Cloning, Expression And Immunogenicity Of Recombinant Bacille Calmette-Guerin (BCG) Containing T And B Cell Epitopes Of Mycobacterium Tuberculosis [QR82.M95 R737 2008 f rb].

Tuberculosis (TB) remains one of the leading causes of morbidity and mortality in humans. The only TB vaccine currently available is an attenuated strain of Mycobacterium bovis, bacille Calmette–Guerin (BCG). Tuberkulosis (TB) merupakan salah satu penyakit yang menyebabkan banyak kematian kepada manusia. Terdapat hanya satu vaksin TB pada masa ini iaitu strain yang telah dilemahkan, Mycobacterium bovis bacille Calmette–Guèrin (BCG)

The Key Role of TNF-TNFR2 Interactions in the Modulation of Allergic Inflammation: A Review

Tumor necrosis factor-alpha (TNF) is a pleiotropic cytokine, which is thought to play a major role in the pathogenesis of inflammatory diseases, including allergy. TNF is produced at the early stage of allergen sensitization, and then continues to promote the inflammation cascade in the effector phase of allergic reactions. Consequently, anti-TNF treatment has been proposed as a potential therapeutic option. However, recent studies reveal anti-intuitive effects of TNF in the activation and proliferative expansion of immunosuppressive Tregs, tolerogenic DCs and MDSCs. This immunosuppressive effect of TNF is mediated by TNFR2, which is preferentially expressed by immunosuppressive cells. These findings redefine the role of TNF in allergic reaction, and suggest that targeting TNF-TNFR2 interaction itself may represent a novel strategy in the treatment of allergy

Immunogenicity of recombinant Mycobacterium bovis bacille Calmette-Guèrin clones expressing T and B cell epitopes of Mycobacterium tuberculosis antigens

Recombinant Mycobacterium bovis bacille Calmette-Guèrin (rBCG) expressing three T cell epitopes of Mycobacterium tuberculosis (MTB) Ag85B antigen (P1, P2, P3) fused to the Mtb8.4 protein (rBCG018) or a combination of these antigens fused to B cell epitopes from ESAT-6, CFP-10 and MTP40 proteins (rBCG032) were used to immunize Balb/c mice. Total IgG responses were determined against Mtb8.4 antigen and ESAT-6 and CFP-10 B cell epitopes after immunization with rBCG032. Mice immunized with rBCG032 showed a significant increase in IgG1 and IgG2a antibodies against ESAT-6 and MTP40 (P1) B cell epitopes and IgG3 against both P1 and P2 B cell epitopes of MPT40. Splenocytes from mice immunized with rBCG018 proliferated against Ag85B P2 and P3 T cell epitopes and Mtb8.4 protein whereas those from mice-immunized with rBCG032 responded against all Ag85B epitopes and the ESAT-6 B cell epitope. CD4+ and CD8+ lymphocytes from mice immunized with rBCG018 produced primarily Th1 type cytokines in response to the T cell epitopes. Similar pattern of recognition against the T cell epitopes were obtained with rBCG032 with the additional recognition of ESAT-6, CFP-10 and one of the MTP40 B cell epitopes with the same pattern of cytokines. This study demonstrates that rBCG constructs expressing either T or T and B cell epitopes of MTB induced appropriate immunogenicity against MTB

Colorectal cancer stem cells: a review of targeted drug delivery by gold nanoparticles

Colorectal cancer (CRC) is one of the most common cancers with equal probability of affecting both men and women worldwide. Recently, the newly emerged theory of cancer stem cells has associated CRC stem cells (CRCSCs) with the high rates of recurrence and poor prognosis. Thus, targeting CRCSCs instead of CRC may resolve cancer relapse. Among the chemotherapeutic drugs, the antimetabolite 5-fluorouracil (5-FU) has shown high efficiency in CRC treatment. However, due to several limitations, the usefulness of 5-FU has been restricted. The application of gold nanoparticles (AuNPs) in drug delivery systems is reported to enhance the effectiveness of anticancer drugs due to their biostability, non-toxicity and feasibility for surface modification. Furthermore, the overexpression of biomolecular surface markers in CRCSCs may elevate the specific targeting by AuNPs, and hence, reduce the non-specific binding, which could lead to systemic side effects. This review briefly presents the proposed therapeutic potential of AuNPs loaded with 5-FU, conjugated with specific antibodies targeting CRCSCs, which could be valuable to improve some limitations in current CRC management

Gold nanoparticles conjugated with anti-CD133 monoclonal antibody and 5-fluorouracil chemotherapeutic agent as nanocarriers for cancer cell targeting

The enhanced permeability and retention effect allows for passive targeting of solid tumours by nanoparticles carrying anticancer drugs. However, active targeting by incorporation of various ligands onto nanoparticles can provide for a more selective and enhanced chemotherapeutic effect and complement the deficiencies of the passive targeting approach. Here we report on the design of the carboxyl-terminated PEGylated gold nanoparticles (AuNPs), their functionalization with anti-CD133 monoclonal antibody (mAb) via a crosslinking reaction, and subsequent 5-fluorouracil (5-FU) drug loading. The synthesized products in the form of stable colloids were characterised using a range of physicochemical techniques, including X-ray diffraction (XRD), UV-Vis spectroscopy, transmission electron microscopy (TEM), and dynamic light scattering (DLS). Conjugation of anti-CD133 mAb onto PEGylated AuNPs was confirmed with the use of UV-Vis, BCA protein assay and fluorescence microscopy. HCT116 colorectal cancer cells abundantly expressed CD133: 92.4 ± 1.3%, as measured by flow cytometry. Whereas PEGylated AuNPs not conjugated with anti-CD133 mAb accumulated mainly at the cellular membrane, nanoparticles conjugated with anti-CD133 mAb were contained within the nuclear region of the cells. Anti-CD133 mAb conjugation facilitated the specific intracellular uptake due to specific antigen–antibody binding interaction. In vitro cytotoxicity studies on HCT116 cells showed that PEGylated AuNPs and PEGylated AuNPs-CD133 did not elicit any toxicity at any of the tested concentrations. Meanwhile, 5-FU-PEGylated AuNPs-CD133 significantly reduced the cell viability relative to the treatment with 5-FU-PEGylated AuNPs without anti-CD133 mAb conjugates (p < 0.0001). This study shows that the conjugation of nanocarriers with the anti-CD133 antibody improves the specific targeting of 5-FU against colorectal cancer cells. These results demonstrate that simultaneous functionalisation of PEGylated AuNPs with antibodies and chemotherapeutic drugs is a viable strategy to combat cancer through targeted drug delivery

COVID-19 infection and nanomedicine applications for development of vaccines and therapeutics: An overview and future perspectives based on polymersomes

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which emerged in December 2019 and caused the coronavirus disease 2019 (COVID-19) pandemic, took the world by surprise with an unprecedented public health emergency. Since this pandemic began, extraordinary efforts have been made by scientists to understand the pathogenesis of COVID-19, and to fight the infection by providing various preventive, diagnostic and treatment opportunities based on either novel hypotheses or past experiences. Despite all the achievements, COVID-19 continues to be an accelerating health threat with no specifically approved vaccine or therapy. This review highlights the recent advances in COVID-19 infection, with a particular emphasis on nanomedicine applications that can help in the development of effective vaccines or therapeutics against COVID-19. A novel future perspective has been proposed in this review based on utilizing polymersome nano-objects for effectively suppressing the cytokine storm, which may reduce the severity of COVID-19 infection

Reported Adverse Effects and Attitudes among Arab Populations Following COVID-19 Vaccination: A Large-Scale Multinational Study Implementing Machine Learning Tools in Predicting Post-Vaccination Adverse Effects Based on Predisposing Factors

Background: The unprecedented global spread of coronavirus disease 2019 (COVID-19) has imposed huge challenges on the healthcare facilities, and impacted every aspect of life. This has led to the development of several vaccines against COVID-19 within one year. This study aimed to assess the attitudes and the side effects among Arab communities after receiving a COVID-19 vaccine and use of machine learning (ML) tools to predict post-vaccination side effects based on predisposing factors. Methods: An online-based multinational survey was carried out via social media platforms from June 14 to 31 August 2021, targeting individuals who received at least one dose of a COVID-19 vaccine from 22 Arab countries. Descriptive statistics, correlation, and chi-square tests were used to analyze the data. Moreover, extensive ML tools were utilized to predict 30 post vaccination adverse effects and their severity based on 15 predisposing factors. The importance of distinct predisposing factors in predicting particular side effects was determined using global feature importance employing gradient boost as AutoML. Results: A total of 10,064 participants from 19 Arab countries were included in this study. Around 56% were female and 59% were aged from 20 to 39 years old. A high rate of vaccine hesitancy (51%) was reported among participants. Almost 88% of the participants were vaccinated with one of three COVID-19 vaccines, including Pfizer BioNTech (52.8%), AstraZeneca (20.7%), and Sinopharm (14.2%). About 72% of participants experienced post-vaccination side effects. This study reports statistically significant associations (p < 0.01) between various predisposing factors and post-vaccinations side effects. In terms of predicting post-vaccination side effects, gradient boost, random forest, and XGBoost outperformed other ML methods. The most important predisposing factors for predicting certain side effects (i.e., tiredness, fever, headache, injection site pain and swelling, myalgia, and sleepiness and laziness) were revealed to be the number of doses, gender, type of vaccine, age, and hesitancy to receive a COVID-19 vaccine. Conclusions: The reported side effects following COVID-19 vaccination among Arab populations are usually non-life-threatening; flu-like symptoms and injection site pain. Certain predisposing factors have greater weight and importance as input data in predicting post-vaccination side effects. Based on the most significant input data, ML can also be used to predict these side effects; people with certain predicted side effects may require additional medical attention, or possibly hospitalization

Synthetic Nanoparticles That Promote Tumor Necrosis Factor Receptor 2 Expressing Regulatory T Cells in the Lung and Resistance to Allergic Airways Inflammation

Synthetic glycine coated 50 nm polystyrene nanoparticles (NP) (PS50G), unlike ambient NP, do not promote pulmonary inflammation, but instead, render lungs resistant to the development of allergic airway inflammation. In this study, we show that PS50G modulate the frequency and phenotype of regulatory T cells (Treg) in the lung, specifically increasing the proportion of tumor necrosis factor 2 (TNFR2) expressing Treg. Mice pre-exposed to PS50G, which were sensitized and then challenged with an allergen a month later, preferentially expanded TNFR2+Foxp3+ Treg, which further expressed enhanced levels of latency associated peptide and cytotoxic T-lymphocyte associated molecule-4. Moreover, PS50G-induced CD103+ dendritic cell activation in the lung was associated with the proliferative expansion of TNFR2+Foxp3+ Treg. These findings provide the first evidence that engineered NP can promote the selective expansion of maximally suppressing TNFR2+Foxp3+ Treg and further suggest a novel mechanism by which NP may promote healthy lung homeostasis

Inhibitors targeting CDK4/6, PARP and PI3K in breast cancer: a review

Breast cancer is the global leading cause of cancer-related death in women and it represents a major health burden worldwide. One of the promising breast cancer therapeutic avenues is through small molecule inhibitors (SMIs) which have undergone rapid progress with successful clinical trials. Recently, three emerging and vital groups of proteins are targeted by SMIs for breast cancer treatment, namely cyclin-dependent kinase 4 and 6 (CDK4/6), poly (adenosine diphosphate-ribose) polymerase (PARP) and phosphoinositide 3-kinase (PI3K). Several of these inhibitors have been approved for the treatment of breast cancer patients or progressed into late-stage clinical trials. Thus, modeling from these successful clinical trials, as well as their limitations, is pivotal for future development and trials of other inhibitors or therapeutic regimens targeting breast cancer patients. In this review, we discuss eight recently approved or novel SMIs against CDK4/6 (palbociclib, ribociclib and abemaciclib), PARP (olaparib, veliparib and talazoparib), and PI3K (buparlisib and alpelisib). The mechanisms of action, series of clinical trials and limitations are described for each inhibitor