As a result of the hostile microenvironment, metabolic alterations are required to enable the malignant growth of cancer cells. To understand metabolic reprogramming during metastasis, we conducted shotgun proteomic analysis of highly metastatic (HM) and non-metastatic (NM) ovarian cancer cells. The results suggest that the genes involved in fatty-acid (FA) metabolism are upregulated, with consequent increases of phospholipids with relatively short FA chains (myristic acid, MA) in HM cells. Among the upregulated proteins, ACSL1 expression could convert the lipid profile of NM cells to that similar of HM cells and make them highly aggressive. Importantly, we demonstrated that ACSL1 activates the AMP-activated protein kinase and Src pathways via protein myristoylation and finally enhances FA beta oxidation. Patient samples and tissue microarray data also suggested that omentum metastatic tumours have higher ACSL1 expression than primary tumours and a strong association with poor clinical outcome. Overall, our data reveal that ACSL1 enhances cancer metastasis by regulating FA metabolism and myristoylation.
  Chronic lymphocytic leukaemia (CLL) patients display a highly variable clinical course, with progressive acquisition of drug resistance. We sought to identify aberrant epigenetic traits that are enriched following exposure to treatment that could impact patient response to therapy.
 
  Epigenome-wide analysis of DNA methylation was performed for 20 patients at two timepoints during treatment. The prognostic significance of differentially methylated regions (DMRs) was assessed in independent cohorts of 139 and 163 patients. Their functional role in drug sensitivity was assessed in vitro.
 
  We identified 490 DMRs following exposure to therapy, of which 31 were CLL-specific and independent of changes occurring in normal B-cell development. Seventeen DMR-associated genes were identified as differentially expressed following treatment in an independent cohort. Methylation of the HOXA4, MAFB and SLCO3A1 DMRs was associated with post-treatment patient survival, with HOXA4 displaying the strongest association. Re-expression of HOXA4 in cell lines and primary CLL cells significantly increased apoptosis in response to treatment with fludarabine, ibrutinib and idelalisib.
 
  Our study demonstrates enrichment for multiple CLL-specific epigenetic traits in response to chemotherapy that predict patient outcomes, and particularly implicate epigenetic silencing of HOXA4 in reducing the sensitivity of CLL cells to therapy.
 Our study demonstrates enrichment for multiple CLL-specific epigenetic traits in response to chemotherapy that predict patient outcomes, and particularly implicate epigenetic silencing of HOXA4 in reducing the sensitivity of CLL cells to therapy.Cell-free DNA (cfDNA) has been investigated in acute graft-versus-host disease (aGvHD) following allogeneic cell transplantation (HSCT). Identifying the tissue of origin of cfDNA in patients with aGvHD is relevant particularly when a biopsy is not feasible.  https://www.selleckchem.com/products/vvd-214.html  We investigate the cfDNA tissue of origin in patients with aGvHD using methylated gene biomarkers. Patients with liver, colon, or skin aGvHD (n = 28) were analyzed. Liver- and colon-derived cfDNA was measured using a colon- (SESN3) and liver (PTK2B)-specific methylation marker with digital droplet PCR. A statistically significant difference (p  less then  0.001) in PTK2B and SESN3 concentration was observed between patients with colon or liver GvHD and the control group. For SESN3 and PTK2B the area under the curve in the receiver-operating characteristic (ROC) space was 0.952 (95% CI, 0.888-1 p  less then  0.001) and 0.971 (95% CI, 0.964-1 p  less then  0.001), respectively. Thresholds to differentiate aGvHD from non-aGvHD in colon were 0 (sensitivity 0.905; specificity 0.989) and liver 1.5 (sensitivity 0.928; specificity 0.910). Clinical improvement of liver or colon aGvHD resulted in PTK2B and SESN3 reduced concentration. Whereas, in those patients without improvement the PTK2B and SESN3 level remained stable or increased. The PTK2B liver-specific marker and the SESN3 colon-specific marker and their longitudinal analysis might improve aGvHD detection.Care of long-term survivors of allogeneic transplant is known to be variable despite international guidelines and accreditation standards. In 2014 a survey of UK NHS-based adult transplant centres identified significant barriers to delivery of long-term follow-up services. In 2019, we repeated the survey to assess changes over a 5-year period when health service policies had mandated JACIE accreditation incorporating standards for long-term care. Improvements were seen in the number of centres having a dedicated long-term follow-up clinic for allogeneic transplant recipients (52% versus 33%) and a standard operating procedure (88% versus 69%). Inclusion of psychological support in standard operating procedures remained low at both time points (32% versus 28%). There was ongoing variation in practice regarding vaccination programmes, access to cancer screening, and audit processes between centres. Perceived barriers to implementation of comprehensive long-term follow-up clinics were similar in 2019; mainly resourcing clinical staff and psychological support. Whilst the survey reflects the changing practice of transplant centres, best explained by increasing recognition of late effects and survivorship by clinicians, health service policy and JACIE accreditation standards, further developments are warranted to address unmet healthcare needs of long-term HSCT survivors, especially access to psychological support, cancer screening and vaccinations.An amendment to this paper has been published and can be accessed via a link at the top of the paper.Glycated haemoglobin (HbA1c) is considered the gold standard for predicting glycaemia-associated risks for the microvascular and macrovascular complications of diabetes mellitus over 5-10 years. The value of HbA1c in the care of patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) is unassailable, yet HbA1c targets remain contentious. Guidelines from diabetes care organizations recommend conflicting HbA1c targets - generally between 6.5% and 8%. However, all such organizations advocate for individualization of HbA1c targets, leaving both health-care providers and their patients confused about what HbA1c target is appropriate in an individual patient. In this Review, we outline the landmark T1DM and T2DM trials that informed the current guidelines, we discuss the evidence that drives individualized HbA1c targets, we examine the limitations of HbA1c, and we consider alternatives for monitoring glycaemic control. Ultimately, in synthesizing this literature, we argue for an HbA1c target of less then 7% for most individuals, but emphasize the importance of helping patients determine their own personal goals and determinants of quality of life that are independent of a particular glycaemic target.