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1.
J Dent Educ ; 2024 Sep 30.
Article in English | MEDLINE | ID: mdl-39350429

ABSTRACT

STATEMENT OF PROBLEM: Digital education using virtual-reality simulators is essential for precise learning in modern education. PURPOSE OF STUDY: This study aimed to develop a virtual-reality dental system for tooth preparation training and assess pre-virtual-reality experiences and perceptions of its potential benefits. We evaluated the post-virtual-reality experience in terms of the effectiveness of the virtual-reality system. MATERIAL AND METHODS: The virtual-reality platform development phase involved learning- and assessment-based frameworks for participants. The first step involved creating a storyboard for a virtual dental clinic environment using virtual-reality glasses. This simulated a dental chair-like setup with instruments and tools, allowing participants to practice dental procedures. This study utilized a mixed-methods approach to assess participants' experience with virtual reality in dental education using a tooth preparation simulation system and evaluated post-virtual reality measures, including the system usability scale, usefulness, educational effectiveness, and participant attitudes through structured survey questionnaires. RESULTS: This study included 150 participants (49 dental students, 52 dental interns, and 49 faculty members). Most participants were females (76%). Significant differences were observed in attitude scores between students and faculty members, with third-year dental students having more positive attitudes toward the integration of virtual-reality in dental education. No significant differences were found in system usability, usefulness, or assessment scores between the groups. CONCLUSION: The virtual-reality dental module system shows promise for improving dental education. CLINICAL IMPLICATION: The varied responses from different user groups should be considered to ensure successful implementation and acceptance.

2.
Cureus ; 16(8): e66329, 2024 Aug.
Article in English | MEDLINE | ID: mdl-39246918

ABSTRACT

When dealing with a partially edentulous patient requiring rehabilitation for a distal extension, the situation becomes challenging if the patient is unwilling to consider placing implants or using a removable prosthesis. A patient with partial tooth loss may find it difficult to receive a satisfactory repair, especially if the missing teeth are at the back. The surrounding gum tissue and the underlying bone ridges provide support for dentures that encase natural teeth. During functional activities, these components are frequently exposed to different stresses, which can substantially affect the remaining natural teeth and bone structure. Precision attachments are complex devices made up of two parts: one incorporated into a detachable dental prosthesis and the other fastened to the natural teeth. Their function is to give the prosthetic stability and retention. A fixed partial denture is impractical when there is no distal abutment. However, by offering a combination prosthesis, this difficulty can be solved. Without requiring surgery, this method provides the benefit of a fixed prosthesis. We are presenting a case of management for a 56-year-old patient with unilateral distal extension with a combined prosthesis of acrylic retained by an extra coronal precision attachment system.

3.
Int J Mol Sci ; 25(17)2024 Aug 29.
Article in English | MEDLINE | ID: mdl-39273322

ABSTRACT

IL-15 is a homeostatic cytokine for human T and NK cells. However, whether other cytokines influence the effect of IL-15 is not known. We studied the impact that IL-10, TGF-ß, IL-17A, and IFN-γ have on the IL-15-induced proliferation of human T cells and the expression of HLA class I (HLA-I) molecules. Peripheral blood lymphocytes (PBLs) were labeled with CFSE and stimulated for 12 days with IL-15 in the absence or presence of the other cytokines. The proportion of proliferating T cells and the expression of cell surface HLA-I molecules were analyzed using flow cytometry. The IL-15-induced proliferation of T cells was paralleled by an increase in the expression of HC-10-reactive HLA-I molecules, namely on T cells that underwent ≥5-6 cycles of cell division. It is noteworthy that the IL-15-induced proliferation of T cells was potentiated by IL-10 and TGF-ß but not by IL-17 or IFN-γ and was associated with a decrease in the expression of HC-10-reactive molecules. The cytokines IL-10 and TGF-ß potentiate the proliferative capacity that IL-15 has on human T cells in vitro, an effect that is associated with a reduction in the amount of HC-10 reactive HLA class I molecules induced by IL-15.


Subject(s)
Cell Proliferation , Histocompatibility Antigens Class I , Interferon-gamma , Interleukin-10 , Interleukin-15 , Interleukin-17 , T-Lymphocytes , Transforming Growth Factor beta , Humans , Cell Proliferation/drug effects , Interferon-gamma/pharmacology , Interferon-gamma/metabolism , Interleukin-17/pharmacology , Interleukin-17/metabolism , Transforming Growth Factor beta/metabolism , Transforming Growth Factor beta/pharmacology , Interleukin-10/metabolism , Interleukin-15/pharmacology , Interleukin-15/metabolism , Histocompatibility Antigens Class I/metabolism , T-Lymphocytes/metabolism , T-Lymphocytes/immunology , T-Lymphocytes/drug effects , T-Lymphocytes/cytology , Cells, Cultured , Lymphocyte Activation/drug effects
4.
Cancer Immunol Immunother ; 73(11): 228, 2024 Sep 09.
Article in English | MEDLINE | ID: mdl-39249578

ABSTRACT

BACKGROUND: The antigen processing machinery (APM) plays a critical role in generating tumor-specific antigens that can be recognized and targeted by the immune system. Proper functioning of APM components is essential for presenting these antigens on the surface of tumor cells, enabling immune detection and destruction. In many cancers, defects in APM can lead to immune evasion, contributing to tumor progression and poor clinical outcomes. However, the status of the APM in sarcomas is not well characterized, limiting the development of effective immunotherapeutic strategies for these patients. METHODS: We investigated 126 patients with 8 types of bone and soft tissue sarcoma operated between 2001-2021. Tissue microarrays mapped 11 specific areas in each case. The presence/absence of APM protein was determined through immunohistochemistry. Bayesian networks were used. RESULTS: All investigated sarcomas had some defects in APM. The least damaged component was HLA Class I subunit ß2-microglobulin and HLA Class II. The proteasome LMP10 subunit was defective in leiomyosarcoma (LMS), myxoid liposarcoma (MLPS), and dedifferentiated liposarcoma (DDLPS), while MHC I transporting unit TAP2 was altered in undifferentiated pleomorphic sarcoma (UPS), gastrointestinal stromal tumor (GIST), and chordoma (CH). Among different neoplastic areas, high-grade areas showed different patterns of expression compared to high lymphocytic infiltrate areas. Heterogeneity at the patient level was also observed. Loss of any APM component was prognostic of distant metastasis (DM) for LMS and DDLPS and of overall survival (OS) for LMS. CONCLUSION: Sarcomas exhibit a high degree of defects in APM components, with differences among histotypes and tumoral areas. The most commonly altered APM components were HLA Class I subunit ß2-microglobulin, HLA Class I subunit α (HC10), and MHC I transporting unit TAP2. The loss of APM components was prognostic of DM and OS and clinically relevant for LMS and DDLPS. This study explores sarcoma molecular mechanisms, enriching personalized therapeutic approaches.


Subject(s)
Antigen Presentation , Sarcoma , Humans , Sarcoma/immunology , Sarcoma/pathology , Antigen Presentation/immunology , Male , Female , Middle Aged , Aged , Adult , Antigens, Neoplasm/immunology , Antigens, Neoplasm/metabolism , Proteasome Endopeptidase Complex/metabolism , beta 2-Microglobulin/metabolism , Prognosis , ATP Binding Cassette Transporter, Subfamily B, Member 3
5.
Article in English | MEDLINE | ID: mdl-39287115

ABSTRACT

HLA-B27 is a major histocompatibility complex (MHC) class I antigen which exhibits strong association (90%) with ankylosing spondylitis. HLA-B27 detection in patients by flow cytometry is a widely used clinical test, performed on many different flow cytometer models. We sought to develop and validate a test conversion protocol for the HLA-B27 test performed on the BD FACSCanto to BD's newer FACSLyric flow cytometers. The development and validation experiments were performed using anti-HLA-B27*FITC/CD3*PE antibody-stained whole blood patient specimens. The anti-HLA-B27*FITC logarithmic median fluorescence (LMF) results on the BD FACSCanto were converted to median fluorescence intensity (MFI) values on the BD FACSLyric. Clustering of the HLA-B27 positive and negative values, using a 3rd order polynomial equation, resulted in a conversion of the BD FACSCanto cutoff values, negative (<150 LMF) and positive (≥160 LMF), to negative (<4530 MFI) and positive (≥6950 MFI) on the BD FACSLyric. Accuracy was assessed by comparing the flow results obtained on the BD FACSCanto and BD FACSLyric to a molecular PCR based assay. Additional validation parameters (compensation verification, intra- and inter-assay precision, and instrument comparison) were performed per the recommendations outlined in the Clinical and Laboratory Standards Institute (CLSI) H62 guidelines for validation of flow cytometry assays.

6.
Surg Endosc ; 2024 Sep 17.
Article in English | MEDLINE | ID: mdl-39289225

ABSTRACT

BACKGROUND: This study aimed to evaluate the 3-year outcomes of sleeve gastrectomy in non-diabetic individuals with class I obesity. METHODS: A total of 78 participants with class I obesity and 78 participants with class II obesity, matched in terms of age, sex (93.6% female), and the rates of dyslipidemia and hypertension, were included in this prospective cohort study. Follow-up data, including metabolic features, body composition, nutritional characteristics, and surgery complications, were gathered at the baseline and 6, 12, 24, and 36 months post-bariatric surgery. Micronutrient deficiencies and comorbidities (hypertension and dyslipidemia) were evaluated in both groups using conditional logistic regression analysis, and Clavien-Dindo classification was used to compare surgical complications. RESULTS: Baseline characteristics of the participants in both groups were similar (n = 78, mean age: 36.4 ± 8.5). The two groups were also comparable in terms of weight loss, cardiovascular risk factors, and remission of obesity-related comorbidities 3 years following sleeve gastrectomy. Overall values of Δ total weight loss (TWL)%, Δ excess weight loss (EWL)%, and ß (95% CI) were - 1.86 (1.19), and - 2.56 (4.5) with a P value of 0.118 and 0.568, respectively. The occurrence of surgical complications and undesirable outcomes were also similar between the two study groups. CONCLUSION: Bariatric surgery is an effective and safe method to achieve weight loss and alleviate cardiovascular risk factors and obesity-related comorbidities in non-diabetic individuals with class I and class II obesity.

7.
Arch Pharm (Weinheim) ; : e2400437, 2024 Sep 18.
Article in English | MEDLINE | ID: mdl-39291901

ABSTRACT

Class I histone deacetylases (HDACs) are considered promising targets in current cancer research. To obtain subtype-selective and potent HDAC inhibitors, we used the aminobenzamide scaffold as the zinc-binding group and prepared new derivatives with a pyrazole ring as the linking group. The synthesized compounds were analyzed in vitro using an enzymatic assay against HDAC1, -2, and -3. Compounds 12b, 15b, and 15i were found to be potent HDAC1 inhibitors, also in comparison to the reference compounds entinostat and tacedinaline, with IC50 values of 0.93, 0.22, and 0.68 µM, respectively. The best compounds were measured for their cellular effect and target engagement in acute myeloid leukemia (AML) cells. In addition, we studied the interaction of the compounds with HDAC subtypes using docking and molecular dynamic simulations. In summary, we have developed a new chemotype of HDAC1 inhibitors that can be used for further structure-based optimization.

8.
Article in English | MEDLINE | ID: mdl-39306605

ABSTRACT

PURPOSE: Female carriers of germline BRCA1 mutations almost invariably develop breast cancer (BC); however, the age at onset is a subject of variation. We hypothesized that the age-related penetrance of BRCA1 mutations may depend on inherited variability in the host immune system. METHODS: Next-generation sequencing was utilized for genotyping of HLA class I/II genes (HLA-A, HLA-B, HLA-C, HLA-DPB1, HLA-DQB1, and HLA-DRB1/3/4/5) in patients with BRCA1-associated BC with early (< / = 38 years, n = 215) and late (> / = 58 years, n = 108) age at onset. RESULTS: HLA-DQB1*06:03P prevalence was higher in the late-onset group due to the excess of allele carriers [25/108 (23.1%) vs. 22/215 (10.2%); OR 2.96, p < 0.001]. For all HLA-I loci, there was a trend toward an increase in the number of homozygotes in the early-onset group. This trend reached statistical significance for the HLA-A [14.4% vs. 6.5%, p = 0.037; OR 2.4, p = 0.042]. The frequencies of HLA-DPB1, HLA-DQB1, and HLA-DRB1/3/4/5 homozygous genotypes did not differ between young-onset and late-onset patients. The maximum degree of homozygosity detected in this study was 6 out of 7 HLA class I/II loci; all six carriers of these genotypes were diagnosed with BC at the age < / = 38 years [OR 6.97, p = 0.187]. CONCLUSION: HLA polymorphism may play a role in modifying the penetrance of BRCA1 pathogenic variants. Certain HLA alleles or HLA homozygosity may modify the risk of BC in BRCA1 carriers.

9.
Hum Immunol ; 85(6): 111148, 2024 Sep 24.
Article in English | MEDLINE | ID: mdl-39321712

ABSTRACT

BACKGROUND: Breast cancer (BC) is a significant global health issue, accounting for 1 in 8 cancer diagnoses worldwide. HLA class I molecules are typically expressed on the cell surface, but cancer cells can develop mechanisms to evade recognition by CTLs, including the downregulation of HLA class I expression. In this context, we aimed to conduct a systematic review and meta-analysis to clarify the role of HLA class I expression in clinical outcomes for patients with BC. METHODS: A comprehensive literature search was conducted across PubMed, Scopus, Web of Science, and the Cochrane databases. Effect sizes, along with I2 and Tau2 statistics, were used to assess heterogeneity through a DerSimonian and Laird random-effects model. Statistical analyses were performed using R statistical software, version 4.2.3. RESULTS: Among the 8 included studies, most of the analyzed samples consisted of ductal carcinoma cases (1588, 86.39 %), from the luminal (A or B) intrinsic subtype (1865, 69.07 %), with no lymph node metastasis (2658, 57.24 %), no HER2 overexpression (2594, 67.46 %), negative Ki67 status (1721, 71.26 %), and positive hormone receptor status (4732, 64.05 %). The analysis revealed a significant reduction in disease-free survival (HR 0.57; 95 % CI 0.34 to 0.95; p = 0.034; I2 = 84 %) in the group with low HLA-I expression. However, no significant difference was found between the groups with high and low HLA-I expression regarding overall survival (HR 0.77; 95 % CI 0.28 to 2.14; p = 0.62; I2 = 86 %). CONCLUSIONS: This systematic review and meta-analysis demonstrated that HLA class I expression is associated with a significant improvement in disease-free survival, though no significant effect on overall survival was observed.

11.
BMC Bioinformatics ; 25(1): 310, 2024 Sep 27.
Article in English | MEDLINE | ID: mdl-39333860

ABSTRACT

BACKGROUND: Antigen presentation is a central step in initiating and shaping the adaptive immune response. To activate CD8+ T cells, pathogen-derived peptides are presented on the cell surface of antigen-presenting cells bound to major histocompatibility complex (MHC) class I molecules. CD8+ T cells that recognize these complexes with their T cell receptor are activated and ideally eliminate infected cells. Prediction of putative peptides binding to MHC class I (MHC-I) is crucial for understanding pathogen recognition in specific immune responses and for supporting drug and vaccine design. There are reliable databases for epitope prediction algorithms available however they primarily focus on the prediction of epitopes in single immunogenic proteins. RESULTS: We have developed the tool DiscovEpi to establish an interface between whole proteomes and epitope prediction. The tool allows the automated identification of all potential MHC-I-binding peptides within a proteome and calculates the epitope density and average binding score for every protein, a protein-centric approach. DiscovEpi provides a convenient interface between automated multiple sequence extraction by organism and cell compartment from the database UniProt for subsequent epitope prediction via NetMHCpan. Furthermore, it allows ranking of proteins by their predicted immunogenicity on the one hand and comparison of different proteomes on the other. By applying the tool, we predict a higher immunogenic potential of membrane-associated proteins of SARS-CoV-2 compared to those of influenza A based on the presented metrics epitope density and binding score. This could be confirmed visually by comparing the epitope maps of the influenza A strain and SARS-CoV-2. CONCLUSION: Automated prediction of whole proteomes and the subsequent visualization of the location of putative epitopes on sequence-level facilitate the search for putative immunogenic proteins or protein regions and support the study of adaptive immune responses and vaccine design.


Subject(s)
Histocompatibility Antigens Class I , Proteome , Proteome/metabolism , Proteome/immunology , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class I/metabolism , Histocompatibility Antigens Class I/chemistry , Humans , COVID-19/immunology , COVID-19/metabolism , COVID-19/virology , SARS-CoV-2/immunology , Software , Epitopes/chemistry , Epitopes/immunology , Databases, Protein , Algorithms
12.
Contemp Clin Dent ; 15(2): 98-104, 2024.
Article in English | MEDLINE | ID: mdl-39206240

ABSTRACT

Background: For the elderly population, efforts are made to simplify the restorative procedure while maintaining good clinical performance. Glass ionomer (GI) cements are showing signs to fulfill many of these qualities. With their new properties and ease of use, they can be developed further to become a useful group of materials to overcome the problems of elderly patients. Aim: The aim of the study was to evaluate the clinical performance of zirconia-reinforced versus conventional viscous GI restorations in Class I cavities of geriatric patients. Setting and Design: The study design was in vivo randomized clinical trial, parallel-arms, allocation ratio: 1:1. Subjects and Methods: A total of 28 Class I carious lesions in 21 geriatric patients were restored randomly either by zirconomer-improved or Ketac Molar Quick Aplicap (n = 14) each. Restorations were evaluated for 1 year by modified USPHS criteria. Statistical Analysis: Data were analyzed with the Chi-square test and Cochran's Q-test. Survival rate was analyzed using the Kaplan-Meier and log-rank test. Results: Twenty-four restorations were evaluated in 19 patients with a recall rate of 85.7% at 12 months. Significant differences were found in marginal integrity and marginal discoloration within both restorative materials between different time intervals (P < 0.05). However, none of the materials were superior to another regarding all assessed criteria. Conclusions: Both zirconia-reinforced GI and conventional highly viscous GI have acceptable clinical performance.

13.
Anticancer Res ; 44(9): 4039-4047, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39197900

ABSTRACT

BACKGROUND/AIM: Various biomarkers are utilized in the field of breast cancer. Human lymphocyte antigen (HLA) class I molecules have a critical role in cancer immune surveillance. Therefore, this study aimed to assess the HLA class I expression and analyze the correlation with clinicopathologic factors in breast cancer. PATIENTS AND METHODS: We investigated the clinical pathology archives of 150 consecutive patients with breast cancer who underwent a curative operation at the Sapporo Medical University, Japan, from January 2012 to December 2014. Immunohistochemical staining was used to evaluate HLA class I expression and CD8-positive T cell infiltration. The Pearson χ2 test was used to assess HLA class I expression level and clinicopathological parameters. The Kaplan-Meier method was used to evaluate survival and the log-rank test to analyze the differences between survival curves. RESULTS: Patients with dull/negative HLA class I had significantly poor disease-free survival (DFS) compared with those with positive HLA class I (p=0.0073). Univariate analyses revealed that pT, pN, positive lymphatic invasion, and dull/negative HLA class I were significantly associated with DFS. Multivariate analyses revealed dull/negative HLA class I as an independent poor prognostic factor (hazard ratio=2.75, 95% confidence interval=1.30-5.80, p=0.008). CONCLUSION: HLA class I expression level may have a very sensitive prognostic effect on patients with breast cancer.


Subject(s)
Breast Neoplasms , Histocompatibility Antigens Class I , Humans , Female , Breast Neoplasms/immunology , Breast Neoplasms/pathology , Breast Neoplasms/mortality , Breast Neoplasms/metabolism , Middle Aged , Histocompatibility Antigens Class I/metabolism , Prognosis , Aged , Adult , Biomarkers, Tumor/metabolism , Disease-Free Survival , Kaplan-Meier Estimate , Aged, 80 and over , Lymphocytes, Tumor-Infiltrating/immunology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Immunohistochemistry
14.
BMC Oral Health ; 24(1): 996, 2024 Aug 24.
Article in English | MEDLINE | ID: mdl-39182104

ABSTRACT

BACKGROUND: The determining effect of facial hard tissues on soft tissue morphology in orthodontic patients has yet to be explained. The aim of this study was to clarify the hard-soft tissue relationships of the lower 1/3 of the face in skeletal Class II-hyperdivergent patients compared with those in Class I-normodivergent patients using network analysis. METHODS: Fifty-two adult patients (42 females, 10 males; age, 26.58 ± 5.80 years) were divided into two groups: Group 1, 25 subjects, skeletal Class I normodivergent pattern with straight profile; Group 2, 27 subjects, skeletal Class II hyperdivergent pattern with convex profile. Pretreatment cone-beam computed tomography and three-dimensional facial scans were taken and superimposed, on which landmarks were identified manually, and their coordinate values were used for network analysis. RESULTS: (1) In sagittal direction, Group 2 correlations were generally weaker than Group 1. In both the vertical and sagittal directions of Group 1, the most influential hard tissue landmarks to soft tissues were located between the level of cemento-enamel junction of upper teeth and root apex of lower teeth. In Group 2, the hard tissue landmarks with the greatest influence in vertical direction were distributed more forward and downward than in Group 1. (2) In Group 1, all the correlations for vertical-hard tissue to sagittal-soft tissue position and sagittal-hard tissue to vertical-soft tissue position were positive. However, Group 2 correlations between vertical-hard tissue and sagittal-soft tissue positions were mostly negative. Between sagittal-hard tissue and vertical-soft tissue positions, Group 2 correlations were negative for mandible, and were positive for maxilla and teeth. CONCLUSION: Compared with Class I normodivergent patients with straight profile, Class II hyperdivergent patients with convex profile had more variations in soft tissue morphology in sagittal direction. In vertical direction, the most relevant hard tissue landmarks on which soft tissue predictions should be based were distributed more forward and downward in Class II hyperdivergent patients with convex profile. Class II hyperdivergent pattern with convex profile was an imbalanced phenotype concerning sagittal and vertical positions of maxillofacial hard and soft tissues.


Subject(s)
Anatomic Landmarks , Cephalometry , Cone-Beam Computed Tomography , Face , Imaging, Three-Dimensional , Malocclusion, Angle Class II , Malocclusion, Angle Class I , Mandible , Humans , Male , Female , Adult , Malocclusion, Angle Class II/diagnostic imaging , Malocclusion, Angle Class II/pathology , Cephalometry/methods , Imaging, Three-Dimensional/methods , Face/anatomy & histology , Face/diagnostic imaging , Malocclusion, Angle Class I/diagnostic imaging , Malocclusion, Angle Class I/pathology , Mandible/diagnostic imaging , Mandible/pathology , Young Adult , Maxilla/diagnostic imaging , Maxilla/pathology , Chin/diagnostic imaging , Chin/anatomy & histology , Chin/pathology , Incisor/diagnostic imaging , Incisor/anatomy & histology , Image Processing, Computer-Assisted/methods
15.
Hum Immunol ; 85(5): 111083, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39111186

ABSTRACT

The Punjabi population, constituting over 45 % of the country's total population, holds the highest prevalence in Pakistan. To understand their HLA genetics, we genotyped 389 Punjabi subjects for major Class-I loci using the PCR-SSO Luminex® method. Our study identified a total of 162 alleles, including 41 different HLA-A, 72 HLA-B, and 49 HLA-C alleles. The most common alleles included A*11:01 (14.6 %), A*01:01 (11.8 %), A*24:02 (11.3 %); B*40:06 (13.3 %), B*08:01 (10.9 %), B*51:01 (8.7 %); C*15:02 (15.5 %), C*07:02 (15.3 %), and C*04:01 (10.8 %). However, only locus B showed a significant deviation from HWE. The dominant Class I haplotype was A*24:02-B*40:06-C*15:02, followed by A*11:01-B*40:06-C*15:02, while significant LD was observed between all pairs of HLA loci. A distinct genetic makeup was observed in the Pakistani Punjabis as compared to Indian Punjabis, emphasizing the impact of the Indo-Pak partition and religious choices for marriage. In comparison to country's other ethnic groups, the Pakistani population exhibited 76 different alleles at a low field-resolution, with the Punjabi population having highest polymorphism. Phylogenetic analysis revealed that the Punjabi population is most closely related to the Sindhi population, while both populations sharing ancient connections with the Burusho population. These findings have significant implications for transplantation procedures, personalized medicine, disease susceptibility, and evolutionary studies.


Subject(s)
Ethnicity , Gene Frequency , Haplotypes , Polymorphism, Genetic , Humans , Pakistan/ethnology , Ethnicity/genetics , Alleles , Genotype , Linkage Disequilibrium , Male , Female , Genetics, Population , Histocompatibility Antigens Class I/genetics
16.
Adv Sci (Weinh) ; : e2404159, 2024 Aug 08.
Article in English | MEDLINE | ID: mdl-39116324

ABSTRACT

The first approved vaccines for human use against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are nanotechnology-based. Although they are modular, rapidly produced, and can reduce disease severity, the currently available vaccines are restricted in preventing infection, stressing the global demand for novel preventive vaccine technologies. Bearing this in mind, we set out to develop a flexible nanovaccine platform for nasal administration to induce mucosal immunity, which is fundamental for optimal protection against respiratory virus infection. The next-generation multiepitope nanovaccines co-deliver immunogenic peptides, selected by an immunoinformatic workflow, along with adjuvants and regulators of the PD-L1 expression. As a case study, we focused on SARS-CoV-2 peptides as relevant antigens to validate the approach. This platform can evoke both local and systemic cellular- and humoral-specific responses against SARS-CoV-2. This led to the secretion of immunoglobulin A (IgA), capable of neutralizing SARS-CoV-2, including variants of concern, following a heterologous immunization strategy. Considering the limitations of the required cold chain distribution for current nanotechnology-based vaccines, it is shown that the lyophilized nanovaccine is stable for long-term at room temperature and retains its in vivo efficacy upon reconstitution. This makes it particularly relevant for developing countries and offers a modular system adaptable to future viral threats.

18.
Biochim Biophys Acta Rev Cancer ; 1879(5): 189161, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39096977

ABSTRACT

Immune checkpoint blockade (ICB) therapy has achieved broad applicability and durable clinical responses across cancer types. However, the overall response rate remains suboptimal because some patients do not respond or develop drug resistance. The low infiltration of CD8+ cytotoxic T cells (CTLs) in the tumor microenvironment due to insufficient antigen presentation is closely related to the innate resistance to ICB. The duration and spatial distribution of major histocompatibility complex class I (MHC-I) expression on the cell surface is critical for the efficient presentation of endogenous tumor antigens and subsequent recognition and clearance by CTLs. Tumor cells reduce the surface expression of MHC-I via multiple mechanisms to impair antigen presentation pathways and evade immunity and/or develop resistance to ICB therapy. As an increasing number of studies have focused on membrane MHC-I trafficking and degradation in tumor cells, which may impact the effectiveness of tumor immunotherapy. It is necessary to summarize the mechanism regulating membrane MHC-I translocation into the cytoplasm and degradation via the lysosome. We reviewed recent advances in the understanding of endosomal-lysosomal MHC-I transport and highlighted the means exploited by tumor cells to evade detection and clearance by CTLs. We also summarized new therapeutic strategies targeting these pathways to enhance classical ICB treatment and provide new avenues for optimizing cancer immunotherapy.


Subject(s)
Endosomes , Histocompatibility Antigens Class I , Immunotherapy , Lysosomes , Neoplasms , Humans , Neoplasms/immunology , Neoplasms/therapy , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Lysosomes/metabolism , Endosomes/metabolism , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class I/metabolism , Immunotherapy/methods , Animals , Protein Transport , Tumor Microenvironment/immunology , Antigen Presentation/immunology , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/pharmacology
19.
Front Immunol ; 15: 1406929, 2024.
Article in English | MEDLINE | ID: mdl-39114655

ABSTRACT

Numerous enveloped viruses, such as coronaviruses, influenza, and respiratory syncytial virus (RSV), utilize class I fusion proteins for cell entry. During this process, the proteins transition from a prefusion to a postfusion state, undergoing substantial and irreversible conformational changes. The prefusion conformation has repeatedly shown significant potential in vaccine development. However, the instability of this state poses challenges for its practical application in vaccines. While non-native disulfides have been effective in maintaining the prefusion structure, identifying stabilizing disulfide bonds remains an intricate task. Here, we present a general computational approach to systematically identify prefusion-stabilizing disulfides. Our method assesses the geometric constraints of disulfide bonds and introduces a ranking system to estimate their potential in stabilizing the prefusion conformation. We hypothesized that disulfides restricting the initial stages of the conformational switch could offer higher stability to the prefusion state than those preventing unfolding at a later stage. The implementation of our algorithm on the RSV F protein led to the discovery of prefusion-stabilizing disulfides that supported our hypothesis. Furthermore, the evaluation of our top design as a vaccine candidate in a cotton rat model demonstrated robust protection against RSV infection, highlighting the potential of our approach for vaccine development.


Subject(s)
Disulfides , Viral Fusion Proteins , Disulfides/chemistry , Animals , Viral Fusion Proteins/immunology , Viral Fusion Proteins/chemistry , Humans , Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Virus Infections/prevention & control , Respiratory Syncytial Virus Infections/virology , Protein Stability , Computer-Aided Design , Protein Conformation , Respiratory Syncytial Viruses/immunology , Respiratory Syncytial Virus Vaccines/immunology , Rats , Models, Molecular
20.
Pak J Med Sci ; 40(7): 1561-1565, 2024 Aug.
Article in English | MEDLINE | ID: mdl-39092068

ABSTRACT

Objective: To compare linear distance of glenoid fossa to frontomaxillary nasal suture in skeletal Class-I and II malocclusions. Methods: This cross-sectional study was conducted at the Department of Orthodontics, Altamash Institute of Dental Medicine, Karachi Pakistan. The duration of study was one year from January, 2019 to January, 2020. After taking informed consent from patient and hospital ethical committee a total of 60 patients were included in the study using WHO sample size calculator. Two groups comprising 30 patients each i.e., Skeletal Class-I malocclusion and Skeletal Class-II malocclusion with mandibular retrusion both having normal vertical relationship were included in the study. The cephalometric measurements SNA, SNB, SNMP, FHMP, GF-FMN, CO-GO, CO GN on lateral cephalograms were measured and compared between the two groups. Independent t test was applied and p value ≤ 0.05 was considered as significant. Results: In skeletal Class-I malocclusion the mean linear distance of GF-FMN was 70.2 ± 4.02 mm and in skeletal Class-II malocclusion it was 73.4 ± 4.04 mm (p value .004). Glenoid fossa was 3.2 mm distally placed in patients with Class-II malocclusion. Conclusion: Glenoid fossa position is a diagnostic feature of Class-II malocclusion associated with mandibular retrusion. One of the effective cephalometric measurements to check glenoid fossa position is the distance from the glenoid fossa(GF) to the frontomaxillary nasal suture FMN (GF-FMN).

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