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Journal of Medical Genetics Jul 2024Transport protein particle (TRAPP) is a multiprotein complex that functions in localising proteins to the Golgi compartment. The TRAPPC11 subunit has been implicated in...
BACKGROUND
Transport protein particle (TRAPP) is a multiprotein complex that functions in localising proteins to the Golgi compartment. The TRAPPC11 subunit has been implicated in diseases affecting muscle, brain, eye and to some extent liver. We present three patients who are compound heterozygotes for a missense variant and a structural variant in the gene. structural variants have not yet been described in association with a disease. In order to reveal the estimated genesis of identified structural variants, we performed sequencing of individual breakpoint junctions and analysed the extent of homology and the presence of repetitive elements in and around the breakpoints.
METHODS
Biochemical methods including isoelectric focusing on serum transferrin and apolipoprotein C-III, as well as mitochondrial respiratory chain complex activity measurements, were used. Muscle biopsy samples underwent histochemical analysis. Next-generation sequencing was employed for identifying sequence variants associated with neuromuscular disorders, and Sanger sequencing was used to confirm findings.
RESULTS
We suppose that non-homologous end joining is a possible mechanism of deletion origin in two patients and non-allelic homologous recombination in one patient. Analyses of mitochondrial function performed in patients' skeletal muscles revealed an imbalance of mitochondrial metabolism, which worsens with age and disease progression.
CONCLUSION
Our results contribute to further knowledge in the field of neuromuscular diseases and mutational mechanisms. This knowledge is important for understanding the molecular nature of human diseases and allows us to improve strategies for identifying disease-causing mutations.
PubMed: 38955476
DOI: 10.1136/jmg-2024-110016 -
Life Science Alliance Sep 2024In addition to mitochondrial DNA, mitochondrial double-stranded RNA (mtdsRNA) is exported from mitochondria. However, specific channels for RNA transport have not been...
In addition to mitochondrial DNA, mitochondrial double-stranded RNA (mtdsRNA) is exported from mitochondria. However, specific channels for RNA transport have not been demonstrated. Here, we begin to characterize channel candidates for mtdsRNA export from the mitochondrial matrix to the cytosol. Down-regulation of SUV3 resulted in the accumulation of mtdsRNAs in the matrix, whereas down-regulation of PNPase resulted in the export of mtdsRNAs to the cytosol. Targeting experiments show that PNPase functions in both the intermembrane space and matrix. Strand-specific sequencing of the double-stranded RNA confirms the mitochondrial origin. Inhibiting or down-regulating outer membrane proteins VDAC1/2 and BAK/BAX or inner membrane proteins PHB1/2 strongly attenuated the export of mtdsRNAs to the cytosol. The cytosolic mtdsRNAs subsequently localized to large granules containing the stress protein TIA-1 and activated the type 1 interferon stress response pathway. Abundant mtdsRNAs were detected in a subset of non-small-cell lung cancer cell lines that were glycolytic, indicating relevance in cancer biology. Thus, we propose that mtdsRNA is a new damage-associated molecular pattern that is exported from mitochondria in a regulated manner.
Topics: Humans; Cytosol; Mitochondria; RNA, Double-Stranded; Prohibitins; RNA, Mitochondrial; Cell Line, Tumor; Repressor Proteins; RNA Transport; Exoribonucleases; Voltage-Dependent Anion Channel 1; Carcinoma, Non-Small-Cell Lung; Mitochondrial Proteins
PubMed: 38955468
DOI: 10.26508/lsa.202302396 -
Saudi Medical Journal Jul 2024To ascertain the prevalence of transfusion transmissible infections (TTIs) across diverse donor groups in the Najran province. Additionally, to establish a potential...
OBJECTIVES
To ascertain the prevalence of transfusion transmissible infections (TTIs) across diverse donor groups in the Najran province. Additionally, to establish a potential association between the development of TTI and the donors' blood group, as determined by the ABO/Rh blood grouping system.
METHODS
Blood donation data of 4120 donors, spanning from January to December 2020, were retrospectively reviewed. The blood were screened for TTI markers, including hepatitis B surface antigen (HBsAg), anti-hepatitis B core (anti-HBc), anti-hepatitis C virus (anti-HCV), anti-human immunodeficiency viruses 1 and 2 (anti-HIV1&2), anti-human T-lymphotropic virus types 1 and 2 (anti-HTLV-1&2), and syphilis antigen.
RESULTS
Positive TTI markers were detected in 10.9% of the donors. The most detected TTI marker was anti-HBc (8.9%), followed by HBsAg (0.7%). Other markers were individually detected in <1% of the donors. Anti-HBc-positive was significantly elevated among non-Saudi blood donors. There was an association between age groups and anti-HCV (=0.002), anti-HTLV (=0.004) and syphilis antigen (=0.02) markers positivity. The AB positive blood group exhibited the most positivity for TTI markers, followed by O positive blood group. Similarly, association was found between ABO group and HBsAg (=0.01), anti-HBc (=0.001), and anti-HCV (<0.001) markers positivity.
CONCLUSION
Emphasis on implementing robust screening measures for donated blood is underscored by this study. There is the need for future study to extensively evaluate TTI status to enhance our understanding of the trend in TTI.
Topics: Humans; ABO Blood-Group System; Adult; Hepatitis B Surface Antigens; Saudi Arabia; Male; Blood Donors; Retrospective Studies; Female; Middle Aged; Biomarkers; Syphilis; Young Adult; Transfusion Reaction; Prevalence; Adolescent; Hepatitis B; Hepatitis B Antibodies; HIV Infections
PubMed: 38955448
DOI: 10.15537/smj.2024.45.7.20240338 -
Journal For Immunotherapy of Cancer Jul 2024Small-cell lung cancer (SCLC) is an aggressive disease with a dismal prognosis. The addition of immune checkpoints inhibitors to standard platinum-based chemotherapy in...
Extensive-stage small-cell lung cancer in patients receiving atezolizumab plus carboplatin-etoposide: stratification of outcome based on a composite score that combines gene expression profiling and immune characterization of microenvironment.
PURPOSE
Small-cell lung cancer (SCLC) is an aggressive disease with a dismal prognosis. The addition of immune checkpoints inhibitors to standard platinum-based chemotherapy in first-line setting achieves a durable benefit only in a patient subgroup. Thus, the identification of predictive biomarkers is an urgent unmet medical need.
EXPERIMENTAL DESIGN
Tumor samples from naive extensive-stage (ES) SCLC patients receiving atezolizumab plus carboplatin-etoposide were analyzed by gene expression profiling and two 9-color multiplex immunofluorescence panels, to characterize the immune infiltrate and SCLC subtypes. Associations of tissue biomarkers with time-to-treatment failure (TTF), progression-free survival (PFS) and overall survival (OS), were assessed.
RESULTS
42 patients were included. Higher expression of exhausted CD8-related genes was independently associated with a longer TTF and PFS while increased density of B lymphocytes correlated with longer TTF and OS. Higher percentage of M2-like macrophages close to tumor cells and of CD8+T cells close to CD4+T lymphocytes correlated with increased risk of TF and longer survival, respectively. A lower risk of TF, disease progression and death was associated with a higher density of ASCL1+tumor cells while the expression of POU2F3 correlated with a shorter survival. A composite score combining the expression of exhausted CD8-related genes, B lymphocyte density, ASCL1 tumor expression and quantification of CD163+macrophages close to tumor cells, was able to stratify patients into high-risk and low-risk groups.
CONCLUSIONS
In conclusion, we identified tissue biomarkers and a combined score that can predict a higher benefit from chemoimmunotherapy in ES-SCLC patients.
Topics: Humans; Carboplatin; Lung Neoplasms; Male; Antibodies, Monoclonal, Humanized; Female; Small Cell Lung Carcinoma; Tumor Microenvironment; Antineoplastic Combined Chemotherapy Protocols; Etoposide; Aged; Middle Aged; Gene Expression Profiling; Adult; Neoplasm Staging
PubMed: 38955418
DOI: 10.1136/jitc-2024-008974 -
Journal For Immunotherapy of Cancer Jul 2024Tertiary lymphoid structures (TLSs) are thought to stimulate antitumor immunity and positively impact prognosis and response to immune checkpoint blockade. In gastric...
BACKGROUND
Tertiary lymphoid structures (TLSs) are thought to stimulate antitumor immunity and positively impact prognosis and response to immune checkpoint blockade. In gastric cancers (GCs), however, TLSs are predominantly found in GC with poor prognosis and limited treatment response. We, therefore, hypothesize that immune cell composition and function of TLS depends on tumor location and the tumor immune environment.
METHODS
Spatial transcriptomics and immunohistochemistry were used to characterize the phenotype of CD45 immune cells inside and outside of TLS using archival resection specimens from GC primary tumors and peritoneal metastases.
RESULTS
We identified significant intrapatient and interpatient diversity of the cellular composition and maturation status of TLS in GC. Tumor location (primary vs metastatic site) accounted for the majority of differences in TLS maturity, as TLS in peritoneal metastases were predominantly immature. This was associated with higher levels of tumor-infiltrating macrophages and Tregs and less plasma cells compared with tumors with mature TLS. Furthermore, mature TLSs were characterized by overexpression of antitumor immune pathways such as B cell-related pathways, MHC class II antigen presentation while immature TLS were associated with protumor pathways, including T cell exhaustion and enhancement of DNA repair pathways in the corresponding cancer.
CONCLUSION
The observation that GC-derived peritoneal metastases often contain immature TLS which are associated with immune suppressive regulatory tumor-infiltrating leucocytes, is in keeping with the lack of response to immune checkpoint blockade and the poor prognostic features of peritoneal metastatic GC, which needs to be taken into account when optimizing immunomodulatory strategies for metastatic GC.
Topics: Humans; Stomach Neoplasms; Tertiary Lymphoid Structures; Peritoneal Neoplasms; Male; Female; Tumor Microenvironment
PubMed: 38955417
DOI: 10.1136/jitc-2024-009243 -
International Journal of Gynecological... Jul 2024Molecular features are essential for estimating the risk of recurrence and impacting overall survival in patients with endometrial cancer. Additionally, the surgical...
OBJECTIVE
Molecular features are essential for estimating the risk of recurrence and impacting overall survival in patients with endometrial cancer. Additionally, the surgical procedure itself could be personalized based on the molecular characteristics of the tumor. This study aims to assess the feasibility of obtaining reliable molecular classification status from biopsy specimens collected during hysteroscopy to better modulate the appropriate surgical treatment.
METHODS
This monocentric, retrospective, observational study was conducted on 106 patients who underwent a biopsy procedure followed by radical surgery for endometrial cancer, with concurrent molecular investigation. The molecular classification was determined through immunohistochemical staining for p53 and mismatch repair proteins, along with gene sequencing for POLE.
RESULTS
Overall, 106 patients underwent molecular investigation, which was finally achieved on 99 patients (93.4%). Among these, the molecular analysis was conducted in 71 patients (67%) on the pre-operative endometrial biopsy and on the final uterine specimen in 28 patients (26.4%). Most of the endometrial biopsies were performed using Bettocchi hysteroscopy (66%). Molecular analysis was not possible in seven patients (6.6%), with six cases due to sample inadequacy and one case attributed to intra-mucosal carcinoma. The molecular results showed that the copy number low sub-group was the most common, and five cases of 'multiple classifiers' were observed in the low-risk category.
CONCLUSION
Our experience in obtaining molecular information from biopsy samples underscores the feasibility and efficacy of this technique, even in small tissue samples. This capability helps define the prognostic group of patients, facilitates timely decision-making, and develops a personalized strategy for each patient.
PubMed: 38955372
DOI: 10.1136/ijgc-2024-005478 -
Critical Reviews in Oncology/hematology Jun 2024If Europe's health systems make a conscious decision to increase their utilization of technology and techniques that can enhance prevention and expedite early-stage... (Review)
Review
If Europe's health systems make a conscious decision to increase their utilization of technology and techniques that can enhance prevention and expedite early-stage diagnosis, they can effectively address the growing challenges of disease. By embracing these advancements, these health systems can significantly improve their response to emerging health issues.However, at present the effective integration and exploitation of these opportunities remains hesitant and suboptimal, and health and health services underperform accordingly, with patients suffering from the continuing variations in diagnosis and access to innovation. This paper presents a comprehensive study that examines the current state of various influential disciplines and factors in European countries. It specifically focuses on the adoption of Next Generation Screening technologies and the development stage of Public Health Genomics. The assessment of these areas is presented in the context of a rapidly changing policy environment, which provides an opportunity for a fundamental reconsideration of how and where new tools can be integrated into healthcare systems and routine practices. Top of Form.
PubMed: 38955310
DOI: 10.1016/j.critrevonc.2024.104433 -
The Journal of Infection Jun 2024
PubMed: 38955247
DOI: 10.1016/j.jinf.2024.106214 -
Immunity Jun 2024An important property of the host innate immune response during microbial infection is its ability to control the expression of antimicrobial effector proteins, but how...
An important property of the host innate immune response during microbial infection is its ability to control the expression of antimicrobial effector proteins, but how this occurs post-transcriptionally is not well defined. Here, we describe a critical antibacterial role for the classic antiviral gene 2'-5'-oligoadenylate synthetase 1 (OAS1). Human OAS1 and its mouse ortholog, Oas1b, are induced by interferon-γ and protect against cytosolic bacterial pathogens such as Francisella novicida and Listeria monocytogenes in vitro and in vivo. Proteomic and transcriptomic analysis showed reduced IRF1 protein expression in OAS1-deficient cells. Mechanistically, OAS1 binds and localizes IRF1 mRNA to the rough endoplasmic reticulum (ER)-Golgi endomembranes, licensing effective translation of IRF1 mRNA without affecting its transcription or decay. OAS1-dependent translation of IRF1 leads to the enhanced expression of antibacterial effectors, such as GBPs, which restrict intracellular bacteria. These findings uncover a noncanonical function of OAS1 in antibacterial innate immunity.
PubMed: 38955184
DOI: 10.1016/j.immuni.2024.06.003 -
Computers in Biology and Medicine Jul 2024This study delves into the therapeutic efficacy of A. pyrethrum in addressing vitiligo, a chronic inflammatory disorder known for inducing psychological distress and...
Inhibition of the Janus kinase protein (JAK1) by the A. Pyrethrum Root Extract for the treatment of Vitiligo pathology. Design, Molecular Docking, ADME-Tox, MD Simulation, and in-silico investigation.
This study delves into the therapeutic efficacy of A. pyrethrum in addressing vitiligo, a chronic inflammatory disorder known for inducing psychological distress and elevating susceptibility to autoimmune diseases. Notably, JAK inhibitors have emerged as promising candidates for treating immune dermatoses, including vitiligo. Our investigation primarily focuses on the anti-vitiligo potential of A. pyrethrum root extract, specifically targeting N-alkyl-amides, utilizing computational methodologies. Density Functional Theory (DFT) is deployed to meticulously scrutinize molecular properties, while comprehensive evaluations of ADME-Tox properties for each molecule contribute to a nuanced understanding of their therapeutic viability, showcasing remarkable drug-like characteristics. Molecular docking analysis probes ligand interactions with pivotal site JAK1, with all compounds demonstrating significant interactions; notably, molecule 6 exhibits the most interactions with crucial inhibition residues. Molecular dynamics simulations over 500ns further validate the importance and sustainability of these interactions observed in molecular docking, favoring energetically both molecules 6 and 1; however, in terms of stability, the complex with molecule 6 outperforms others. DFT analyses elucidate the distribution of electron-rich oxygen atoms and electron-poor regions within heteroatoms-linked hydrogens. Remarkably, N-alkyl-amides extracted from A. pyrethrum roots exhibit similar compositions, yielding comparable DFT and Electrostatic Potential (ESP) results with subtle distinctions. These findings underscore the considerable potential of A. pyrethrum root extracts as a natural remedy for vitiligo.
PubMed: 38955123
DOI: 10.1016/j.compbiomed.2024.108816