Several susceptibility loci for classical Hodgkin lymphoma have been reported. However, much of the heritable risk is unknown. Here, we perform a meta-analysis of two existing genome-wide association studies, a new genome-wide association study, and replication totalling 5,314 cases and 16,749 controls. We identify risk loci for all classical Hodgkin lymphoma at 6q22.33 (rs9482849, P = 1.52 × 10
Base excision repair (BER) is a frontline system that is responsible for maintaining genome integrity and thus preventing premature aging and cancer by repairing DNA lesions and strand breaks caused by endogenous and exogenous mutagens. However, it is also the principal cellular system in cancer cells that counteracts the killing effect of the major cancer treatments, e.g. chemotherapy and ionizing radiation. Although it is clear that an individual's DNA repair capacity varies, the mechanisms involved in the regulation of repair systems responsible for such variations is only just emerging. This knowledge gap is impeding the finding of new cancer therapy targets and the development of novel treatment strategies. In recent years the vital role of post-translational modifications of BER proteins, including ubiquitylation, has been uncovered. Interestingly, new players in the regulation of BER include proteins encoded by well-known tumour suppressors. This review covers recent progress in our understanding of the post-translational regulation of BER, including the proteins involved, with a specific focus on the role of the ARF (p14) tumour suppressor protein in BER.
Abstract Genome-wide association studies have identified several risk loci for multiple myeloma (MM); however, the mechanisms by which they influence MM are unknown. Here by using genetic association data and functional characterization, we demonstrate that rs4487645 G>T, the most highly associated variant ( P = 5.30 × 10 −25 ), resides in an enhancer element 47 kb upstream of the transcription start site of c-Myc-interacting CDCA7L . The G-risk allele, associated with increased CDCA7L expression ( P =1.95 × 10 −36 ), increases IRF4 binding and the enhancer interacts with the CDCA7L promoter. We show that suppression of CDCA7L limits MM proliferation through apoptosis, and increased CDCA7L expression is associated with adverse patient survival. These findings implicate IRF4-mediated CDCA7L expression in MM biology and indicate how germline variation might confer susceptibility to MM.
In gallbladder bile, lipids aggregate as micelles and vesicles, yet the presence of lamellae remains controversial. Little is known on lipid assembly in dilute hepatic bile. Liver transplantation represents a condition in which bile is diluted immediately after transplant and tends to normalize thereafter.To study biliary lipidic carriers after liver transplantation in relation to the increasing bile lipid concentration.Three bile samples were harvested from six patients (3M/3F) with normal post-transplant outcome: sample 1 at days 2-3, sample 2 at 1 week, and sample 3 at 2 weeks after transplant. Samples were analyzed by biochemical, morphological and quasi-elastic light scattering methodology.Lipid concentration increased from 0.6g/dl at day 2-3 to 3.6g/dl at week 2. Electron microscopy showed the presence of unilamellar vesicles in all samples. Large amorphous particles interpreted as proteic aggregates were also present at day 2-3, while lamellae coexisted with vesicles later. Quasi-elastic light scattering data were consistent with electron microscopic findings. Liquid crystals were observed at polarizing microscopy with increasing bile lipid concentration.Normalization of biliary lipid secretion after liver transplantation is associated with: (i) increased proportion of vesicles and reduction of their size; (ii) presence of lamellae.
Abstract Increased sympathetic and reduced parasympathetic nerve activity is associated with disease progression and poor outcomes in patients with chronic heart failure. The demonstration that markers of autonomic imbalance and vagal dysfunction, such as reduced heart rate variability and baroreflex sensitivity, hold prognostic value in patients with chronic heart failure despite modern therapies encourages the research for neuromodulation strategies targeting the vagus nerve. However, the approaches tested so far have yielded inconclusive results. This review aims to summarize the current knowledge about the role of the parasympathetic nervous system in chronic heart failure, describing the pathophysiological background, the methods of assessment, and the rationale, limits, and future perspectives of parasympathetic stimulation either by drugs or bioelectronic devices.
Adenocarcinoma (ADC) is the most common histologic type of lung cancer, including in situ (lepidic), minimally invasive, and invasive forms. While the former 2 types are associated with a favorable outcome, the latter includes tumors with variable behavior, often tumor stage–related. A recent study proposed strict morphologic criteria defining a new subgroup of resected stage I invasive ADC (16% of cases) with favorable outcomes (100% disease-specific survival), named “ADC of low malignant potential (LMP-ADC).” The following criteria were met: ≤3 cm size, nonmucinous histotype, ≥15% lepidic growth, and the absence of the following: high-grade patterns, >1 mitosis/2 mm 2 , necrosis, and vascular/pleural invasion. The aim of the present study was to validate the performance of such criteria to identify LMP-ADC in a series of 274 stage IA resected lung ADCs from a single institution. Thirty-four tumors (12.4%) met the proposed criteria for LMP-ADC, as confirmed by additional stains for mitotic figures, Ki67 index, and elastic fibers (helpful to assess alveolar wall invasion). Minor differences between the lepidic and invasive components were observed regarding cell atypia and proliferation. p53 was normally expressed by invasive tumor cells. Mutations occurred in known lung cancer genes (mostly KRAS and EGFR). Five patients (14.7%) developed disease progression and 2 of them (5.9%) died of the disease. In our series, the disease-specific survival was 94.1%. In conclusion, in resected invasive lung ADC, a subgroup presenting low-grade morphologic features and associated with favorable prognosis does exist. Morphologic criteria for LMP-ADC supported by ancillary techniques represent a valid tool to better define this novel subgroup and to refine the stratification of invasive lung ADC, possibly suggesting modified follow-up protocols, based on the observed indolent behavior in most cases.
Pleural mesothelioma (PM) is an aggressive cancer with poor prognosis and no effective therapies, mainly caused by exposure to asbestos. Antagonists of growth hormone-releasing hormone (GHRH) display strong antitumor effects in many experimental cancers, including lung cancer and mesothelioma. Here, we aimed to determine whether GHRH antagonist MIA-690 potentiates the antitumor effect of cisplatin and pemetrexed in PM. In vitro, MIA-690, in combination with cisplatin and pemetrexed, synergistically reduced cell viability, restrained cell proliferation and enhanced apoptosis, compared with drugs alone. In vivo, the same combination resulted in a strong growth inhibition of MSTO-211H xenografts, decreased tumor cell proliferation and increased apoptosis. Mechanistically, MIA-690, particularly with chemotherapeutic drugs, inhibited proliferative and oncogenic pathways, such as MAPK ERK1/2 and cMyc, and downregulated cyclin D1 and B1 mRNAs. Inflammatory pathways such as NF-kB and STAT3 were also reduced, as well as oxidative, angiogenic and tumorigenic markers (iNOS, COX-2, MMP2, MMP9 and HMGB1) and growth factors (VEGF and IGF-1). Overall, these findings strongly suggest that GHRH antagonists of MIA class, such as MIA-690, could increase the efficacy of standard therapy in PM.
Cardiac amyloidosis (CA) is a progressive, underdiagnosed condition caused by the deposition of misfolded proteins in the myocardium, forming amyloid fibrils that impair cardiac structure and function. This review highlights recent advances in the diagnosis and treatment of amyloid light-chain (AL) and transthyretin (ATTR) CA, which globally account for most cases of CA. Novel diagnostic tools, including artificial intelligence-enhanced analysis and advanced imaging modalities like positron emission tomography with amyloid-specific tracers, might improve detection rates and diagnostic accuracy to enable non-invasive subtype differentiation. Furthermore, many innovative treatments are being investigated. For AL-CA, anti-fibril therapies are showing promising results, complementing traditional chemotherapy and autologous stem cell transplantation. In ATTR-CA, gene silencing and anti-fibril therapies are being tested in clinical trials and hold promise of halting disease progression and reducing amyloid deposits, respectively.
Background: Chronic lymphocytic leukemia (CLL) has a strong genetic component, evidenced by an eight‐fold increased risk to develop CLL in relatives of CLL patients. Genome‐wide association studies (GWAS) have provided evidence for inherited predisposition to CLL, identifying 42 (non‐HLA) genomic regions influencing CLL risk. However, efforts to define the mechanisms mediating the risk at these, largely non‐coding, loci have been constrained by a lack of integrated genome‐wide data in large CLL series. Aims: We aimed to refine the gene regulatory mechanisms and biological significance of CLL risk loci. Methods: We (i) analysed high‐resolution chromatin state maps of primary CLL samples, (ii) integrated genetic, epigenetic and transcriptomic data in up to 452 primary CLL cases by quantitative trait loci (QTL) analysis, (iii) performed in silico transcription factor (TF) binding analysis using motifbreakR and (iv) studied the three‐dimensional (3D) chromatin structure of normal B cells and CLL using promoter capture Hi‐C data. Results: Eighty‐one percent of the 42 genomic risk loci were enriched for active regulatory elements (active promoters and enhancers) in CLL, suggesting a specific regulatory role for these loci in CLL pathogenesis. Additionally, at 18 risk loci we detected regulatory regions showing genotype dependent levels of genome activity (H3K27ac QTLs) and chromatin accessibility (ATAC‐seq QTLs) in primary CLL cases. Moreover, within these QTLs, we defined 60 potential functional variants underlying genetic CLL predisposition. Next, we focused on the underlying biological mechanisms through which genetic variants at CLL risk loci shape the regulatory genome by performing in silico TF binding analysis. We observed that genotypes associated with higher risk to develop CLL, among others, resulted in decreased binding affinity for B‐cell related TFs and increased affinity for FOX, NFAT and TCF/LEF TF family members. Thus, our findings point towards a regulatory role for these TFs in CLL predisposition. Thirdly, to infer the biological significance of CLL risk loci, we identified 36 genes that showed genotype dependent gene expression levels (eQTLs) in primary CLLs. These represent the potential target genes through which CLL risk loci mediate their effect and affected pathways known to be involved in CLL pathogenesis such as immune response, Wnt signalling and apoptosis. Interestingly, the eQTLs included new genes, such as TLE3 , that have not been associated with CLL risk before. Lastly, we observed significant 3D chromatin interactions in CLL and normal B cells between the risk loci and 15 eQTL gene loci, highly suggestive for direct regulatory links between the risk loci and expression of these genes in relation to CLL predisposition. Importantly, these analyses showed that CLL risk loci not necessarily affect expression of the nearest gene but may mediate their effect in a more distant fashion, as shown for UBR5 , due to long‐range 3D chromatin interactions. Summary/Conclusion: By (i) characterising the potential functional variants that influence the risk to develop CLL, (ii) defining the regulatory elements and the TFs that play a role in mediating the effect of genetic variation at the CLL risk loci and (iii) determining the downstream genotype‐dependent effects on expression of both proximal and distant target genes at these regions, we offer improved insights into the functional and biological basis of CLL predisposition.
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