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Although both growth hormone (GH) and insulin-like growth factor 1 (IGF-1) signaling were shown to regulate life span in lower organisms, the role of GH signaling in human longevity remains unclear. Because a GH receptor exon 3 deletion (d3-GHR) appears to modulate GH sensitivity in humans, we hypothesized that this polymorphism could play a role in human longevity. We report a linear increased prevalence of d3-GHR homozygosity with age in four independent cohorts of long-lived individuals: 841 participants [567 of the Longevity Genes Project (LGP) (8% increase; P = 0.01), 152 of the Old Order Amish (16% increase; P = 0.02), 61 of the Cardiovascular Health Study (14.2% increase; P = 0.14), and 61 of the French Long-Lived Study (23.5% increase; P = 0.02)]. In addition, mega analysis of males in all cohorts resulted in a significant positive trend with age (26% increase; P = 0.007), suggesting sexual dimorphism for GH action in longevity. Further, on average, LGP d3/d3 homozygotes were 1 inch taller than the wild-type (WT) allele carriers (P = 0.05) and also showed lower serum IGF-1 levels (P = 0.003). Multivariate regression analysis indicated that the presence of d3/d3 genotype adds approximately 10 years to life span. The LGP d3/d3-GHR transformed lymphocytes exhibited superior growth and extracellular signal–regulated kinase activation, to GH treatment relative to WT GHR lymphocytes (P < 0.01), indicating a GH dose response. The d3-GHR variant is a common genetic polymorphism that modulates GH responsiveness throughout the life span and positively affects male longevity.

None of the polymorphic variants of the IL2RA gene found associated with Type 1 Diabetes (T1D) was shown to have a functional effect. To test if the epigenetic variation could play a role at this locus, we studied the methylation of 6 CpGs located within the proximal promoter of IL2RA gene in 252 T1D patients compared with 286 age-matched controls. We found that DNA methylation at CpGs −373 and −456 was slightly but significantly higher in patients than in controls (40.4±4.6 vs 38.3±5.4, p = 1.4E4; 91.4±2.8 vs 89.5±5.3, p = 1.8E-6), while other CpG showed a strictly comparable methylation. Among 106 single nucleotide polymorphisms (SNPs) located in the neighboring 180kb region, we found that 28 SNPs were associated with DNA methylation at CpG −373. Sixteen of these SNPs were known to be associated with T1D. Our findings suggest that the effect of IL2RA risk alleles on T1D may be partially mediated through epigenetic changes. [ABSTRACT FROM AUTHOR]

Background: HA14-1 is a small-molecule, stable B-cell lymphoma 2 (Bcl-2) antagonist that promotes apoptosis in malignant cells through an incompletely-defined mechanism of action. Bcl-2 and related anti-apoptotic proteins, such as B-cell lymphoma-extra-large [Bcl-XL]), are predominantly localized to the outer mitochondrial membrane, where they regulate cell death pathways. However, the notably short half-life of HA14-1 in vitro limits its potential therapeutic application. To address this limitation, a more stable analog, ethyl-2-amino-6-phenyl-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (sHA14-1), was developed., Objective: This study investigated the relationship between sHA14-1 and Bcl-2/Bcl-XL. The sHA14-1 molecule acts as a hormetic substance. Therefore, it is crucial to determine whether the hormetic zone corresponds to a putative therapeutic window, that is, the optimal concentration at which sHA14-1 selectively kills cancer cells overexpressing Bcl-2 or Bcl-XL while causing minimal damage to normal cells., Methods: Using classical cell biology and flow cytometry, we examined the main signaling pathways involving Bcl-2 or Bcl-XL, and their modification in the presence of sHA14-1., Results: We showed that sHA14-1 exerted a dual effect on mitochondria: (i) it sensitized cells to increased permeability, and (ii) it inhibited adenosine diphosphate-stimulated respiration and uncoupled respiration. At relatively low concentrations, sHA14-1 induced mitochondrial swelling, reminiscent of "pore opening" but with distinct characteristics. Over 30 μM, sHA14-1 caused mitochondrial transition depolarization independent of permeability transition and cell death that resembled secondary necrosis ( i.e ., occurring after maximal mitochondrial permeability) rather than apoptosis. The balance between apoptotic and necrotic cell death induced by sHA14-1 was also evaluated., Conclusion: Our results suggested that sHA14-1 plays a multifunctional role, involving both mitochondria and the endoplasmic reticulum. Its actions are more complex than its originally intended role in targeting anti-apoptotic Bcl-2 family members, which may complicate its potential application as an anticancer therapy., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Journal of Biological Methods, All rights reserved.)

Extracellular vesicles (EVs), such as exosomes, are critical mediators of intercellular communication between tumor cells and other cells located in the microenvironment but also in more distant sites. Exosomes are small EVs that can carry a variety of molecules, such as lipids, proteins, and non-coding RNA, especially microRNAs (miRNAs). In thoracic cancers, including lung cancers and malignant pleural mesothelioma, EVs contribute to the immune-suppressive tumor microenvironment and to tumor growth and metastasis. In this review, we discuss the recent understanding of how exosomes behave in thoracic cancers and how and why they are promising liquid biomarkers for diagnosis, prognosis, and therapy, with a special focus on exosomal miRNAs.

Background: Genome editing offers unique perspectives for optimizing the functional properties of T cells for adoptive cell transfer purposes. So far, PDCD1 editing has been successfully tested mainly in chimeric antigen receptor T (CAR-T) cells and human primary T cells. Nonetheless, for patients with solid tumors, the adoptive transfer of effector memory T cells specific for tumor antigens remains a relevant option, and the use of high avidity T cells deficient for programmed cell death-1 (PD-1) expression is susceptible to improve the therapeutic benefit of these treatments., Methods: Here we used the transfection of CAS9/sgRNA ribonucleoproteic complexes to edit PDCD1 gene in human effector memory CD8 + T cells specific for the melanoma antigen Melan-A. We cloned edited T cell populations and validated PDCD1 editing through sequencing and cytometry in each T cell clone, together with T-cell receptor (TCR) chain's sequencing. We also performed whole transcriptomic analyses on wild-type (WT) and edited T cell clones. Finally, we documented in vitro and in vivo through adoptive transfer in NOD scid gamma (NSG) mice, the antitumor properties of WT and PD-1KO T cell clones, expressing the same TCR., Results: Here we demonstrated the feasibility to edit PDCD1 gene in human effector memory melanoma-specific T lymphocytes. We showed that PD-1 expression was dramatically reduced or totally absent on PDCD1 -edited T cell clones. Extensive characterization of a panel of T cell clones expressing the same TCR and exhibiting similar functional avidity demonstrated superior antitumor reactivity against a PD-L1 expressing melanoma cell line. Transcriptomic analysis revealed a downregulation of genes involved in proliferation and DNA replication in PD-1-deficient T cell clones, whereas genes involved in metabolism and cell signaling were upregulated. Finally, we documented the superior ability of PD-1-deficient T cells to significantly delay the growth of a PD-L1 expressing human melanoma tumor in an NSG mouse model., Conclusion: The use of such lymphocytes for adoptive cell transfer purposes, associated with other approaches modulating the tumor microenvironment, would be a promising alternative to improve immunotherapy efficacy in solid tumors., Competing Interests: Competing interests: The authors declare that JS and MH are employed by Qiagen; however, the research was conducted in the absence of any potential conflict of interest., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Over recent decades, it has become clear that epigenetic abnormalities are involved in the hallmarks of cancer. Histone modifications, such as acetylation, play a crucial role in cancer development and progression, by regulating gene expression, such as for oncogenes or tumor suppressor genes. Therefore, histone deacetylase inhibitors (HDACi) have recently shown efficacy against both hematological and solid cancers. Designed to target histone deacetylases (HDAC), these drugs can modify the expression pattern of numerous genes including those coding for micro-RNAs (miRNA). miRNAs are small non-coding RNAs that regulate gene expression by targeting messenger RNA. Current research has found that miRNAs from a tumor can be investigated in the tumor itself, as well as in patient body fluids. In this review, we summarized current knowledge about HDAC and HDACi in several cancers, and described their impact on miRNA expression. We discuss briefly how circulating miRNAs may be used as biomarkers of HDACi response and used to investigate response to treatment.

Genome-wide association studies (GWAS) have identified more than 40 T1D loci associated with type 1 diabetes (T1D). How these polymorphisms interact with environmental factors to trigger T1D is unknown, but recent evidence suggests that epigenetic mechanisms could play a role. To begin to explore the contribution of epigenetics to T1D, we have examined DNA methylation in a pilot study of whole blood cells DNA from 10 young T1D patients and 10 young controls. Through the study of >900 000 CG loci across a diverse set of functionally relevant genomic regions using a custom DNA methylation array, we identified 250 T1D-differentially methylated region (DMR) at p < 0.05 and 1 DMR using next a permutation-based multiple testing correction method. This DMR is located in an imprinted region previously associated with T1D on the chromosome 14 that encompasses RTL1 gene and 2 miRNAs (miR136 and miR432). Using pyrosequencing-based bisulfite PCR, we replicated this association in a different and larger set of T1D patients and controls. DNA methylation at this DMR was inversely correlated with RTL1 gene expression and positively correlated with miR136 expression in human placentas. The DMR identified in this study presents suggestive evidence for altered methylation site in T1D and provide a promising new candidate gene. RTL1 is essential for placental permeability function in the mid-to-late fetal stages. We suggest that hypo-methylation could increase the fetal exposure to environmental factors in T1D susceptibility., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Context: Twin and family studies indicate a significant heritability of pubertal timing and more specifically of age at menarche (AAM)., Objective: Test the association of AAM with common variants of three candidate genes suspected to have a prominent role in reproductive physiology: leptin (LEP), neuropeptide Y receptor 1 (NPY1R) and GPR54., Design and Methods: We selected the -2459 LEP, the rs7687423 NPY1R and thers350132 GPR54 variants as the more common coding or regulatory variants (minor allelic frequency >0.10) in these gene regions. To avoid stratification problems that can impair association studies, we used the Q-TDT method based on allele transmission to evaluate the relationship of these variants with AAM in 245 healthy women from 107 families of European ancestry., Results: We found no association of AAM with any of the studied variants., Conclusions: Keeping in mind that common variants do not recapitulate the whole genetic variation in a given gene region, this study indicates that the studied LEP, NPY1R and GPR54 variants do not have a major influence upon pubertal timing in Caucasian women. Effects of these genetic loci on age at menarche can definitively be excluded only through determination of extended haplotypes in a larger cohort., (2009 S. Karger AG, Basel)