Immune checkpoint inhibitors (ICI) have revolutionized treatment for various cancers; however, durable response is limited to only a subset of patients. Discovery of blood-based biomarkers that ...reflect dynamic change of the tumor microenvironment, and predict response to ICI, will markedly improve current treatment regimens. Here, we investigate CX3C chemokine receptor 1 (CX3CR1), a marker of T-cell differentiation, as a predictive correlate of response to ICI therapy. Successful treatment of tumor-bearing mice with ICI increases the frequency and T-cell receptor clonality of the peripheral CX3CR1
CD8
T-cell subset that includes an enriched repertoire of tumor-specific and tumor-infiltrating CD8
T cells. Furthermore, an increase in the frequency of the CX3CR1
subset in circulating CD8
T cells early after initiation of anti-PD-1 therapy correlates with response and survival in patients with non-small cell lung cancer. Collectively, these data support T-cell CX3CR1 expression as a blood-based dynamic early on-treatment predictor of response to ICI therapy.
We elucidated the molecular cross-talk between cartilage and synovium in osteoarthritis, the most widespread arthritis in the world, using the powerful tool of single-cell RNA-sequencing. Multiple ...cell types were identified based on profiling of 10,640 synoviocytes and 26,192 chondrocytes: 12 distinct synovial cell types and 7 distinct articular chondrocyte phenotypes from matched tissues. Intact cartilage was enriched for homeostatic and hypertrophic chondrocytes, while damaged cartilage was enriched for prefibro- and fibro-, regulatory, reparative and prehypertrophic chondrocytes. A total of 61 cytokines and growth factors were predicted to regulate the 7 chondrocyte cell phenotypes. Based on production by > 1% of cells, 55% of the cytokines were produced by synovial cells (39% exclusive to synoviocytes and not expressed by chondrocytes) and their presence in osteoarthritic synovial fluid confirmed. The synoviocytes producing IL-1beta (a classic pathogenic cytokine in osteoarthritis), mainly inflammatory macrophages and dendritic cells, were characterized by co-expression of surface proteins corresponding to HLA-DQA1, HLA-DQA2, OLR1 or TLR2. Strategies to deplete these pathogenic intra-articular cell subpopulations could be a therapeutic option for human osteoarthritis.
Asthma is a complex disease of airways, where the interactions of immune and structural cells result in disease outcomes with airway remodeling and airway hyper-responsiveness. Polyamines, which are ...small-sized, natural super-cations, interact with negatively charged intracellular macromolecules, and altered levels of polyamines and their interactions have been associated with different pathological conditions including asthma. Elevated levels of polyamines have been reported in the circulation of asthmatic patients as well as in the lungs of a murine model of asthma. In various studies, polyamines were found to potentiate the pathogenic potential of inflammatory cells, such as mast cells and granulocytes (eosinophils and neutrophils), by either inducing the release of their pro-inflammatory mediators or prolonging their life span. Additionally, polyamines were crucial in the differentiation and alternative activation of macrophages, which play an important role in asthma pathology. Importantly, polyamines cause airway smooth muscle contraction and thus airway hyper-responsiveness, which is the key feature in asthma pathophysiology. High levels of polyamines in asthma and their active cellular and macromolecular interactions indicate the importance of the polyamine pathway in asthma pathogenesis; therefore, modulation of polyamine levels could be a suitable approach in acute and severe asthma management. This review summarizes the possible roles of polyamines in different pathophysiological features of asthma.
A major fraction of the transcriptome of higher organisms comprised an extensive repertoire of long non-coding RNA (lncRNA) which express in a cell type and development stage-specific manner. While ...lncRNAs are a proven component of epigenetic gene expression modulation, epigenetic regulation of lncRNA itself remains poorly understood. Here we have analysed pan-genomic DNA methylation and histone modification marks (H3K4me3, H3K9me3, H3K27me3 and H3K36me3) associated with transcription start site (TSS) of lncRNA in four different cell types and three different tissue types representing various cellular stages. We observe that histone marks associated with active transcription H3K4me3 and H3K36me3 along with the repressive histone mark H3K27me3 have similar distribution pattern around TSS irrespective of cell types. Also, the density of these marks correlates well with expression of protein-coding and lncRNA genes. In contrast, the lncRNA genes harbour higher methylation density around TSS than protein-coding genes regardless of their expression status. Furthermore, we found that DNA methylation along with the other repressive histone mark H3K9me3 does not seem to play a role in lncRNA expression. Thus, our observation suggests that epigenetic regulation of lncRNA shares common features with mRNA except the role of DNA methylation which is markedly dissimilar.
Purpose: The aim of this study was to determine the alteration in ganglion cell complex and its relationship with retinal nerve fiber layer (RNFL) thickness as measured by spectral-domain optical ...coherence tomography (OCT) in pituitary adenoma cases and also its correlation with visual field (VF). Methods: This is a prospective comparative study wherein detailed neuro-ophthalmic examination including perimetry, RNFL and ganglion cell layer inner plexiform layer (GCL-IPL) thickness were measured preoperatively in the cases of pituitary adenoma with chiasmal compression with visual symptoms and field changes who were planned for neuro-surgical intervention. These parameters were repeated 1 year after the surgery. GCL-IPL, RNFL parameters were compared with controls and were correlated with VF mean deviation (MD). The diagnostic power of GCL-IPL was tested using the receiver operating characteristic (ROC) curve. Healthy age and sex-matched controls without any ocular and systemic abnormality were taken for comparison. Results: Twenty-four patients qualified the inclusion criteria. A significant thinning of GCL-IPL (P = 0.002) and RNFL (P = 0.039) was noticed in the pituitary adenoma group. GCL-IPL (r = 0.780 P < 0.001) and RNFL (r = 0.669, P < 0.001) were significantly correlated with the MD. The ROC curve values of GCL-IPL were 0.859 (95% confidence interval 0.744% to 0.973) and of RNFL were 0.731 (95% confidence interval 0.585-0.877). The diagnostic ability of GCL-IPL was more as compared to the RNFL analysis, although it was statistically insignificant (P = 0.122). Conclusion: GCL-IPL measurements on the OCT are a sensitive tool to detect early anterior visual pathway changes in chiasmal compression for pituitary adenoma patients.
We report a case of a 7-year-old girl who presented to us with diminution of vision in her both eyes since childhood. On ophthalmic evaluation, she was found to have the characteristic “sino ...pigmento” variety of pigmentary changes in retina. The other associated features were central obesity, polydactyly of hands and foot, syndactyly of foot, reduced hearing, and genital abnormalities. Based on these clinical features, a diagnosis of Bardet–Biedl syndrome was made. Her genetic analysis revealed the heterozygous variant for
BBS12
gene. A refractive correction was done with explanation of disease. A multidisciplinary approach is required to enable them lead an improved quality of life.
Ischemic stroke is a medical emergency that primarily affects the elderly. A complex immune response in the post-stroke brain constitutes a key component of stroke pathophysiology. This study aimed ...to determine how stroke affects immune cell populations in the aged brain based on molecular profiles of individual cells.
Single-cell RNA sequencing and a new transient ischemic stroke mouse model with late reperfusion were used.
We generated, for the first time, a composite picture of immune cell populations in the stroke aged brain at single-cell resolution. We discovered at least 6 microglial subsets in the stroke aged brain, including a potentially stroke-specific subtype. Moreover, we identified major cell subpopulations formed by infiltrated myeloid cells after stroke, and revealed their unique molecular profiles.
This study provided the first scRNA-seq data set for immune cells in the stroke aged brain, and offered novel insights into post-stroke immune cell heterogeneity.
Alternative splicing (AS) coupled to nonsense-mediated decay (AS-NMD) is a conserved mechanism for post-transcriptional gene regulation. Here we show that, during dietary restriction (DR), AS is ...enhanced in Caenorhabditis elegans and mice. A splicing mediator hrpu-1 regulates a significant part of these AS events in C. elegans; knocking it down suppresses DR-mediated longevity. Concurrently, due to increased AS, NMD pathway genes are upregulated and knocking down UPF1 homologue smg-2 suppresses DR lifespan. Knockdown of NMD during DR significantly increases the inclusion of PTC-containing introns and the lengths of the 3'UTRs. Finally, we demonstrate that PHA-4/FOXA transcriptionally regulates the AS-NMD genes. Our study suggests that DR uses AS to amplify the proteome, supporting physiological remodelling required for enhanced longevity. This increases the dependence on NMD, but also helps fine-tune the expression of metabolic and splicing mediators. AS-NMD may thus provide an energetically favourable level of dynamic gene expression control during dietary restriction.Alternative splicing coupled to nonsense-mediated decay (AS-NMD) is a conserved mechanism for post-transcriptional gene regulation. Here, the authors provide evidence that AS-NMD is enhanced during dietary restriction (DR) and is required for DR-mediated longevity assurance in C. elegans.
Owing to its inductive attributes, hydroxyapatite is an ideal reinforcement to tailor the degradation kinetics of magnesium-based temporary orthopedic implants. However, the large difference in the ...melting temperature of hydroxyapatite and magnesium lead to an insignificant interaction between them during the sintering process, which has been a major limitation in their consolidation. Doping of pure HA with Mg2+ and Zn2+ ions could be a viable solution by making it coherent with the Mg matrix. Further, such doping also results in a chemistry more similar to the natural apatite in human bone. In this study, Mg2+ and Zn2+ ions doped hydroxyapatite (CoHA) is synthesized and reinforced to obtain high density in Mg-based composites, fabricated through spark plasma sintering. Composite with 15 wt % CoHA offered ~113% improvement in the ultimate compressive strength. Higher relative density, due to improved consolidation, might be the reason for higher mechanical strength. Hydrogen evolution (up to 64 h) and static immersion studies (up to 28 days) revealed comparatively higher corrosion resistance for 10 wt% CoHA composites. This study gives insight into the potential of fabrication and designing of the M3Z-CoHA composites for temporary orthopedic implants.
(rat sarcoma virus) mutant cancers remain difficult to treat despite the advances in targeted therapy and immunotherapy. Targeted therapies against the components of mitogen-activated protein kinase ...(MAPK) pathways, including
, RAF, MEK, and ERK, have demonstrated activity in
mutant and, in limited cases,
mutant cancer.
mutant cancers have been found to activate adaptive resistance mechanisms such as autophagy during MAPK inhibition. Here, we review the recent clinically relevant advances in the development of the MAPK pathway and autophagy inhibitors and focus on their application to
mutant cancers. We provide analysis of the preclinical rationale for combining the MAPK pathway and autophagy and highlight the most recent clinical trials that have been launched to capitalize on this potentially synthetic lethal approach to cancer therapy.
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