but there also may be differences in other PK parameters. High variability of both ITZ and HITZ concentrations in both genders confirmed that ITZ is a highly variable drug. Further examinations of its PK are needed to justify strategies for therapeutic drug monitoring in patients treated by this antifungal agent.

Keywords: itraconazole, gender, hydroxyitraconazole, pharmacokinetics

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Authors: M. Sulieman, H. Arabiyat, H. Ali, K. Potiszil, I. Abbas, R. English, P. King, I. Brown, P. Drew

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Introduction: The incidence of breast ductal Carcinoma in Situ (DCIS) has been increasing; it currently represents up 20-25% of all breast carcinomas. Some aspects of DCIS management are still controversial, mainly due to the heterogeneity of its clinical presentation and of its biological and pathological characteristics. In DCIS, histological diagnosis obtained preoperatively, carries the risk of sampling error if the presence of invasive cancer is subsequently diagnosed. The mammographic extent over than 4–5 cm and the presence of architectural distortion, focal asymmetric density or mass on mammography are proven important risk factors of preoperative histological under staging. Intracystic papillary cancer (IPC) is a rare form of breast carcinoma. Despite being previously compared to DCIS it has been shown to present histologically with invasion of the basement membrane and even metastasis. SLNB – Carries the risk of associated comorbidity that should be considered when planning surgery for DCIS and IPC. Objectives: The aim of this Audit was to better define a ‘high risk’ group of patients with pre-op diagnosis of non-invasive cancer undergoing breast conserving surgery, who would benefit from sentinel node biopsy. Method: Retrospective data collection of all patients with ductal carcinoma in situ over 5 years. 636 patients identified, and after exclusion criteria applied: 394 patients were included. High risk defined as: Extensive micro-calcification >40mm OR any mass forming DCIS. IPC: Winpath search from for the term ‘papillary carcinoma’ in any breast specimen for 5 years duration;.29 patients were included in this group. Results: DCIS: 188 deemed high risk due to >40mm calcification or a mass forming (radiological or palpable) 61% of those had a mastectomy and 32% BCS. Overall, in that high-risk group - the number with invasive disease was 38%. Of those high-risk DCIS pts 85% had a SLN - 80% at the time of surgery and 5% at a second operation. For the BCS patients - 42% had SLN at time of surgery and 13% (8 patients) at a second operation. 15 (7.9%) pts in the high-risk group had a positive SLNB, 11 having a mastectomy and 4 having BCS. IPC: The provisional diagnosis of encysted papillary carcinoma is upgraded to an invasive carcinoma on final histology in around a third of cases. This has may have implications when deciding whether to offer sentinel node removal at the time of therapeutic surgery. Conclusions: We have defined a ‘high risk’ group of pts with pre-op diagnosis of non-invasive cancer undergoing BCS, who would benefit from SLNB at the time of the surgery. In patients with high-risk features; the risk of invasive disease is up to 40% but the risk of nodal involvement is approximately 8%. The risk of morbidity from SLN is up to about 5% especially the risk of lymphedema.

Keywords: breast ductal carcinoma in Situ (DCIS), intracystic papillary carcinoma (IPC), sentinel node biopsy (SLNB), high-risk, non-invasive, cancer disease

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Authors: E. G. Karvelas, C. Liosis, A. Theodorakakos, T. E. Karakasidis

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Magnetic navigation of the drug inside the human vessels is a very important concept since the drug is delivered to the desired area. Consequently, the quantity of the drug required to reach therapeutic levels is being reduced while the drug concentration at targeted sites is increased. Magnetic navigation of drug agents can be achieved with the use of magnetic nanoparticles where anti-tumor agents are loaded on the surface of the nanoparticles. The magnetic field that is required to navigate the particles inside the human arteries is produced by a magnetic resonance imaging (MRI) device. The main factors which influence the efficiency of the usage of magnetic nanoparticles for biomedical applications in magnetic driving are the size and the magnetization of the biocompatible nanoparticles. In this study, a computational platform for the simulation of the optimal gradient magnetic fields for the navigation of magnetic nanoparticles inside a carotid artery is presented. For the propulsion model of the particles, seven major forces are considered, i.e., the magnetic force from MRIs main magnet static field as well as the magnetic field gradient force from the special propulsion gradient coils. The static field is responsible for the aggregation of nanoparticles, while the magnetic gradient contributes to the navigation of the agglomerates that are formed. Moreover, the contact forces among the aggregated nanoparticles and the wall and the Stokes drag force for each particle are considered, while only spherical particles are used in this study. In addition, gravitational forces due to gravity and the force due to buoyancy are included. Finally, Van der Walls force and Brownian motion are taken into account in the simulation. The OpenFoam platform is used for the calculation of the flow field and the uncoupled equations of particles' motion. To verify the optimal gradient magnetic fields, a covariance matrix adaptation evolution strategy (CMAES) is used in order to navigate the particles into the desired area. A desired trajectory is inserted into the computational geometry, which the particles are going to be navigated in. Initially, the CMAES optimization strategy provides the OpenFOAM program with random values of the gradient magnetic field. At the end of each simulation, the computational platform evaluates the distance between the particles and the desired trajectory. The present model can simulate the motion of particles when they are navigated by the magnetic field that is produced by the MRI device. Under the influence of fluid flow, the model investigates the effect of different gradient magnetic fields in order to minimize the distance of particles from the desired trajectory. In addition, the platform can navigate the particles into the desired trajectory with an efficiency between 80-90%. On the other hand, a small number of particles are stuck to the walls and remains there for the rest of the simulation.

Keywords: artery, drug, nanoparticles, navigation

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Authors: Nicholas McNamara, John Brookes, Michael Williams, Manish Mathew, Elizabeth Brookes, Tristan Yan, Paul Bannon

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Objective: Pericardial effusions are an uncommon but potentially fatal complication after cardiac surgery. The goal of this study was to describe the incidence and risk factors associated with the development of pericardial effusion requiring drainage after coronary artery bypass graft surgery (CABG). Methods: A retrospective analysis was undertaken using prospectively collected data. All adult patients who underwent CABG at our institution between 1st January 2017 and 31st December 2018 were included. Pericardial effusion was diagnosed using transthoracic echocardiography (TTE) performed for clinical suspicion of pre-tamponade or tamponade. Drainage was undertaken if considered clinically necessary and performed via a sub-xiphoid incision, pericardiocentesis, or via re-sternotomy at the discretion of the treating surgeon. Patient demographics, operative characteristics, anticoagulant exposure, and postoperative outcomes were examined to identify those variables associated with the development of pericardial effusion requiring drainage. Tests of association were performed using the Fischer exact test for dichotomous variables and the Student t-test for continuous variables. Logistic regression models were used to determine univariate predictors of pericardial effusion requiring drainage. Results: Between January 1st, 2017, and December 31st, 2018, a total of 408 patients underwent CABG at our institution, and eight (1.9%) required drainage of pericardial effusion. There was no difference in age, gender, or the proportion of patients on preoperative therapeutic heparin between the study and control groups. Univariate analysis identified preoperative atrial arrhythmia (37.5% vs 8.8%, p = 0.03), reduced left ventricular ejection fraction (47% vs 56%, p = 0.04), longer cardiopulmonary bypass (130 vs 84 min, p < 0.01) and cross-clamp (107 vs 62 min, p < 0.01) times, higher drain output in the first four postoperative hours (420 vs 213 mL, p <0.01), postoperative atrial fibrillation (100% vs 32%, p < 0.01), and pleural effusion requiring drainage (87.5% vs 12.5%, p < 0.01) to be associated with development of pericardial effusion requiring drainage. Conclusion: In this study, the incidence of pericardial effusion requiring drainage was 1.9%. Several factors, mainly related to preoperative or postoperative arrhythmia, length of surgery, and pleural effusion requiring drainage, were identified to be associated with developing clinically significant pericardial effusions. High clinical suspicion and low threshold for transthoracic echo are pertinent to ensure this potentially lethal condition is not missed.

Keywords: coronary artery bypass, pericardial effusion, pericardiocentesis, tamponade, sub-xiphoid drainage

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Authors: Ivette Gonzalez-Rivera, Diana B. Paz-Trejo, Oscar Galicia-Castillo, David N. Velazquez-Martinez, Hugo Sanchez-Castillo

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Prolonged exposure to stress can cause disorders related with dysfunction in the prefrontal cortex such as generalized anxiety and depression. These disorders involve alterations in neurotransmitter systems; the serotonergic system—a target of the drugs that are commonly used as a treatment to these disorders—is one of them. Recent studies suggest that 5-HT1A receptors play a pivotal role in the serotonergic system regulation and in stress responses. In the same way, there is increasing evidence that astrocytes are involved in the pathophysiology of stress. The aim of this study was to examine the effects of 8-OH-DPAT, a selective agonist of 5-HT1A receptors, in the behavioral signs of anxiety and anhedonia as well as in the number of astrocytes in the medial prefrontal cortex (mPFC) after exposure to chronic stress. They used 50 male Wistar rats of 250-350 grams housed in standard laboratory conditions and treated in accordance with the ethical standards of use and care of laboratory animals. A protocol of chronic unpredictable stress was used for 10 consecutive days during which the presentation of stressors such as motion restriction, water deprivation, wet bed, among others, were used. 40 rats were subjected to the stress protocol and then were divided into 4 groups of 10 rats each, which were administered 8-OH-DPAT (Tocris, USA) intraperitoneally with saline as vehicle in doses 0.0, 0.3, 1.0 and 2.0 mg/kg respectively. Another 10 rats were not subjected to the stress protocol or the drug. Subsequently, all the rats were measured in an open field test, a forced swimming test, sucrose consume, and a cero maze test. At the end of this procedure, the animals were sacrificed, the brain was removed and the tissue of the mPFC (Bregma: 4.20, 3.70, 2.70, 2.20) was processed in immunofluorescence staining for astrocytes (Anti-GFAP antibody - astrocyte maker, ABCAM). Statistically significant differences were found in the behavioral tests of all groups, showing that the stress group with saline administration had more indicators of anxiety and anhedonia than the control group and the groups with administration of 8-OH-DPAT. Also, a dose dependent effect of 8-OH-DPAT was found on the number of astrocytes in the mPFC. The results show that 8-OH-DPAT can modulate the effect of stress in both behavioral and anatomical level. Also they indicate that 5-HT1A receptors and astrocytes play an important role in the stress response and may modulate the therapeutic effect of serotonergic drugs, so they should be explored as a fundamental part in the treatment of symptoms of stress and in the understanding of the mechanisms of stress responses.

Keywords: anxiety, prefrontal cortex, serotonergic system, stress

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Authors: Vanlounni Sibounheuang, Wanarat Anusornsangiam, Pattarin Kittiboonyakun, Chanthanom Manithip

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In worldwide, one of the most common use of oral anticoagulant is warfarin. Its margin between therapeutic inhibition of clot formation and bleeding complications is narrow. Mahosot Hospital, warfarin clinic had not been established yet. The descriptive study was conducted by investigating drug-related problems of outpatients using warfarin, the value of the international normalized ratio (INR) higher than normal ranges (25.40 % of the total 272 outpatients) were mostly identified at Lao-Luxembourg Heart Centre, Mahosot Hospital, Lao PDR. This result led to the present study conducting qualitative interviews in order to help establish a warfarin clinic at Mahosot Hospital for the better outcomes of patients using warfarin. The purpose of this study was to explore perspectives of healthcare professional providing services for outpatients using warfarin. The face to face, in-depth interviews were undertaken among nine healthcare professionals (doctor=3, nurse=3, pharmacist=3) working at out-patient clinic, Lao-Luxembourg Heart Centre, Mahosot Hospital, Lao PDR. The interview guides were developed, and they were validated by the experts in the fields of qualitative research. Each interview lasted approximately 20 minutes. Three major themes emerged; healthcare professional’s experiences of current practice problems with warfarin therapy, healthcare professionals’ views of medical problems related to patients using warfarin, and healthcare professionals’ perspectives on ways of service improvement. All healthcare professionals had the same views that it’s difficult to achieve INR goal for individual patients because of some important patient barriers especially lack of knowledge about to use warfarin properly and safety, patients not regularly follow-up due to problems with transportations and financial support. Doctors and nurses agreed to have a pharmacist running a routine warfarin clinic and provided counselling to individual patients on the following points: how to take drug properly and safety, drug-drug and food-drug interactions, common side effects and how to manage them, lifestyle modifications. From the interviews, some important components of the establishment of a warfarin clinic included financial support, increased human resources, improved the system of keeping patients’ medical records, short course training for pharmacists. This study indicated the acceptance of healthcare professionals on the important roles of pharmacists and the feasibility of setting up warfarin clinic by working together with the multidisciplinary health care team in order to help improve health outcomes of patients using warfarin at Mahosot Hospital, Lao PDR.

Keywords: perspectives, healthcare professional, warfarin therapy, Mahosot Hospital

Procedia PDF Downloads 69

Authors: Elidrissi Laila, El Rhaoussi Fatima-Zahra, Haddad Fouad, Tahiri Mohamed, Hliwa Wafaa, Bellabah Ahmed, Badre Wafaa

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Introduction: Metabolic Dysfunction Associated with Non-Alcoholic Fatty Liver Disease (MASLD), formerly known as Non-Alcoholic Fatty Liver Disease (NAFLD), is the leading cause of chronic liver disease. The cardiometabolic risk factors associated with MASLD represent common health issues and significant public health challenges. Medical students, being active participants in the healthcare system and a young demographic, are particularly relevant for understanding this entity to prevent its occurrence on a personal and collective level. The objective of our study is to assess the level of knowledge among medical students regarding MASLD, its risk factors, and its long-term consequences. Materials and Methods: We conducted a descriptive cross-sectional study using an anonymous questionnaire distributed through social media over a period of 2 weeks. Medical students from various faculties in Morocco answered 22 questions about MASLD, its etiological factors, diagnosis, complications, and principles of treatment. All responses were analyzed using the Jamovi software. Results: A total of 124 students voluntarily provided complete responses. 59% of our participants were in their 3rd year, with a median age of 21 years. Among the respondents, 27% were overweight, obese, or diabetic. 83% correctly answered more than half of the questions, and 77% believed they knew about MASLD. However, 84% of students were unaware that MASLD is the leading cause of chronic liver disease, and 12% even considered it a rare condition. Regarding etiological factors, overweight and obesity were mentioned in 93% of responses, and type 2 diabetes in 84%. 62% of participants believed that type 1 diabetes could not be implicated in MASLD. For 83 students, MASLD was considered a diagnosis of exclusion, while 41 students believed that a biopsy was mandatory for diagnosis. 12% believed that MASLD did not lead to long-term complications, and 44% were unaware that MASLD could progress to hepatocellular carcinoma. Regarding treatment, 85% included weight loss, and 19% did not consider diabetes management as a therapeutic approach for MASLD. At the end of the questionnaire, 89% of the students expressed a desire to learn more about MASLD and were invited to access an informative sheet through a hyperlink. Conclusion: MASLD represents a significant public health concern due to the prevalence of its risk factors, notably the obesity pandemic, which is widespread among the young population. There is a need for awareness about the seriousness of this emerging and long-underestimated condition among young future physicians.

Keywords: MASLD, medical students, obesity, diabetes

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Authors: Ashima Sharma, Tapan K. Chaudhuri

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Human Serum Albumin (HSA) is one of the most demanded therapeutic protein with immense biotechnological applications. The current source of HSA is human blood plasma. Blood is a limited and an unsafe source as it possesses the risk of contamination by various blood derived pathogens. This issue led to exploitation of various hosts with the aim to obtain an alternative source for the production of the rHSA. But, till now no host has been proven to be effective commercially for rHSA production because of their respective limitations. Thus, there exists an indispensable need to promote non-animal derived rHSA production. Of all the host systems, Escherichia coli is one of the most convenient hosts which has contributed in the production of more than 30% of the FDA approved recombinant pharmaceuticals. E. coli grows rapidly and its culture reaches high cell density using inexpensive and simple substrates. The fermentation batch turnaround number for E. coli culture is 300 per year, which is far greater than any of the host systems available. Therefore, E. coli derived recombinant products have more economical potential as fermentation processes are cheaper compared to the other expression hosts available. Despite of all the mentioned advantages, E. coli had not been successfully adopted as a host for rHSA production. The major bottleneck in exploiting E. coli as a host for rHSA production was aggregation i.e. majority of the expressed recombinant protein was forming inclusion bodies (more than 90% of the total expressed rHSA) in the E. coli cytosol. Recovery of functional rHSA form inclusion body is not preferred because it is tedious, time consuming, laborious and expensive. Because of this limitation, E. coli host system was neglected for rHSA production for last few decades. Considering the advantages of E. coli as a host, the present work has targeted E. coli as an alternate host for rHSA production through resolving the major issue of inclusion body formation associated with it. In the present study, we have developed a novel and innovative method for enhanced soluble and functional production of rHSA in E.coli (~60% of the total expressed rHSA in the soluble fraction) through modulation of the cellular growth, folding and environmental parameters, thereby leading to significantly improved and enhanced -expression levels as well as the functional and soluble proportion of the total expressed rHSA in the cytosolic fraction of the host. Therefore, in the present case we have filled in the gap in the literature, by exploiting the most well studied host system Escherichia coli which is of low cost, fast growing, scalable and ‘yet neglected’, for the enhancement of functional production of HSA- one of the most crucial biomolecule for clinical and biotechnological applications.

Keywords: enhanced functional production of rHSA in E. coli, recombinant human serum albumin, recombinant protein expression, recombinant protein processing

Procedia PDF Downloads 310

Authors: Asikhia Olubusayo Aduke

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Students’ inability to set data-based (specific, measurable, attainable, reliable, and time-bound) personal improvement goals threatens their academic success. Hence, the study aimed to investigate year-one students’ academic goal-setting practices at Lagos State University of Education, Nigeria. Descriptive survey research was used in carrying out this study. The study population consisted of 3,101 year-one students of the University. A sample size of five hundred (501) participants was selected through a proportional and simple random sampling technique. The Formative Goal Setting Questionnaire (FGSQ) developed by Research Collaboration (2015) was adapted and used as an instrument for the study. Two main research questions were answered, while two null hypotheses were formulated and tested for the study. The study revealed higher data-based goals for all students than personal improvement goals. Nevertheless, data-based and personal improvement goal-setting for female students was higher than for male students. One sample test statistic and Anova used to analyse data for the two hypotheses also revealed that the mean difference between male and female year one students’ data-based and personal improvement goal-setting formation was statistically significant (p < 0.05). This means year one students’ data-based and personal improvement goals showed significant gender differences. Based on the findings of this study, it was recommended, among others, that therapeutic techniques that can help to change students’ faulty thinking and challenge their lack of desire for personal improvement should be sought to treat students who have problems with setting high personal improvement goals. Counsellors also need to advocate continued research into how to increase the goal-setting ability of male students and should focus more on counselling male students’ goal-setting ability. The main contributions of the study are higher institutions must prioritize early intervention in first-year students' academic goal setting. Researching gender differences in this practice reveals a crucial insight: male students often lag behind in setting meaningful goals, impacting their motivation and performance. Focusing on this demographic with data-driven personal improvement goals can be transformative. By promoting goal setting that is specific, measurable, and focused on self-growth (rather than competition), male students can unlock their full potential. Researchers and counselors play a vital role in detecting and supporting students with lower goal-setting tendencies. By prioritizing this intervention, we can empower all students to set ambitious, personalized goals that ignite their passion for learning and pave the way for academic success.

Keywords: academic goal setting, counselling, practice, university, year one students

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Authors: Nina Ivanova

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More than one third of the population and animals are infected with parasitic helminths. It is especially difficult to cure the larval forms of parasites. The larvae of Hymenolepis nana invade the villi of the intestinal mucosa. Toxocara larvae can live in the liver, heart, lungs, brain, eyes, and pancreas. Commercial antiparasitic drugs cannot guarantee a 100% cure after a single course of treatment, because parasite larvae invade the villi of the intestinal mucosa and the anthelmintics do not reach and kill cestode larvae. The aim of this work was to conduct a study of liposomal antihelminthics on the laboratory animals under the certification received from the Committee on Bioethics and Deontology. It has been checked: 1) anthelmintic activity of the liposomal form of fenasal in experimental hymenolepidosis of white mice (larval stage - Hymenolepis nana). 2) anthelmintic activity of the liposomal form of albendazole in experimental toxocariasis of white mice (in the lungs at the stage of larval migration). Since some helminths cause hemolysis of erythrocytes as we used a mixture of polar lipids developed by us with antihemolytic activity to obtain liposomes Fenasal and albendazole were included in the liposome membrane in the ratio of anthelmintic: lipids 1:10. . The average size of liposomes was 180 nm, and the concentration of lipids in liposomes was 1%. The researches were carried out on white male mice who were infected with Hymenolepis Nana invasional eggs in a peroral way with a doze of 100 eggs per animal. On the 5th day after infection, a liposomal fenasal and commercial fenasal were administered orally for comparison. The animals were observed for 15 days. Before the introduction of liposomes and on the 3rd, 5th, 15th day after the administration of the drug, studies were carried out on the presence of helminths in the organs of animals. The liposomal fenasal, when administered orally, had an anthelmintic effect on Hymenolepis Nana cysticercoids at a dose of 25 mg/kg. The percentage of efficiency was 90.06, 91.36 96.85% on days 3, 5, 15, respectively. For comparison, the commercial activity was at a dose of 200 mg/ml, which is 8 times higher than the dose of liposomal fenasal. To evaluate the anthelmintic effect of the liposomal form of albendazole in experimental toxocariasis of white mice (toxascaris in the lungs at the stage of larval migration), studies were also carried out on white mice. The animals were infected with invasive eggs of Toxocara canis, orally, at a dose of 100 eggs per animal. On the 5th day after infection, the liposomal albendazole was administered orally. The efficacy of the study dosage form was determined by counting Larva mirgans larvae in the lungs. The results obtained showed that the liposomal albendazole had the greatest anthelmintic effect on Toxocara larvae at a dose of 2.0 mg/kg, which was 3.75 times less than the therapeutic one. At the same time, the percentage of efficiency was 93.75% on the 3rd day, and 98.66% on the 5th day.

Keywords: hymenolepis, Toxocara, larvae, liposomes

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Authors: Chang Liang, Weizhi Gong, Yan Zhang

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Purpose: Hepatocellular carcinoma (HCC) is a malignant tumor with a high mortality rate and poor prognosis worldwide. Murine double minute 2 (MDM2) regulates the tumor suppressor p53, increasing cancer risk and accelerating tumor progression. Speckle-type POX virus and zinc finger protein (SPOP), a key of subunit of Cullin-Ring E3 ligase, inhibits tumor genesis and progression by the ubiquitination of its downstream substrates. This study aimed to clarify whether SPOP and MDM2 are mutually regulated in HCC and the correlation between SPOP and MDM2 and the prognosis of HCC patients. Methods: First, the expression of SPOP and MDM2 in HCC tissues were detected by TCGA database. Then, 53 paired samples of HCC tumor and adjacent tissues were collected to evaluate the expression of SPOP and MDM2 using immunohistochemistry. Chi-square test or Fisher’s exact test were used to analyze the relationship between clinicopathological features and the expression levels of SPOP and MDM2. In addition, Kaplan‒Meier curve analysis and log-rank test were used to investigate the effects of SPOP and MDM2 on the survival of HCC patients. Last, the Multivariate Cox proportional risk regression model analyzed whether the different expression levels of SPOP and MDM2 were independent risk factors for the prognosis of HCC patients. Results: Bioinformatics analysis revealed the low expression of SPOP and high expression of MDM2 were related to worse prognosis of HCC patients. The relationship between the expression of SPOP and MDM2 and tumor stem-like features showed an opposite trend. The immunohistochemistry showed the expression of SPOP protein was significantly downregulated while MDM2 protein significantly upregulated in HCC tissue compared to that in para-cancerous tissue. Tumors with low SPOP expression were related to worse T stage and Barcelona Clinic Liver Cancer (BCLC) stage, but tumors with high MDM2 expression were related to worse T stage, M stage, and BCLC stage. Kaplan–Meier curves showed HCC patients with high SPOP expression and low MDM2 expression had better survival than those with low SPOP expression and high MDM2 expression (P < 0.05). A multivariate Cox proportional risk regression model confirmed that a high MDM2 expression level was an independent risk factor for poor prognosis in HCC patients (P <0.05). Conclusion: The expression of SPOP protein was significantly downregulated, while the expression of MDM2 significantly upregulated in HCC. The low expression of SPOP and high expression. of MDM2 were associated with malignant progression and poor prognosis of HCC patients, indicating a potential therapeutic target for HCC patients.

Keywords: hepatocellular carcinoma, murine double minute 2, speckle-type POX virus and zinc finger protein, ubiquitination

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Authors: Sanjay Shukla

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Excessive use of antibiotics is a main problem in the treatment of wounds and other chronic infections and antibiotic treatment is frequently non-curative, thus alternative treatment is necessary. Phage therapy is considered one of the most effective approaches to treat multi-drug resistant bacterial pathogens. Infections caused by Staphylococcus aureus are very efficiently controlled with phage cocktails, containing a different individual phages lysate infecting a majority of known pathogenic S. aureus strains. The aim of current study was to investigate the efficiency of a purified phage cocktail for prophylactic as well as therapeutic application in mouse model and in large animals with chronic septic infection of wounds. A total of 150 sewage samples were collected from various livestock farms. These samples were subjected for the isolation of bacteriophage by double agar layer method. A total of 27 sewage samples showed plaque formation by producing lytic activity against S. aureus in double agar overlay method out of 150 sewage samples. In TEM recovered isolates of bacteriophages showed hexagonal structure with tail fiber. In the bacteriophage (ØVS) had an icosahedral symmetry with the head size 52.20 nm in diameter and long tail of 109 nm. Head and tail were held together by connector and can be classified as a member of the Myoviridae family under the order of Caudovirale. Recovered bacteriophage had shown the antibacterial activity against the S. aureus in vitro. Cocktail (ØVS1, ØVS5, ØVS9 and ØVS 27) of phage lysate were tested to know in vivo antibacterial activity as well as the safety profile. Result of mice experiment indicated that the bacteriophage lysate was very safe, did not show any appearance of abscess formation which indicates its safety in living system. The mice were also prophylactically protected against S. aureus when administered with cocktail of bacteriophage lysate just before the administration of S. aureus which indicates that they are good prophylactic agent. The S. aureus inoculated mice were completely recovered by bacteriophage administration with 100% recovery which was very good as compere to conventional therapy. In present study ten chronic cases of wound were treated with phage lysate and follow up of these cases was done regularly up to ten days (at 0, 5 and 10 d). Result indicated that the six cases out of ten showed complete recovery of wounds within 10 d. The efficacy of bacteriophage therapy was found to be 60% which was very good as compared to the conventional antibiotic therapy in chronic septic wounds infections. Thus, the application of lytic phage in single dose proved to be innovative and effective therapy for treatment of septic chronic wounds.

Keywords: phage therapy, phage lysate, antimicrobial resistance, S. aureus

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Authors: Josiah Damisa, Michelle Louise Richardson, Morenike Adewuyi

Abstract:

Lower back pain is a significant cause of disability worldwide and associated with great implications in terms of the well-being of affected individuals and society as a whole due to its undeniable socio-economic impact. With its prevalence on the increase as a result of an aging global population, the need for novel forms of pain management is ever paramount. This review aims to provide further insight into current research regarding a role for the endocannabinoid signaling pathway as a target in the treatment of chronic pain, with particular emphasis on its potential use as part of the treatment of lower back pain. Potential advantages and limitations of cannabis-based medicines over other forms of analgesia currently licensed for medical use are discussed in addition to areas that require ongoing consideration and research. To evaluate the efficacy of cannabis-based medicines in chronic pain, studies pertaining to the role of medical cannabis in chronic disease were reviewed. Standard searches of PubMed, Google Scholar and Web of Science databases were undertaken with peer-reviewed journal articles reviewed based on the indication for pain management, cannabis treatment modality used and study outcomes. Multiple studies suggest an emerging role for cannabis-based medicines as therapeutic agents in the treatment of chronic back pain. A potential synergistic effect has also been purported if these medicines are co-administered with opiate analgesia due to the similarity of the opiate and endocannabinoid signaling pathways. However, whilst recent changes to legislation in the United Kingdom mean that cannabis is now licensed for medicinal use on NHS prescription for a number of chronic health conditions, concerns remain as to the efficacy and safety of cannabis-based medicines. Research is lacking into both their side effect profiles and the long-term effects of cannabis use. Legal and ethical considerations to the use of these products in standardized medical practice also persist due to the notoriety of cannabis as a drug of abuse. Despite this, cannabis is beginning to gain traction as an alternative or even complementary drug to opiates, with some preclinical studies showing opiate-sparing effects. Whilst there is a paucity of clinical trials in this field, there is scope for cannabinoids to be successful anti-nociceptive agents in managing chronic back pain. The ultimate aim would be to utilize cannabis-based medicines as alternative or complementary therapies, thereby reducing opiate over-reliance and providing hope to individuals who have exhausted all other forms of standard treatment.

Keywords: endocannabinoids, cannabis-based medicines, chronic pain, lower back pain

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Authors: D. O. Miranda, L. R. Azevedo, J. F. C. Cordeiro, A. H. Dos Santos, S. F. Lisboa, F. S. Guimarães, G. S. Bisson

Abstract:

Background: The Colorectal cancer (CRC) is one of the most common cancers and the fourth leading cause of cancer death in the world. The prevalence of psychiatric-disorders among CRC patients, mainly depression, is high, resulting in impaired quality of life and side effects of primary treatment. High levels of proinflammatory cytokines at tumor microenvironment is a feature of CRC and the literature suggests that those mediators could contribute to the development of psychiatric disorders. Nevertheless, the ability of tumor-associated biological processes to affect the central nervous system (CNS) has only recently been explored in the context of symptoms of depression and is still not well understood. Therefore, the aim of the present study was to test the hypothesis that depressive-like behavior in an experimental model of CCR induced by N-methyl-N-nitro-N-nitrosoguanidine (MNNG) was correlated to proinflammatory profile in the periphery and in the brain. Methods: Colorectal carcinogenesis was induced in adult C57BL/6 mice (n=12) by administration of MNNG (5mg/kg, 0.1ml/intrarectal instillation) 2 times a week, for 2 week. Control group (n=12) received saline (0.1ml/intrarectal instillation). Eight weeks after beginning of MNNG administration animals were submitted to the forced swim test (FST) and the sucrose preference test for evaluation, respectively, of depressive- and anhedonia-like behaviors. After behavioral evaluation, the colon was collected and brain regions dissected (cortex-C, striatum-ST and hippocampus-HIP) for posterior evaluation of cytokine levels (IL-1β, IL-10, IL-17, and CX3CL1) by ELISA. Results: MNNG induced depressive-like behavior, represented by increased immobility time in the FST (Student t test, p < 0.05) and lower sucrose preference (Student t test, p < 0.05). Moreover, there were increased levels of IL-1β, IL-17 and CX3CL1 in the colonic tissue (Student t test, p < 0.05) and in the brain (IL-1 β in the ST and HIP, Student t test, p < 0.05; IL-17 and CX3CL1 in the C and HIP, p < 0.05). IL-10 levels, in contrast, were decreased in both the colon (p < 0.05) and the brain (C and HIP, p < 0.05). Conclusions: The results obtained in the present work support the notion that tumor growth induces neuroinflammation in stress-related brain regions and depressive-like behavior, which could be related to the high incidence of depression in colorectal carcinogenesis. This work have important clinical and research implications, taken into account that cytokine levels may be a marker promissory for the developing depression in CRC patients. New therapeutic strategies to assist in alleviating mental suffering in cancer patients might result from a better understanding of the role of cytokines in the pathophysiology of depression in these subjects.

Keywords: cytokines, brain, depression, colorectal cancer

Procedia PDF Downloads 246

Authors: Vardan Melkonyan, Arman Azizyan, Astghik Boyajyan

Abstract:

Virtual reality (VR) exposure therapy is a form of cognitive-behavioral therapy that uses immersive virtual environments to expose individuals to the feared stimuli or situations that trigger their phobia. VR exposure therapy has become an increasingly popular treatment for phobias, including fear of heights, public speaking, and flying, due to its ability to provide a controlled and safe environment for individuals to confront their fears while also allowing therapists to tailor the virtual exposure to the specific needs and goals of each individual. It is also a cost-effective and accessible treatment option, as it can be delivered remotely and does not require the use of drugs. Overall, VR exposure therapy has the potential to be a valuable tool for therapists in the treatment of phobias. But current methods may be improved by incorporating advanced technology such as photorealistic VR environments, tactile feedback suits, and responsive systems. The aim of this study was to identify the most effective approach for enhancing VR exposure therapy for the treatment of phobias. Photorealistic VR environments and stimuli can greatly enhance the effectiveness of VR exposure therapy for the treatment of phobias. By creating immersive, realistic virtual environments that closely mimic the real-life situations that trigger phobia responses, patients are able to more fully engage in the therapeutic process and confront their fears in a controlled and safe manner. This can help to reduce the severity of phobia symptoms and increase treatment outcomes. The use of tactile feedback suits and responsive systems can further enhance the VR exposure therapy experience by adding a physical element to the virtual environment. These suits, which can mimic the sensations of touch, pressure, and movement, allow patients to fully immerse themselves in the virtual world and feel as if they are physically present in the situation. This can help to increase the realism of the virtual environment and make it more effective in reducing phobia symptoms. Additionally, responsive systems can be used to trigger specific events or responses within the virtual environment based on the patient's actions, providing a more interactive and personalized treatment experience. A comprehensive literature review was conducted, including studies on VR exposure therapy for phobias and the use of advanced technology to enhance the therapy. Results indicate that incorporating these enhancements may significantly increase the effectiveness of VR exposure therapy for phobias. Further research is needed to fully understand the potential of these enhancements and to determine the optimal combination and implementation.

Keywords: virtual reality, mental health, phobias, fears, treatment, photorealistic, immersive, phobia

Procedia PDF Downloads 57

Authors: Mohammad Afzal Khan, Fatimah Alanazi, Hala Abdalrahman Ahmed, Talal Shamma, Kilian Kelly, Mohammed A. Hammad, Abdullah O. Alawad, Abdullah Mohammed Assiri, Dieter Clemens Broering

Abstract:

Lung transplantation is a life-saving surgical replacement of diseased lungs in patients with end-stage respiratory malfunctions. Despite the remarkable short-term recovery, long-term lung survival continues to face several significant challenges, including chronic rejection and severe toxic side-effects due to global immunosuppression. Stem cell-based immunotherapy has been recognized as a crucial immunoregulatory regimen in various preclinical and clinical studies. Despite initial therapeutic outcomes, conventional stem cells face key limitations. The Cymerus™ manufacturing facilitates the production of a virtually limitless supply of consistent human induced pluripotent stem cell (iPSC)-derived mesenchymal stem cells, which could play a key role in selective immunosuppression and graft repair during rejection. Here, we demonstrated the impact of iPSC-derived human MSCs on the development of immune-tolerance and long-term graft survival in mouse orthotopic airway allografts. BALB/c→C57BL/6 allografts were reconstituted with iPSC-derived MSCs (2 million/transplant/ at d0), and allografts were examined for regulatory T cells (Tregs), oxygenation, microvascular blood flow, airway epithelium and collagen deposition during rejection. We demonstrated that iPSC-derived MSC treatment leads to significant increase in tissue expression of hTSG-6 protein, followed by an upregulation of mouse Tregs and IL-5, IL-10, IL-15 cytokines, which augments graft microvascular blood flow and oxygenation, and thereby maintained a healthy airway epithelium and prevented the subepithelial deposition of collagen at d90 post-transplantation. Collectively, these data confirmed that iPSC-derived MSC-mediated immunosuppression has potential to establish immune-tolerance and rescue allograft from sustained hypoxic/ischemic phase and subsequently limits long-term airway epithelial injury and collagen progression, which therapeutically warrant a study of Cymerus iPSC-derived MSCs as a potential management option for immunosuppression in transplant recipients.

Keywords: stem cell therapy, immunotolerance, regulatory T cells, hypoxia and ischemia, microvasculature

Procedia PDF Downloads 133

Authors: A. Poukens, I. Sluyts, A. Krings, J. Swartenbroekx, D. Geeroms, J. Poukens

Abstract:

Introduction and Objectives: It has been known for many years that with the administration of intravenous medication, a rather significant part of the planned to be administered infusion solution, the residual volume ( the volume that remains in the IV line and or infusion bag), does not reach the patient and is wasted. This could possibly result in under dosage and diminished therapeutic effect. Despite the important impact on the patient, the reduction of residual volume lacks attention. An optimized and clearly stated protocol concerning the reduction of residual volume in an IV line is necessary for each hospital. As described in my Master’s thesis, acquiring the degree of Master in Hospital Pharmacy, administration of intravenous medication can be optimized by reduction of the residual volume. Herewith effectiveness, user-friendliness, cost efficiency and safety were taken into account. Material and Methods: By usage of a literature study and an online questionnaire sent out to all Flemish hospitals and hospitals in the Netherlands (province Limburg), current flush methods could be mapped out. In laboratory research, possible flush methods aiming to reduce the residual volume were measured. Furthermore, a self-developed experimental method to reduce the residual volume was added to the study. The current flush methods and the self-developed experimental method were compared to each other based on cost efficiency, user-friendliness and safety. Results: There is a major difference between the Flemish and the hospitals in the Netherlands (Province Limburg) concerning the approach and method of flushing IV lines after administration of intravenous medication. The residual volumes were measured and laboratory research showed that if flushing was done minimally 1-time equivalent to the residual volume, 95 percent of glucose would be flushed through. Based on the comparison, it became clear that flushing by use of a pre-filled syringe would be the most cost-efficient, user-friendly and safest method. According to laboratory research, the self-developed experimental method is feasible and has the advantage that the remaining fraction of the medication can be administered to the patient in unchanged concentration without dilution. Furthermore, this technique can be applied regardless of the level of the residual volume. Conclusion and Recommendations: It is recommendable to revise the current infusion systems and flushing methods in most hospitals. Aside from education of the hospital staff and alignment on a uniform substantiated protocol, an optimized and clear policy on the reduction of residual volume is necessary for each hospital. It is recommended to flush all IV lines with rinsing fluid with at least the equivalent volume of the residual volume. Further laboratory and clinical research for the self-developed experimental method are needed before this method can be implemented clinically in a broader setting.

Keywords: intravenous medication, infusion therapy, IV flushing, residual volume

Procedia PDF Downloads 105