Evaluating high-resolution computed tomography derived 3-D joint space metrics of the metacarpophalangeal joints between rheumatoid arthritis and age- and sex-matched control participants

IntroductionRheumatoid arthritis (RA) is commonly characterized by joint space narrowing. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides unparalleled in vivo visualization and quantification of joint space in extremity joints commonly affected by RA, such as the 2nd and 3rd metacarpophalangeal joints. However, age, sex, and obesity can also influence joint space narrowing. Thus, this study aimed to determine whether HR-pQCT joint space metrics could distinguish between RA patients and controls, and determine the effects of age, sex and body mass index (BMI) on these joint space metrics.MethodsHR-pQCT joint space metrics (volume, width, standard deviation of width, maximum/minimum width, and asymmetry) were acquired from RA patients and age-and sex-matched healthy control participants 2nd and 3rd MCP joints. Joint health and functionality were assessed with ultrasound (i.e., effusion and inflammation), hand function tests, and questionnaires.ResultsHR-pQCT-derived 3D joint space metrics were not significantly different between RA and control groups (p > 0.05), despite significant differences in inflammation and joint function (p < 0.05). Joint space volume, mean joint space width (JSW), maximum JSW, minimum JSW were larger in males than females (p < 0.05), while maximum JSW decreased with age. No significant association between joint space metrics and BMI were found.ConclusionHR-pQCT did not detect group level differences between RA and age-and sex-matched controls. Further research is necessary to determine whether this is due to a true lack of group level differences due to well-controlled RA, or the inability of HR-pQCT to detect a difference

miR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia

MicroRNAs are subject to precise regulation and have key roles in tumorigenesis. In contrast to the oncogenic role of miR-22 reported in myelodysplastic syndrome (MDS) and breast cancer, here we show that miR-22 is an essential anti-tumour gatekeeper in de novo acute myeloid leukaemia (AML) where it is significantly downregulated. Forced expression of miR-22 significantly suppresses leukaemic cell viability and growth in vitro, and substantially inhibits leukaemia development and maintenance in vivo. Mechanistically, miR-22 targets multiple oncogenes, including CRTC1, FLT3 and MYCBP, and thus represses the CREB and MYC pathways. The downregulation of miR-22 in AML is caused by TET1/GFI1/EZH2/SIN3A-mediated epigenetic repression and/or DNA copy-number loss. Furthermore, nanoparticles carrying miR-22 oligos significantly inhibit leukaemia progression in vivo. Together, our study uncovers a TET1/GFI1/EZH2/SIN3A/miR-22/CREB-MYC signalling circuit and thereby provides insights into epigenetic/genetic mechanisms underlying the pathogenesis of AML, and also highlights the clinical potential of miR-22-based AML therapy

The Arp2/3 complex is involved in the non-homologous end joining repair pathway and can nucleate actin while bound to DNA

Actin has been extensively studied in the cytoplasm for its structural functions such as cell morphology, movement, and adhesion. On the other hand, research on the functions of actin in the nucleus has only begun to emerge. Previous work in the lab has shown nuclear actin filaments form in response to DNA damage. The development of a nuclear specific actin probe was crucial in visualizing actin filaments in the nucleus and determining that actin assembly is required for the DNA damage response. Actin regulators are involved in controlling when and where actin is assembled and recent research has found that the Actin Related Protein 2/3 (Arp2/3) complex, an actin nucleator that creates branches off existing filaments, is required for efficient DNA repair. Our lab has found that the Arp2/3 complex nucleation activity is not disrupted by DNA binding and shown that the Arp2/3 complex is required for efficient cell proliferation and non-homologous end joining (NHEJ) during immunoglobulin class switch recombination

miR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia

MicroRNAs are subject to precise regulation and have key roles in tumorigenesis. In contrast to the oncogenic role of miR-22 reported in myelodysplastic syndrome (MDS) and breast cancer, here we show that miR-22 is an essential anti-tumour gatekeeper in de novo acute myeloid leukaemia (AML) where it is significantly downregulated. Forced expression of miR-22 significantly suppresses leukaemic cell viability and growth in vitro, and substantially inhibits leukaemia development and maintenance in vivo. Mechanistically, miR-22 targets multiple oncogenes, including CRTC1, FLT3 and MYCBP, and thus represses the CREB and MYC pathways. The downregulation of miR-22 in AML is caused by TET1/GFI1/EZH2/SIN3A-mediated epigenetic repression and/or DNA copy-number loss. Furthermore, nanoparticles carrying miR-22 oligos significantly inhibit leukaemia progression in vivo. Together, our study uncovers a TET1/GFI1/EZH2/SIN3A/miR-22/CREB-MYC signalling circuit and thereby provides insights into epigenetic/genetic mechanisms underlying the pathogenesis of AML, and also highlights the clinical potential of miR-22-based AML therapy

miR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia

MicroRNAs are subject to precise regulation and have key roles in tumorigenesis. In contrast to the oncogenic role of miR-22 reported in myelodysplastic syndrome (MDS) and breast cancer, here we show that miR-22 is an essential anti-tumour gatekeeper in de novo acute myeloid leukaemia (AML) where it is significantly downregulated. Forced expression of miR-22 significantly suppresses leukaemic cell viability and growth in vitro, and substantially inhibits leukaemia development and maintenance in vivo. Mechanistically, miR-22 targets multiple oncogenes, including CRTC1, FLT3 and MYCBP, and thus represses the CREB and MYC pathways. The downregulation of miR-22 in AML is caused by TET1/GFI1/EZH2/SIN3A-mediated epigenetic repression and/or DNA copy-number loss. Furthermore, nanoparticles carrying miR-22 oligos significantly inhibit leukaemia progression in vivo. Together, our study uncovers a TET1/GFI1/EZH2/SIN3A/miR-22/CREB-MYC signalling circuit and thereby provides insights into epigenetic/genetic mechanisms underlying the pathogenesis of AML, and also highlights the clinical potential of miR-22-based AML therapy

Smaller Hippocampal Volume in Posttraumatic Stress Disorder : A Multisite ENIGMA-PGC Study: Subcortical Volumetry Results From Posttraumatic Stress Disorder Consortia

Background Many studies report smaller hippocampal and amygdala volumes in posttraumatic stress disorder (PTSD), but findings have not always been consistent. Here, we present the results of a large-scale neuroimaging consortium study on PTSD conducted by the Psychiatric Genomics Consortium (PGC)–Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) PTSD Working Group. Methods We analyzed neuroimaging and clinical data from 1868 subjects (794 PTSD patients) contributed by 16 cohorts, representing the largest neuroimaging study of PTSD to date. We assessed the volumes of eight subcortical structures (nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, and lateral ventricle). We used a standardized image-analysis and quality-control pipeline established by the ENIGMA consortium. Results In a meta-analysis of all samples, we found significantly smaller hippocampi in subjects with current PTSD compared with trauma-exposed control subjects (Cohen's d = −0.17, p =.00054), and smaller amygdalae (d = −0.11, p =.025), although the amygdala finding did not survive a significance level that was Bonferroni corrected for multiple subcortical region comparisons (p <.0063). Conclusions Our study is not subject to the biases of meta-analyses of published data, and it represents an important milestone in an ongoing collaborative effort to examine the neurobiological underpinnings of PTSD and the brain's response to trauma

Smaller Hippocampal Volume in Posttraumatic Stress Disorder: A Multisite ENIGMA-PGC Study: Subcortical Volumetry Results From Posttraumatic Stress Disorder Consortia

Background Many studies report smaller hippocampal and amygdala volumes in posttraumatic stress disorder (PTSD), but findings have not always been consistent. Here, we present the results of a large-scale neuroimaging consortium study on PTSD conducted by the Psychiatric Genomics Consortium (PGC)–Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) PTSD Working Group. Methods We analyzed neuroimaging and clinical data from 1868 subjects (794 PTSD patients) contributed by 16 cohorts, representing the largest neuroimaging study of PTSD to date. We assessed the volumes of eight subcortical structures (nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, and lateral ventricle). We used a standardized image-analysis and quality-control pipeline established by the ENIGMA consortium. Results In a meta-analysis of all samples, we found significantly smaller hippocampi in subjects with current PTSD compared with trauma-exposed control subjects (Cohen's d = −0.17, p =.00054), and smaller amygdalae (d = −0.11, p =.025), although the amygdala finding did not survive a significance level that was Bonferroni corrected for multiple subcortical region comparisons (p <.0063). Conclusions Our study is not subject to the biases of meta-analyses of published data, and it represents an important milestone in an ongoing collaborative effort to examine the neurobiological underpinnings of PTSD and the brain's response to trauma