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Frontiers in Immunology 2024The therapeutic effectiveness of immune checkpoint inhibitors (ICIs) in bladder cancer varies among individuals. Identifying reliable predictors of response to these...
BACKGROUND
The therapeutic effectiveness of immune checkpoint inhibitors (ICIs) in bladder cancer varies among individuals. Identifying reliable predictors of response to these therapies is crucial for optimizing patient outcomes.
METHODS
This retrospective study analyzed 348 bladder cancer patients treated with ICIs, with additional validation using data from 248 patients at our institution who underwent PD-L1 immunohistochemical staining. We examined patient smoking history, clinicopathological characteristics, and immune phenotypes. The main focus was the correlation between smoking history and immunotherapy outcomes. Multivariate logistic and Cox proportional hazard regressions were used to adjust for confounders.
RESULTS
The study cohort comprised 348 bladder cancer patients receiving ICIs. Among them, 116 (33.3%) were never smokers, 197 (56.6%) were former smokers (median pack-years = 28), and 35 (10.1%) were current smokers (median pack-years = 40). Analysis revealed no statistically significant difference in overall survival across different smoking statuses (objective response rates were 11.4% for current smokers, 17.2% for never smokers, and 22.3% for former smokers; = 0.142, 0.410, and 0.281, respectively). However, a notable trend indicated a potentially better response to immunotherapy in former smokers compared to current and never smokers. In the validation cohort of 248 patients from our institution, immunohistochemical analysis showed that PD-L1 expression was significantly higher in former smokers (55%) compared to current smokers (37%) and never smokers (47%). This observation underscores the potential influence of smoking history on the tumor microenvironment and its responsiveness to ICIs.
CONCLUSION
In conclusion, our study demonstrates the importance of incorporating smoking history in predicting the response to immunotherapy in bladder cancer patients, highlighting its role in personalized cancer treatment approaches. Further research is suggested to explore the comprehensive impact of lifestyle factors on treatment outcomes.
Topics: Humans; Urinary Bladder Neoplasms; Male; Female; Aged; Middle Aged; Retrospective Studies; Smoking; Immune Checkpoint Inhibitors; Immunotherapy; Treatment Outcome; B7-H1 Antigen; Aged, 80 and over; Adult
PubMed: 38938564
DOI: 10.3389/fimmu.2024.1404812 -
International Journal of Genomics 2024In the context of hepatocellular carcinoma (HCC), tumor-associated macrophages (TAMs) are pivotal for the immunosuppressive nature of the tumor microenvironment (TME)....
BACKGROUND
In the context of hepatocellular carcinoma (HCC), tumor-associated macrophages (TAMs) are pivotal for the immunosuppressive nature of the tumor microenvironment (TME). This investigation delves into the functional transformations of TAMs within the TME by leveraging single-cell transcriptomics to pinpoint critical genes influencing TAM subset polarization.
METHODS
We procured single-cell and bulk transcriptomic data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA), implementing quality assurance, dimensional reduction, clustering, and annotation on the single-cell sequencing data. To examine cellular interactions, CellChat was utilized, while single-cell regulatory network inference and clustering (SCENIC) was applied to deduce transcription factors (TFs) and their associated targets. Through gene enrichment, survival, and immune infiltration correlation analyses, we sought to pinpoint and validate influential genes. A TAM model under HCC conditions was then established to confirm the expression levels of these key genes.
RESULTS
Our analysis encompassed 74,742 cells and 23,110 genes. Through postdimensional reduction and clustering, we identified seven distinct cell types and nine TAM subtypes. Analysis via CellChat highlighted a predominance of M2-phenotype-inclined TAM subsets within the tumor's core. SCENIC pinpointed the transcription factor PRDM1 and its target genes as pivotal in this region. Further analysis indicated these genes' involvement in macrophage polarization. Employing trajectory analysis, survival analysis, and immune infiltration correlation, we scrutinized and validated genes likely directing M2 polarization. Experimental validation confirmed PRDM1's heightened expression in TAMs conditioned by HCC.
CONCLUSIONS
Our findings suggest the PRDM1 gene is a key regulator of M2 macrophage polarization, contributing to the immunosuppressive TME in HCC.
PubMed: 38938448
DOI: 10.1155/2024/7263358 -
International Journal of Genomics 2024related hypertriglyceridemia occurs due to biallelic variants of this gene. Here, genotype-phenotype architecture of all pathogenic variants is investigated among...
related hypertriglyceridemia occurs due to biallelic variants of this gene. Here, genotype-phenotype architecture of all pathogenic variants is investigated among heterozygous and homozygous individuals. Clinical heterogeneity of various types of the variants is also described, and pancreatitis in more than half of homozygotes carrying chain-termination variants is highlighted as well. For this study, patients were selected who had a plasma triglyceride level above 250 mg/dL. The coding and intronic regions of the gene were amplified using the Sanger sequencing to investigate the presence of variants. The genotypes, lipid profiles, and detailed clinical features were documented for all -related patients and heterozygous individuals. Pathogenicity of the variants was predicted and categorized using available bioinformatics tools such as MutationTaster and PolyPhen-2 and ACMG criteria. MetaDome and Phyre2 were applied for structural and functional in silico analyses. 40% (12 out of 30) of variants were chain-termination (nonsense and frameshift) variants. These types of variants were determined in 60.53% of patients. 55% of these patients showed pancreatitis followed by lipemia retinalis (29%), abdominal pain (24%), hepatosplenomegaly (24%), and xanthomas (18%). The mean age of onset was about 22 years old. In at least 50% of 38 homozygous individuals, the TG level was more than 2000 mg/dL. More than 25% of heterozygous individuals showed at least one symptom. Pancreatitis and a severe form of HTG were found in 5 and 2% of heterozygous individuals, respectively. The main clinical features of -related hypertriglyceridemia include pancreatitis, lipemia retinalis, abdominal pain, hepatosplenomegaly, and xanthomas. Nonsense and frameshift homozygous variants usually lead to a severe form of hypertriglyceridemia. Pancreatitis is one of the main consequences of these types of mutations; thus, it is important to consider this point when evaluating asymptomatic individuals. Heterozygous individuals may become symptomatic due to the role of unknown modifying agent including environmental genetic factors.
PubMed: 38938447
DOI: 10.1155/2024/6653857 -
Frontiers in Medicine 2024Previous studies have reported Caspase-1 () is upregulated in mouse models of Juvenile X-linked Retinoschisis (XLRS), however no functional role for in disease...
PURPOSE
Previous studies have reported Caspase-1 () is upregulated in mouse models of Juvenile X-linked Retinoschisis (XLRS), however no functional role for in disease progression has been identified. We performed electroretinogram (ERG) and standardized optical coherence tomography (OCT) in mice deficient in the Retinoschisin-1 () and and Caspase-11 genes (-KO ) to test the hypothesis that may play a role in disease evolution and or severity of disease. Currently, no studies have ventured to investigate the longer-term effects of on phenotypic severity and disease progression over time in XLRS, and specifically the effect on electroretinogram.
METHODS
-KO; mice were generated by breeding -KO mice with mice. OCT imaging was analyzed at 2-, 4-, and 15-16 months of age. Outer nuclear layer (ONL) thickness and adapted standardized cyst severity score were measured and averaged from 4 locations 500 μm from the optic nerve. Adapted standardized cyst severity score was 1: absent cysts, 2: <30 μm, 3: 30-49 μm, 4: 50-69 μm, 5: 70-99 μm, 6: >99 μm. Electroretinograms (ERG) were recorded in dark-adapted and light-adapted conditions at 2 and 4 months. Results obtained from -KO and -KO; eyes were compared with age matched WT control eyes at 2 months.
RESULTS
Intraretinal schisis was not observed on OCT in WT eyes, while schisis was apparent in most -KO and -KO; eyes at 2 and 4 months of age. There was no difference in the cyst severity score from 2 to 4 months of age, or ONL thickness from 2 to 16 months of age between -KO and -KO; eyes. ERG amplitudes were similarly reduced in -KO and -KO; compared to WT controls at 2 months of age, and there was no difference between KO and -KO; eyes at 2 or 4 months of age, suggesting no impact on the electrical function of photoreceptors over time in the absence of .
CONCLUSION
Although has been reported to be significantly upregulated in KO mice, our preliminary data suggest that removing does not modulate photoreceptor electrical function or alter the trajectory of the retinal architecture over time.
PubMed: 38938378
DOI: 10.3389/fmed.2024.1347599 -
Molecular Genetics & Genomic Medicine Jun 2024Spastic paraplegia 11 (SPG11) is the most prevalent form of autosomal recessive hereditary spastic paraplegia, resulting from biallelic pathogenic variants in the SPG11...
BACKGROUND
Spastic paraplegia 11 (SPG11) is the most prevalent form of autosomal recessive hereditary spastic paraplegia, resulting from biallelic pathogenic variants in the SPG11 gene (MIM *610844).
METHODS
The proband is a 36-year-old female referred for genetic evaluation due to cognitive dysfunction, gait impairment, and corpus callosum atrophy (brain MRI was normal at 25-years-old). Diagnostic approaches included CGH array, next-generation sequencing, and whole transcriptome sequencing.
RESULTS
CGH array revealed a 180 kb deletion located upstream of SPG11. Sequencing of SPG11 uncovered two rare single nucleotide variants: the novel variant c.3143C>T in exon 17 (in cis with the deletion), and the previously reported pathogenic variant c.6409C>T in exon 34 (in trans). Whole transcriptome sequencing revealed that the variant c.3143C>T caused exon 17 skipping.
CONCLUSION
We report a novel sequence variant in the SPG11 gene resulting in exon 17 skipping, which, along with a nonsense variant, causes Spastic Paraplegia 11 in our proband. In addition, a deletion upstream of SPG11 was identified in the patient, whose implication in the phenotype remains uncertain. Nonetheless, the deletion apparently affects cis-regulatory elements of the gene, suggesting a potential new pathogenic mechanism underlying the disease in a subset of undiagnosed patients. Our findings further support the hypothesis that the origin of thin corpus callosum in patients with SPG11 is of progressive nature.
Topics: Humans; Female; Adult; Spastic Paraplegia, Hereditary; Exons; Proteins; Codon, Nonsense; Corpus Callosum; Sequence Deletion; Phenotype
PubMed: 38938072
DOI: 10.1002/mgg3.2475 -
Animal Bioscience Jun 2024The remarkable adaptability to the environment, high growth rate, meat with good taste and aroma, and ornamental appearance of the Pradu Hang Dam (PDH) and Samae Dam...
OBJECTIVE
The remarkable adaptability to the environment, high growth rate, meat with good taste and aroma, and ornamental appearance of the Pradu Hang Dam (PDH) and Samae Dam (SD) chickens make them valuable for improvement of poultry production to enhance food security. However, despite their close phenotypic similarity, distinct classification of PDH and SD chickens remains controversial. Thus, this study aimed to clarify genetic origins and variation between PDH and SD chickens, genetic diversity and structures of PDH and SD chickens.
METHODS
This study analyzed 5 populations of PDH and 2 populations of SD chickens using 28 microsatellite markers and compared with those of other indigenous and local chicken breeds using Thailand's "The Siam Chicken Bioresource Project" database.
RESULTS
Considerably high genetic variability was observed within PDH (370 total alleles; 4.086 ± 0.312 alleles/locus) and SD chickens (179 total alleles; 3.607 ± 0.349 alleles/locus). A partial overlap of gene pools was observed between SD chickens from the Department of Livestock, Uthai Thani (SD1) and PDH chickens, suggesting a potentially close relationship between the two chicken breeds. A gene pool that is partially overlapped with that of the red junglefowl was observed in the SD chicken population from the Sanhawat Farm Uthai Thani population (SD2). Distinct subclusters were observed within SD chickens, indicating the possibility that genetic differentiation occurred early in the process of establishment of SD chickens.
CONCLUSION
These findings could offer valuable insights into genetic verification of Thai local chicken breeds and their sustainable conservation and utilization.
PubMed: 38938037
DOI: 10.5713/ab.24.0161 -
Stem Cell Research & Therapy Jun 2024Due to the advanced studies on stem cells in developmental biology, the roles of stem cells in the body and their phenotypes in related diseases have not been covered... (Review)
Review
Due to the advanced studies on stem cells in developmental biology, the roles of stem cells in the body and their phenotypes in related diseases have not been covered clearly. Meanwhile, with the intensive research on the mechanisms of stem cells in regulating various diseases, stem cell therapy is increasingly being attention because of its effectiveness and safety. As one of the most widely used stem cell in stem cell therapies, hematopoietic stem cell transplantation shows huge advantage in treatment of leukemia and other blood-malignant diseases. Besides, due to the effect of anti-inflammatory and immunomodulatory, mesenchymal stem cells could be a potential therapeutic strategy for variety infectious diseases. In this review, we summarized the effects of Staphylococcus aureus (S. aureus) and its components on different types of adult stem cells and their downstream signaling pathways. Also, we reviewed the roles of different kinds of stem cells in various disease models caused by S. aureus, providing new insights for applying stem cell therapy to treat infectious diseases.
Topics: Humans; Staphylococcus aureus; Animals; Inflammation; Staphylococcal Infections; Signal Transduction; Mesenchymal Stem Cells
PubMed: 38937829
DOI: 10.1186/s13287-024-03781-6 -
Journal of Biomedical Science Jun 2024The endoplasmic reticulum (ER) employs stringent quality control mechanisms to ensure the integrity of protein folding, allowing only properly folded, processed and... (Review)
Review
The endoplasmic reticulum (ER) employs stringent quality control mechanisms to ensure the integrity of protein folding, allowing only properly folded, processed and assembled proteins to exit the ER and reach their functional destinations. Mutant proteins unable to attain their correct tertiary conformation or form complexes with their partners are retained in the ER and subsequently degraded through ER-associated protein degradation (ERAD) and associated mechanisms. ER retention contributes to a spectrum of monogenic diseases with diverse modes of inheritance and molecular mechanisms. In autosomal dominant diseases, when mutant proteins get retained in the ER, they can interact with their wild-type counterparts. This interaction may lead to the formation of mixed dimers or aberrant complexes, disrupting their normal trafficking and function in a dominant-negative manner. The combination of ER retention and dominant-negative effects has been frequently documented to cause a significant loss of functional proteins, thereby exacerbating disease severity. This review aims to examine existing literature and provide insights into the impact of dominant-negative effects exerted by mutant proteins retained in the ER in a range of autosomal dominant diseases including skeletal and connective tissue disorders, vascular disorders, neurological disorders, eye disorders and serpinopathies. Most crucially, we aim to emphasize the importance of this area of research, offering substantial potential for understanding the factors influencing phenotypic variability associated with genetic variants. Furthermore, we highlight current and prospective therapeutic approaches targeted at ameliorating the effects of mutations exhibiting dominant-negative effects. These approaches encompass experimental studies exploring treatments and their translation into clinical practice.
Topics: Humans; Endoplasmic Reticulum; Genes, Dominant; Endoplasmic Reticulum-Associated Degradation; Protein Folding; Mutation
PubMed: 38937821
DOI: 10.1186/s12929-024-01054-1 -
Journal of Translational Medicine Jun 2024Monocyte-derived alveolar macrophages (Mo_AMs) are increasingly recognised as potential pathogenic factors for idiopathic pulmonary fibrosis (IPF). While scRNAseq...
BACKGROUND
Monocyte-derived alveolar macrophages (Mo_AMs) are increasingly recognised as potential pathogenic factors for idiopathic pulmonary fibrosis (IPF). While scRNAseq analysis has proven valuable in the transcriptome profiling of Mo_AMs, the integration analysis of multi-omics may provide additional dimensions of understanding of these cellular populations.
METHODS
We performed multi-omics analysis on 116 scRNAseq, 119 bulkseq and five scATACseq lung tissue samples from IPF. We built a large-scale IPF scRNAseq atlas and conducted the Monocle 2/3 as well as the Cellchat to explore the developmental path and intercellular communication on Mo_AMs. We also reported the difference in metabolisms, tissue repair and phagocytosis between Mo_AMs and tissue-resident alveolar macrophages (TRMs). To determine whether Mo_AMs affected pulmonary function, we projected clinical phenotypes (FVC%pred) from the bulkseq dataset onto the scRNAseq atlas. Finally, we used scATATCseq to uncover the upstream regulatory mechanisms and determine key drivers in Mo_AMs.
RESULTS
We identified three Mo_AMs clusters and the trajectory analysis further validated the origin of these clusters. Moreover, via the Cellchat analysis, the CXCL12/CXCR4 axis was found to be involved in the molecular basis of reciprocal interactions between Mo_AMs and fibroblasts through the activation of the ERK pathway in Mo_AMs. SPP1_RecMacs (RecMacs, recruited macrophages) were higher in the low-FVC group than in the high-FVC group. Specifically, compared with TRMs, the functions of lipid and energetic metabolism as well as tissue repair were higher in Mo_AMs than TRMs. But, TRMs may have higher level of phagocytosis than TRMs. SPIB (PU.1), JUNB, JUND, BACH2, FOSL2, and SMARCC1 showed stronger association with open chromatin of Mo_AMs than TRMs. Significant upregulated expression and deep chromatin accessibility of APOE were observed in both SPP1_RecMacs and TRMs.
CONCLUSION
Through trajectory analysis, it was confirmed that SPP1_RecMacs derived from Monocytes. Besides, Mo_AMs may influence FVC% pred and aggravate pulmonary fibrosis through the communication with fibroblasts. Furthermore, distinctive transcriptional regulators between Mo_AMs and TRMs implied that they may depend on different upstream regulatory mechanisms. Overall, this work provides a global overview of how Mo_AMs govern IPF and also helps determine better approaches and intervention therapies.
Topics: Humans; Idiopathic Pulmonary Fibrosis; Macrophages, Alveolar; Monocytes; Male; Gene Expression Profiling; Female; Receptors, CXCR4; Middle Aged; Phenotype; Lung; Gene Expression Regulation
PubMed: 38937806
DOI: 10.1186/s12967-024-05398-y -
Cell Communication and Signaling : CCS Jun 2024Tumor cells release extracellular vesicles (EVs) that contribute to the polarization of macrophages towards tumor-associated macrophages (TAMs). High expression levels...
BACKGROUND
Tumor cells release extracellular vesicles (EVs) that contribute to the polarization of macrophages towards tumor-associated macrophages (TAMs). High expression levels of the RNA binding protein IGF2BP2/IMP2 are correlated with increased tumor cell proliferation, invasion, and poor prognosis in the clinic. However, there is a lack of understanding of whether IMP2 affects the cargo of cancer cell-derived EVs, thereby modulating macrophage polarization.
METHODS
EVs were isolated from IMP2-expressing HCT116 parental cells (WT) and CRISPR/Cas9 IMP2 knockout (KO) cells. EVs were characterized according to MISEV guidelines, microRNA cargo was assessed by microRNA-Seq, and the protein cargo was analyzed by proteomics. Primary human monocyte-derived macrophages (HMDMs) were polarized by EVs, and the expression of genes and surface markers was assessed using qPCR and flow cytometry, respectively. Morphological changes of macrophages, as well as the migratory potential of cancer cells, were assessed by the Incucyte system and macrophage matrix degradation potential by zymography. Changes in the metabolic activity of macrophages were quantified using a Seahorse analyzer. For in vivo studies, EVs were injected into the yolk sac of zebrafish larvae, and macrophages were isolated by fluorescence-activated cell sorting.
RESULTS
EVs from WT and KO cells had a similar size and concentration and were positive for 25 vesicle markers. The expression of tumor-promoting genes was higher in macrophages polarized with WT EVs than KO EVs, while the expression of TNF and IL6 was reduced. A similar pattern was observed in macrophages from zebrafish larvae treated in vivo. WT EV-polarized macrophages showed a higher abundance of TAM-like surface markers, higher matrix degrading activity, as well as a higher promotion of cancer cell migration. MicroRNA-Seq revealed a significant difference in the microRNA composition of WT and KO EVs, particularly a high abundance of miR-181a-5p in WT EVs, which was absent in KO EVs. Inhibitors of macropinocytosis and phagocytosis antagonized the delivery of miR-181a-5p into macrophages and the downregulation of the miR-181a-5p target DUSP6. Proteomics data showed differences in protein cargo in KO vs. WT EVs, with the differentially abundant proteins mainly involved in metabolic pathways. WT EV-treated macrophages exhibited a higher basal oxygen consumption rate and a lower extracellular acidification rate than KO EV-treated cells.
CONCLUSION
Our results show that IMP2 determines the cargo of EVs released by cancer cells, thereby modulating the EVs' actions on macrophages. Expression of IMP2 is linked to the secretion of EVs that polarize macrophages towards a tumor-promoting phenotype.
Topics: Humans; Extracellular Vesicles; RNA-Binding Proteins; Animals; Zebrafish; Tumor-Associated Macrophages; HCT116 Cells; MicroRNAs; Cell Movement; Macrophages
PubMed: 38937789
DOI: 10.1186/s12964-024-01701-y