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Background aims: Corticosteroids are the standard first-line treatment for acute graft-versus-host disease (aGVHD), but they are associated with many complications, and less than half of patients have a sustained response. Methods: To improve outcomes, we performed a retrospective study to analyze the efficacy of the addition of extracorporeal photopheresis (ECP) to low-dose corticosteroids in 37 adult patients (median age, 57 years) with skin-predominant aGVHD (grade I, n = 17; grade II, n = 18; and grade III, n = 2). All patients received ECP in combination with 1 mg/kg prednisone (n = 26) or topical steroids (n = 11). Results: Overall response rate was 81% after a median of three ECP procedures (range, 2–8), including 22 complete responses (CR, 59%) and eight very good partial responses (VGPR, 22%). The 11 patients treated with topical corticosteroids achieved CR. Furthermore, 16 (62%) patients reached prednisone withdrawal at a median of 100 days (range, 42–174 days) after its initiation. Eighteen patients developed chronic GVHD (cGVHD); 11 of them (who were in CR of aGVHD) had a new-onset cGVHD, and seven experienced progressive cGVHD (five non-responding and two VGPR patients). A second-line immunosuppressive treatment was initiated in only five (14%) non-responding patients. With a median follow-up of 31 months (range, 6–57 months) 2-year overall survival and non-relapse mortality were 74% and 11%, respectively. Conclusions: Overall, the combination of low-dose corticosteroids and ECP appear to be safe and effective for first-line treatment of skin predominant aGVHD. [ABSTRACT FROM AUTHOR]

Murine hepatic carboxylesterase 2c (Ces2c) and the presumed human ortholog carboxylesterase 2 (CES2) have been implicated in the development of nonalcoholic fatty liver disease (NAFLD) in mice and obese humans. These studies demonstrated that Ces2c hydrolyzes triglycerides (TGs) in hepatocytes. Interestingly, Ces2c/CES2 is most abundantly expressed in the intestine, indicating a role of Ces2c/CES2 in intestinal TG metabolism. Here we show that Ces2c is an important enzyme in intestinal lipid metabolism in mice. Intestine‐specific Ces2c overexpression (Ces2cint) provoked increased fatty acid oxidation (FAO) in the small intestine accompanied by enhanced chylomicron clearance from the circulation. As a consequence, high‐fat diet–fed Ces2cint mice were resistant to excessive diet‐induced weight gain and adipose tissue expansion. Notably, intestinal Ces2c overexpression increased hepatic insulin sensitivity and protected mice from NAFLD development. Although lipid absorption was not affected in Ces2cint mice, fecal energy content was significantly increased. Mechanistically, we demonstrate that Ces2c is a potent neutral lipase, which efficiently hydrolyzes TGs and diglycerides (DGs) in the small intestine, thereby generating fatty acids (FAs) for FAO and monoglycerides (MGs) and DGs for potential re‐esterification. Consequently, the increased availability of MGs and DGs for re‐esterification and primordial apolipoprotein B48 particle lipidation may increase chylomicron size, ultimately mediating more efficient chylomicron clearance from the circulation. Conclusion: This study suggests a critical role for Ces2c in intestinal lipid metabolism and highlights the importance of intestinal lipolysis to protect mice from the development of hepatic insulin resistance, NAFLD, and excessive diet‐induced weight gain during metabolic stress. In this study, we investigated the role of carboxylesterase 2c (Ces2c) in the intestine. Low levels of Ces2c in the liver was recently linked to the development of nonalcoholic fatty liver disease. Here we show that increasing Ces2c protein abundance in the intestine protected mice from excessive diet‐induced weight gain and most importantly NAFLD development by altering intestinal lipid catabolism, thereby affecting whole body energy metabolism. [ABSTRACT FROM AUTHOR]

Background: Sorafenib has shown encouraging results in patients with Fms-like tyrosine kinase 3 (FLT3)-positive acute myeloid leukemia. Its role after allogeneic stem cell transplantation (HSCT) has been reported in a few cases with encouraging results.Methods: The authors describe the use of sorafenib as a maintenance agent after HSCT in 27 patients with FLT3-positive acute myeloid leukemia.Results: The median age of the patients was 46 years (range, 15-57 years). Sorafenib was introduced at a median of 70 days (range, 29-337 days) after HSCT. The median treatment duration was 8.4 months (range, 0.2-46 months). Eleven patients experienced treatment toxicities, mainly of grade 1 to 2 (graded according to the National Cancer Institute Common Toxicity Criteria [version 4.0]). Dose reduction or withdrawal was required in 4 patients and 4 patients, respectively. The persistence of toxicity prompted treatment withdrawal in 1 patient. Clinical improvement followed dose modifications. Thirteen patients experienced chronic graft-versus-host disease (limited in 9 patients and extensive in 4 patients), resulting in dose reduction in 5 patients followed by withdrawal in 1 of these individuals. At a median follow-up of 18 months (range, 4-48 months), 25 patients were alive (all of whom were in complete molecular remission) and 18 were still receiving treatment, with 1-year overall survival and progression-free survival rates of 92% ± 6% and 92% ± 5%, respectively.Conclusions: Sorafenib treatment after HSCT appears to be feasible and highly effective with dose individualization according to patient tolerability. Further analysis is needed to evaluate the immunomodulating role of sorafenib after HSCT. The data from the current support prospective controlled trials of sorafenib after HSCT. Cancer 2017;123:2867-74. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate genes involved in energy metabolism and inflammation. For biological activity, PPARs require cognate lipid ligands, heterodimerization with retinoic X receptors, and coactivation by PPAR-? coactivator-1? or PPAR-? coactivator-1? (PGC-1? or PGC-1?, encoded by Ppargc1a and Ppargc1b, respectively). Here we show that lipolysis of cellular triglycerides by adipose triglyceride lipase (patatin-like phospholipase domain containing protein 2, encoded by Pnpla2; hereafter referred to as Atgl) generates essential mediator(s) involved in the generation of lipid ligands for PPAR activation. Atgl deficiency in mice decreases mRNA levels of PPAR-? and PPAR-? target genes. In the heart, this leads to decreased PGC-1? and PGC-1? expression and severely disrupted mitochondrial substrate oxidation and respiration; this is followed by excessive lipid accumulation, cardiac insufficiency and lethal cardiomyopathy. Reconstituting normal PPAR target gene expression by pharmacological treatment of Atgl-deficient mice with PPAR-? agonists completely reverses the mitochondrial defects, restores normal heart function and prevents premature death. These findings reveal a potential treatment for the excessive cardiac lipid accumulation and often-lethal cardiomyopathy in people with neutral lipid storage disease, a disease marked by reduced or absent ATGL activity. [ABSTRACT FROM AUTHOR]

The term 'gender role' was coined at Johns Hopkins's paediatric endocrinology clinic in the 1950s, where Dr Lawson Wilkins and psychologist John Money diagnosed, treated and evaluated intersexual children, most of them suffering from a condition called congenital adrenal hyperplasia (CAH). Going beyond existing discourses on the medicalisation of intersexuality, I reframe the emergence of gender as an element in the development of a specific medical treatment for an endocrinological condition and excavate the complex and contingent historical factors that led to the formulation of gender role in the Hopkins context. Using previously unavailable patient records from the clinic, this article follows the patients through their medical encounters and describes the process of normalisation around the diagnosis, treatment and management of CAH. By paying specific attention to the practices at the clinic, I show that diagnosing a child's sex often depended on the physicians' skill, experience and techniques. Correct gender role was folded into the management of CAH as one aspect of successful treatment. Normalisation was a process, in which treating somatic effects and assuring psychological healthiness were deeply enmeshed in the conviction that a normal life would only be possible as a clearly gendered and sexed person. [ABSTRACT FROM AUTHOR]

Abstract: High density lipoproteins (HDL) represent a protective factor of central importance that counteracts the development of cardiovascular disease, in part by normalizing platelet (hyper)reactivity. As HDL represent an efficient scavenger of the naturally occurring oxidant hypochlorite, this work was intended to investigate the influence of hypochlorite-oxidized HDL on platelet function. Addition of hypochlorite-oxidized HDL to human platelets results in an immediate and transient raise in intracellular calcium, surface expression of P-selectin and platelet aggregation. The observed effects are dose dependent and can be blocked by an antibody directed against the lipoprotein-binding domain of platelet thrombospondin- and scavenger receptor CD36. [Copyright &y& Elsevier]

Efficient catabolism of cellular triacylglycerol (TG) stores requires the TG hydrolytic activity of adipose triglyceride lipase (ATGL). The presence of comparative gene identification-58 (CGI-58) strongly increased ATGL-mediated TG catabolism in cell culture experiments. Mutations in the genes coding for ATGL or CGI-58 in humans cause neutral lipid storage disease characterized by TG accumulation in multiple tissues. ATGL gene mutations cause a severe phenotype especially in cardiac muscle leading to cardiomyopathy that can be lethal. In contrast, CGI-58 gene mutations provoke severe ichthyosis and hepatosteatosis in humans and mice, whereas the role of CGI-58 in muscle energy metabolism is less understood. Here we show that mice lacking CGI-58 exclusively in muscle (CGI-58KOM) developed severe cardiac steatosis and cardiomyopathy linked to impaired TG catabolism and mitochondrial fatty acid oxidation. The marked increase in ATGL protein levels in cardiac muscle of CGI-58KOM mice was unable to compensate the lack of CGI-58. The addition of recombinant CGI-58 to cardiac lysates of CGI-58KOM mice completely reconstituted TG hydrolytic activities. In skeletal muscle, the lack of CGI-58 similarly provoked TG accumulation. The addition of recombinant CGI-58 increased TG hydrolytic activities in control and CGI-58KOM tissue lysates, elucidating the limiting role of CGI-58 in skeletal muscle TG catabolism. Finally, muscle CGI-58 deficiency affected whole body energy homeostasis, which is caused by impaired muscle TG catabolism and increased cardiac glucose uptake. In summary, this study demonstrates that functional muscle lipolysis depends on both CGI-58 and ATGL. [ABSTRACT FROM AUTHOR]

Comparative gene identification-58 (CGI-58), also designated as α/β-hydrolase domain containing-5 (ABHD-5), is a lipid droplet-associated protein that activates adipose triglyceride lipase (ATGL) and acylates lysophosphatidic acid. Activation of ATGL initiates the hydrolytic catabolism of cellular triacyiglycerol (TG) stores to glycerol and nonesterified fatty acids. Mutations in both ATGL and CGI-58 cause "neutral lipid storage disease" characterized by massive accumulation of TG in various tissues. The analysis of CGI-58-deficient (Cgi-58-/-) mice, presented in this study, reveals a dual function of CGI-58 in lipid metabolism. First, systemic TG accumulation and severe hepatic steatosis in newborn Cgi-58-/- mice establish a limiting role for CGI-58 in ATGL-mediated TG hydrolysis and supply of nonesterified fatty acids as energy substrate. Second, a severe skin permeability barrier defect uncovers an essential ATGL independent role of CGI-58 in skin lipid metabolism. The neonatal lethal skin barrier defect is linked to an impaired hydrolysis of epidermal TG. As a consequence, sequestration of fatty acids in TG prevents the synthesis of acylceramides, which are essential lipid precursors for the formation of a functional skin permeability barrier. This mechanism may also underlie the pathogenesis of ichthyosis in neutral lipid storage disease patients lacking functional CGI-58. [ABSTRACT FROM AUTHOR]