Limited clinical activity has been seen in osteosarcoma (OS) patients treated with immune checkpoint inhibitors (ICI). To gain insights into the immunogenic potential of these tumors, we conducted ...whole genome, RNA, and T-cell receptor sequencing, immunohistochemistry and reverse phase protein array profiling (RPPA) on OS specimens from 48 pediatric and adult patients with primary, relapsed, and metastatic OS. Median immune infiltrate level was lower than in other tumor types where ICI are effective, with concomitant low T-cell receptor clonalities. Neoantigen expression in OS was lacking and significantly associated with high levels of nonsense-mediated decay (NMD). Samples with low immune infiltrate had higher number of deleted genes while those with high immune infiltrate expressed higher levels of adaptive resistance pathways. PARP2 expression levels were significantly negatively associated with the immune infiltrate. Together, these data reveal multiple immunosuppressive features of OS and suggest immunotherapeutic opportunities in OS patients.
Sodium Fluoride (NaF) can change the expression of skeletal muscle proteins. Since skeletal muscle is rich in mitochondrial and contractile (sarcomeric) proteins, these proteins are sensitive to the ...effects of NaF, and the changes are dose-and time-dependent. In the current study, we have analysed the effect of high concentrations of NaF (80ppm) on mouse skeletal muscle at two different time points, i.e., 15 days and 60 days. At the end of the experimental time, the animals were sacrificed, skeletal muscles were isolated, and proteins were extracted and subjected to bioinformatic (Mass Spectrometric) analysis. The results were analysed based on changes in different mitochondrial complexes, contractile (sarcomeric) proteins, 26S proteasome, and ubiquitin-proteasome pathway. The results showed that the mitochondrial proteins of complex I, II, III, IV and V were differentially regulated in the groups treated with 80ppm of NaF for 15 days and 60 days. The network analysis indicated more changes in mitochondrial proteins in the group treated with the higher dose for 15 days rather than 60 days. Furthermore, differential expression of (sarcomeric) proteins, downregulation of 26S proteasome subunits, and differential expression in proteins related to the ubiquitin-proteasome pathway lead to muscle atrophy. The differential expression might be due to the adaptative mechanism to counteract the deleterious effects of NaF on energy metabolism. Data are available via ProteomeXchange with identifier PXD035014.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Skeletal muscle is one of the leading frameworks of the musculo-skeletal system, which works in synergy with the bones. Long skeletal muscles provide stability and mobility to the human body and are ...primarily composed of proteins. Conversely, improper functioning of various skeletal muscles leads to diseases and disorders, namely, age-related muscle disorder called sarcopenia, a group of genetic muscle disorders such as muscular dystrophies, and severe muscle wasting in cancer known as cachexia. However, skeletal muscle has an excellent ability to undergo hypertrophy and enhanced functioning during sustained exercise over time. Indeed, these processes of skeletal muscle regeneration/hypertrophy, as well as degeneration and atrophy, involve an interplay of various signaling pathways. Myostatin is one such chemokine/myokine with a significant contribution to muscle regeneration or atrophy in multiple conditions. In this review, we try to put together the role and regulation of myostatin as a function of muscle regeneration extrapolated to multiple aspects of its molecular functions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Complex tumor microenvironmental (TME) features influence the outcome of cancer immunotherapy (IO). Here we perform immunogenomic analyses on 67 intratumor sub-regions of a PD-1 inhibitor-resistant ...melanoma tumor and 2 additional metastases arising over 8 years, to characterize TME interactions. We identify spatially distinct evolution of copy number alterations influencing local immune composition. Sub-regions with chromosome 7 gain display a relative lack of leukocyte infiltrate but evidence of neutrophil activation, recapitulated in The Cancer Genome Atlas (TCGA) samples, and associated with lack of response to IO across three clinical cohorts. Whether neutrophil activation represents cause or consequence of local tumor necrosis requires further study. Analyses of T-cell clonotypes reveal the presence of recurrent priming events manifesting in a dominant T-cell clonotype over many years. Our findings highlight the links between marked levels of genomic and immune heterogeneity within the physical space of a tumor, with implications for biomarker evaluation and immunotherapy response.
Lung cancer is the leading cause of cancer death, partially owing to its extensive heterogeneity. The analysis of intertumor heterogeneity has been limited by an inability to concurrently obtain ...tissue from synchronous metastases unaltered by multiple prior lines of therapy.
In order to study the relationship between genomic, epigenomic and T cell repertoire heterogeneity in a rare autopsy case from a 32-year-old female never-smoker with left lung primary late-stage lung adenocarcinoma (LUAD), we did whole-exome sequencing (WES), DNA methylation and T cell receptor (TCR) sequencing to characterize the immunogenomic landscape of one primary and 19 synchronous metastatic tumors.
We observed heterogeneous mutation, methylation, and T cell patterns across distinct metastases. Only TP53 mutation was detected in all tumors suggesting an early event while other cancer gene mutations were later events which may have followed subclonal diversification. A set of prevalent T cell clonotypes were completely excluded from left-side thoracic tumors indicating distinct T cell repertoire profiles between left-side and non left-side thoracic tumors. Though a limited number of predicted neoantigens were shared, these were associated with homology of the T cell repertoire across metastases. Lastly, ratio of methylated neoantigen coding mutations was negatively associated with T-cell density, richness and clonality, suggesting neoantigen methylation may partially drive immunosuppression.
Our study demonstrates heterogeneous genomic and T cell profiles across synchronous metastases and how restriction of unique T cell clonotypes within an individual may differentially shape the genomic and epigenomic landscapes of synchronous lung metastases.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
BackgroundClinical evidence suggests that early changes in circulating tumor DNA fraction estimates (ctFEs) may be predictive of immune checkpoint inhibitor (ICI) response. However, data on the ...validity and utilization of this biomarker in clinical practice is lacking. Further, existing biomarkers often track mutations from small panels and exclude non-mutational events. We present a novel approach for estimating ctFE (denoted xF Monitor) utilizing diverse genomic events, and the association of changes in ctFEs with ICI outcomes in a real-world pan-cancer cohort.Methods ctDNA profiling was performed using the Tempus xF liquid biopsy assay of 105 genes. ctFE is computed by applying an ensemble algorithm incorporating copy number variant data, and somatic and germline variant allele frequencies (VAFs). The limit of blank (LOB) was established using 20 presumed-healthy samples. The accuracy of the ctFE algorithm was evaluated using held-out 17 presumed-healthy plasma samples and 124 clinical plasma samples and compared against performance of a median VAF approach.Deidentified patient records from the Tempus multimodal database were analyzed if patients had an xF test ≤ 60 days prior to the start of ICI (alone or in combination with chemotherapy (CT)) and an xF test 15–180 days post-ICI. Patients were evaluable if they had ctDNA > LOB at baseline. Molecular responders (MR) were defined as patients with a >25% decrease in cTFE between tests. Clinical endpoints were defined from ICI start to the first progression event or death (rwPFS) or death (rwOS), both censored on the last follow-up in event-free patients.ResultsThe evaluable pan-cancer cohort (n= 86 patients, median age 63 yrs, F = 38%) had > 10 solid tumor types (49% with lung diagnosis). The majority of patients received ICI + CT (66%). The baseline ctFE detection rate was 76%, with a median ctFE of 7.3%. The ctFE algorithm showed improved sensitivity and specificity compared to median VAF, 100% vs. 97%, and 100% vs. 80%, respectively. MRs, with a median decrease from baseline of 83%, had significantly longer rwPFS (HR=0.34, p<0.001, figure 1) and rwOS (HR=0.35, p=0.002, figure 2) than non-MRs.ConclusionsxF Monitor is a novel serial quantitative cTFE algorithm off the Tempus xF assay that has the potential to be used clinically as a predictive biomarker to stratify patients who are likely to benefit from ICI therapy, sparing ineffective therapeutic approaches. The xF Monitor biomarker needs to be prospectively validated in a larger cohort.Abstract 34 Figure 1Real-world progression-free survival by molecular response.Abstract 34 Figure 2Real-world overall survival by molecular response.
Globin (Gb) domains function in sensing gaseous ligands like oxygen and nitric oxide. In recent years, Gb domain containing heme binding adenylate cyclases (OsAC or GbAC) emerged as significant ...modulator of
Leishmania
response to hypoxia and oxidative stress. During progression of life cycle stages, kinetoplastids experience altered condition in insect vectors or other hosts. Moreover, marked diversity in life style has been accounted among kinetoplastids. Distribution and abundance of Gb-domains vary between different groups of kinetoplastids. While in bodonoids, Gbs are not combined with any other functional domains, in trypanosomatids it is either fused with adenylate cyclase (AC) or oxidoreductase (OxR) domains. In salivarian trypanosomatids and
Leishmania
(Viannia) subtypes, no gene product featuring Gbs can be identified. In this context, evolution of Gb-domains in kinetoplastids was explored. GbOxR derived Gbs clustered with bacterial flavohemoglobins (fHb) including one fHb from
Advenella
, an endosymbiont of monoxeneous trypanosomatids. Codon adaptation and other evolutionary analysis suggested that OsAC (LmjF.28.0090), the solitary Gb-domain featuring gene product in
Leishmania
, was acquired via possible horizontal gene transfer. Substantial functional divergence was estimated between orthologues of genes encoding GbAC or GbOxR; an observation also reflected in structural alignment and heme-binding residue predictions. Orthologue–paralogue and synteny analysis indicated genomic reduction in GbOxR and GbAC loci for dixeneous trypanosomatids.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Toxicity caused by chronic hyperglycemia is a significant factor affecting skeletal muscle myogenesis, resulting in diabetic myopathy. Chronic and persistent hyperglycemia causes activation of the ...atrophy-related pathways in the skeletal muscles, which eventually results in inflammation and muscle degeneration. To counteract this process, various bioactive compound has been studied for their reversal or hypertrophic effect. In this study, we explored the molecular mechanisms associated with reversing glucotoxicity's effect in C2C12 cells by arachidonic acid (AA). We found a substantial increase in the pro-inflammatory cytokines and ROS production in hyperglycemic conditions, mitigated by AA supplementation. We found that AA supplementation restored protein synthesis that was downregulated under glucotoxicity conditions. AA enhanced myogenesis by suppressing high glucose induced inflammation and ROS production and enhancing protein synthesis. These results imply that AA has cytoprotective actions against hyperglycemia-induced cytotoxicity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The quorum quenching (QQ) potential of three pentacyclic triterpenoids, glycyrrhetinic acid (GRA), ursolic acid (UA) and betulinic acid (BA), representing distinct groups of compounds, was evaluated. ...Violacein production by Chromobacterium violaceum and pyocyanin production by Pseudomonas aeruginosa were severely affected by GRA, UA and BA, suggesting a perturbation of N-acyl homoserine lactone (ASL) based signaling. Molecular docking analysis revealed a possible interaction between ASL-synthase and ASL-dependent transcriptional activator homologs from P. aeruginosa and Acinetobacter baumannii with common binding pockets for GRA, UA and BA. The triterpenoids inhibited biofilm formation by A. baumannii and affected the overall structure of biofilms. When administered in combination, two of the three molecules fostered antibiotic action against A. baumannii biofilms, widening the scope for developing novel combinations against the pathogen.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
Obestatin is derived from the same gene as that of ghrelin and their functions were perceived to be antagonistic. Recent developments have shown that although they are known to have contradictory ...functions, effect of obestatin on skeletal muscle regeneration is similar to that of ghrelin. Obestatin works through a receptor called GPR39, a ghrelin and motilin family receptor and transduces signals in skeletal muscle similar to that of ghrelin. Not only there is a similarity in the receptor family, but also obestatin targets similar proteins and transcription factors as that of ghrelin (for example, FoxO family members) for salvaging skeletal muscle atrophy. Moreover, like ghrelin, obestatin also works by inducing the transcription of Pax7 which is required for muscle stem cell mobilisation. Hence, there are quite some evidences which points to the fact that obestatin can be purposed as a peptide intervention to prevent skeletal muscle wasting and induce myogenesis. This review elaborates these aspects of obestatin which can be further exploited and addressed to bring obestatin as a clinical intervention towards preventing skeletal muscle atrophy and sarcopenia.
Graphical Abstract
Summary of action of obestatin in skeletal muscle atrophy. (Icon image source: www.flaticon.com; Obestatin structure: PDB id 2JSH)
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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