Risk of progression in smouldering myeloma and monoclonal gammopathies of unknown significance: comparative analysis of the evolution of monoclonal component and multiparameter flow cytometry of bone marrow plasma cells

The present study explored the impact of two novel criteria; having >95% abnormal plasma cells by flow cytometry at diagnosis and the evolving subtype of the disease, as predictors of progression in 61 smouldering multiple myeloma (SMM) and 311 monoclonal gammopathy of unknown significance (MGUS) patients. Although both criteria were of prognostic value, the risk of progression was better identified by immunophenotyping [Hazard Ratio (HR) 6·2 and 17·2 for SMM and MGUS, respectively] than evolving subtype, which had independent prognostic value only in MGUS (HR 3·6). Immunophenotyping discriminated the different risk of progression within the evolving and non-evolving subgroups of SMM ( P  = 0·01) and MGUS ( P  < 0·001).     

Challenges in the diagnosis and management of acromegaly: a focus on comorbidities

Introduction

Acromegaly is a rare, insidious disease resulting from the overproduction of growth hormone (GH) and insulin-like growth factor 1 (IGF-1), and is associated with a range of comorbidities. The extent of associated complications and mortality risk is related to length of exposure to the excess GH and IGF-1, thus early diagnosis and treatment is imperative. Unfortunately, acromegaly is often diagnosed late, when patients already have a wide range of comorbidities. The presence of comorbid conditions contributes significantly to patient morbidity/mortality and impaired quality of life.

Methods

We conducted a retrospective literature review for information relating to the diagnosis of acromegaly, and its associated comorbidities using PubMed. The main aim of this review is to highlight the issues of comorbidities in acromegaly, and to reinforce the importance of early diagnosis and treatment.

Findings and conclusions

Successful management of acromegaly goes beyond treating the disease itself, since many patients are diagnosed late in disease evolution, they present with a range of comorbid conditions, such as cardiovascular disease, diabetes, hypertension, and sleep apnea. It is important that patients are screened carefully at diagnosis (and thereafter), for common associated complications, and that biochemical control does not become the only treatment goal. Mortality and morbidities in acromegaly can be reduced successfully if patients are treated using a multimodal approach with comprehensive comorbidity management.

     

Melanin concentration maps by label-free super-resolution photo-thermal imaging on melanoma biopsies

Surgical excision followed by histopathological examination is the gold standard for melanoma screening. However, the color-based inspection of hematoxylin-and-eosin-stained biopsies does not provide a space-resolved quantification of the melanin content in melanocytic lesions. We propose a non-destructive photo-thermal imaging method capable of characterizing the microscopic distribution and absolute concentration of melanin pigments in excised melanoma biopsies. By exploiting the photo-thermal effect primed by melanin absorption of visible laser light we obtain label-free super-resolution far-infrared thermal images of tissue sections where melanin is spatially mapped at sub-diffraction 40-μm resolution. Based on the finite-element simulation of the full 3D heat transfer model, we are able to convert temperature maps into quantitative images of the melanin molar concentration on B16 murine melanoma biopsies, with 4·10^-4 M concentration sensitivity. Being readily applicable to human melanoma biopsies in combination with hematoxylin-and-eosin staining, the proposed approach could complement traditional histopathology in the characterization of pigmented lesions ex-vivo.     

The base excision repair enzyme MED1 mediates DNA damage response to antitumor drugs and is associated with mismatch repair system integrity

Cytotoxicity of methylating agents is caused mostly by methylation of the O6 position of guanine in DNA to form O6-methylguanine (O6-meG). O6-meG can direct misincorporation of thymine during replication, generating O6-meG:T mismatches. Recognition of these mispairs by the mismatch repair (MMR) system leads to cell cycle arrest and apoptosis. MMR also modulates sensitivity to other antitumor drugs. The base excision repair (BER) enzyme MED1 (also known as MBD4) interacts with the MMR protein MLH1. MED1 was found to exhibit thymine glycosylase activity on O6-meG:T mismatches. To examine the biological significance of this activity, we generated mice with targeted inactivation of the Med1 gene and prepared mouse embryonic fibroblasts (MEF) with different Med1 genotype. Unlike wild-type and heterozygous cultures, Med1-/- MEF failed to undergo G2-M cell cycle arrest and apoptosis upon treatment with the methylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Similar results were obtained with platinum compounds' 5-fluorouracil and irinotecan. As is the case with MMR-defective cells, resistance of Med1-/- MEF to MNNG was due to a tolerance mechanism because DNA damage accumulated but did not elicit checkpoint activation. Interestingly, steady state amounts of several MMR proteins are reduced in Med1-/- MEF, in comparison with Med1+/+ and Med1+/- MEF. We conclude that MED1 has an additional role in DNA damage response to antitumor agents and is associated with integrity of the MMR system. MED1 defects (much like MMR defects) may impair cell cycle arrest and apoptosis induced by DNA damage.     

Effect of supplementation with docosahexaenoic acid ethyl ester and sn-2 docosahexaenyl monoacylglyceride on plasma and erythrocyte fatty acids in rats

BACKGROUND/AIMS: Docosahexaenoic acid (C22:6, DHA) is an omega-3 fatty acid required for the normal development of the mammalian nervous and visual system. DHA is provided by the mother during pregnancy and lactating period. Mother's DHA supplementation during pregnancy, and even before pregnancy, has been suggested. DHA can be provided by marine oils, egg's yolk phospholipids, single cell algae oils, the pure fatty acid, or by the ethyl ester derivative (DHA-EE). Another way to provide DHA can be by sn-2 docosahexaenyl monoacylglyceride (DHA-MG), obtained by the treatment of fish oil with stereospecific lipases. sn-2 Fatty acid monoacylglycerides can be more easily absorbed at the intestine than other fatty acid derivatives. METHODS: Female rats fed with a synthetic, which provided essentially no DHA, received a 40-day supplementation of either DHA-EE or DHA-MG. Plasma and erythrocyte fatty acid composition were assessed by gas chromatography at day 0 and 40 of supplementation. RESULTS: DHA-EE increased plasma and erythrocyte DHA by 15 and 11.9%, respectively, with no modification of arachidonic acid (AA) content. DHA-MG supplementation increased plasma and erythrocyte DHA by 24 and 23.8%, respectively, but reduced AA by 5.5 and 3%, respectively. CONCLUSIONS: We conclude that in the rat, DHA-MG supplementation allows a higher plasma and erythrocyte DHA content than DHA-EE with minor modification of AA content.     

Podocytes are new cellular targets of haemoglobin‐mediated renal damage

Recurrent and massive intravascular haemolysis induces proteinuria, glomerulosclerosis, and progressive impairment of renal function, suggesting podocyte injury. However, the effects of haemoglobin (Hb) on podocytes remain unexplored. Our results show that cultured human podocytes or podocytes isolated from murine glomeruli bound and endocytosed Hb through the megalin–cubilin receptor system, thus resulting in increased intracellular Hb catabolism, oxidative stress, activation of the intrinsic apoptosis pathway, and altered podocyte morphology, with decreased expression of the slit diaphragm proteins nephrin and synaptopodin. Hb uptake activated nuclear factor erythroid‐2‐related factor 2 (Nrf2) and induced expression of the Nrf2‐related antioxidant proteins haem oxygenase‐1 (HO‐1) and ferritin. Nrf2 activation and Hb staining was observed in podocytes of mice with intravascular haemolysis. These mice developed proteinuria and showed podocyte injury, characterized by foot process effacement, decreased synaptopodin and nephrin expression, and podocyte apoptosis. These pathological effects were enhanced in Nrf2‐deficient mice, whereas Nrf2 activation with sulphoraphane protected podocytes against Hb toxicity both in vivo and in vitro. Supporting the translational significance of our findings, we observed podocyte damage and podocytes stained for Hb, HO‐1, ferritin and phosphorylated Nrf2 in renal sections and urinary sediments of patients with massive intravascular haemolysis, such as atypical haemolytic uraemic syndrome and paroxysmal nocturnal haemoglobinuria. In conclusion, podocytes take up Hb both in vitro and during intravascular haemolysis, promoting oxidative stress, podocyte dysfunction, and apoptosis. Nrf2 may be a potential therapeutic target to prevent loss of renal function in patients with intravascular haemolysis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Association between A218C polymorphism of the tryptophan-hydroxylase-1 gene,harm avoidance and binge eating behavior in bulimia nervosa

Genes involved in serotonin transmission are likely involved in the biological predisposition to bulimia nervosa. We investigated whether the A218C polymorphism of the tryptophan-hydroxylase-1 gene was associated to bulimia nervosa and/or to some phenotypic aspects of the disorder. One hundred eighty Caucasian women (91 patients with bulimia nervosa and 89 healthy controls) were enrolled into the study. They underwent a blood sample collection for A218C polymorphism of the tryptophan-hydroxylase-1 genotyping and a clinical evaluation assessing comorbidity for Axis I and II psychiatric disorders, harm avoidance personality dimension and bulimic symptoms. The distribution of both tryptophan-hydroxylase-1 A218C genotypes and alleles did not significantly differ between patients and controls. Bulimic women with the AA genotype exhibited a more severe binge eating behavior and higher harm avoidance scores than those with CC genotype. These findings support the idea that tryptophan-hydroxylase-1 A218C polymorphism does not play a part in the genetic susceptibility to bulimia nervosa, but it seems to be involved in predisposing bulimic patients to a more disturbed eating behavior and higher harm avoidance.     

Airborne measurements of organic bromine compounds in the Pacific tropical tropopause layer

Very short-lived brominated substances (VSLBr) are an important source of stratospheric bromine, an effective ozone destruction catalyst. However, the accurate estimation of the organic and inorganic partitioning of bromine and the input to the stratosphere remains uncertain. Here, we report near-tropopause measurements of organic brominated substances found over the tropical Pacific during the NASA Airborne Tropical Tropopause Experiment campaigns. We combine aircraft observations and a chemistry−climate model to quantify the total bromine loading injected to the stratosphere. Surprisingly, despite differences in vertical transport between the Eastern and Western Pacific, VSLBr (organic + inorganic) contribute approximately similar amounts of bromine [∼6 (4−9) parts per thousand] to the stratospheric input at the tropical tropopause. These levels of bromine cause substantial ozone depletion in the lower stratosphere, and any increases in future abundances (e.g., as a result of aquaculture) will lead to larger depletions.Until the end of the last century, it was believed that only long-lived species, like bromomethane (CH₃Br) and halons, contributed to the global burden of stratospheric bromine. However, disagreement between the observed amount of reactive stratospheric bromine and the sources of long-lived trace gases suggested the existence of an additional contributor: Very short-lived brominated substances (VSL_org) [VSL_org = bromoform (3CHBr₃) + dibromomethane (2CH₂Br₂) + minor_VSLBr, where minor_VSLBr = bromochloromethane (CH₂BrCl) + dibromochloromethane (2CHBr₂Cl) + bromodichloromethane (CHBrCl₂)] that originate mainly from ocean biogenic sources (1, 2).Several studies have described the processes involved in the transformation of biogenic bromocarbons to inorganic bromine, and their transport through the tropical tropopause layer (TTL) (1–5). These studies have led to significant progress in modeling the VSL_org contribution to the formation of stratospheric inorganic bromine (Br_y) (3, 4, 6–11). However, the scarcity of observations to constrain the emissions, the impact of deep convection, and the effect of dehydration processes limit the prediction of short-lived source gases that reach the stratosphere (3). On the other hand, atmospheric observations of VSL_org have been provided by ground measurements and cruise, balloon, and airborne campaigns (12–14), but the different instruments used between campaigns, and the low spatial and temporal coverage of each study, contribute to the uncertainties in the estimations of total bromine and its partitioning (15). In an attempt to reduce these limitations, we present unique measurements of organic bromine substances carried out with the same instrument, the Global Hawk Whole Air Sampler (GWAS), deployed during the NASA Airborne Tropical Tropopause Experiment (ATTREX), which covered the tropical Pacific region during 2013 and 2014 (see SI Text for details of the campaign).Because coastal areas of tropical waters (like the Maritime Continent) are an important source for VSL_org (16–18) and highly convective zones can transport air masses from the troposphere into the stratosphere through the TTL (19), we focus this study on observations taken over the Western Pacific (120°E−165°E) and the Eastern Pacific (187°E−268°E) (Fig. S1). We compared these regions in terms of VSL_org mixing ratios at the tropopause level (∼17 km; Fig. S2), which defines the chemical composition of air that enters the stratosphere.Open in a separate windowFig. S1.GWAS sample locations during ATTREX campaign. Dotted lines define the Western (120°E–165°E) and Eastern Pacific (187°E–268°E) limits for this study.Open in a separate windowFig. S2.Sample density of measurements of organic bromine species (A) during ATTREX-2014 (Western Pacific) and (B) during ATTREX-2013 (Eastern Pacific).Whole air samples were collected during two deployments of the ATTREX campaigns, on board the unmanned aerial vehicle Global Hawk. Measurements of VSL_org were carried out in the field using a combination of gas chromatography with mass selective, flame ionization, and electron capture detectors (Materials and Methods). Fig. 1 A and B displays the observations of CHBr₃, CH₂Br₂, and minor_VSLBr, as well as the total organic bromine mixing ratio, in the upper troposphere/lower stratosphere (UTLS) of the Western and Eastern Pacific. GWAS observations indicate that the total amount of VSL_org that enters the stratosphere over the Western and Eastern Pacific is approximately similar, 3.27 ± 0.47 parts per thousand (ppt) and 2.96 ± 0.42 ppt, respectively. These observations are compared with the state-of-the-art Community Atmosphere Model (CAM-Chem) simulations (4, 20) (see Materials and Methods). The results show good agreement with the measurements, and simulate the injection of VSL_org to the stratosphere of 3.84 ± 0.64 ppt and 3.18 ± 1.49 ppt organic Br for the Western and Eastern Pacific, respectively (Fig. 1 A and B).Open in a separate windowFig. 1.GWAS measurements and CAM-Chem simulations ±1 SD. Filled symbols are the 1 km average bins from GWAS measurements. Lines are the CAM-Chem simulation. Values from the arrows represent the mean mixing ratio (ppt) of VSL_org and Br_y at the tropopause level (∼17 km) derived from CAM-Chem simulations. (A and B) Organic brominated species multiplied by their atomicity for (A) Western Pacific and (B) Eastern Pacific. (C and D) CAM-Chem estimations of inorganic bromine (Br_y) from measured brominated VSLS with shaded ±1 SD for (C) Western Pacific and (D) Eastern Pacific.Although negligible differences of the organic fraction of VSLBr were observed between the Western and Eastern Pacific, we quantified the inorganic fraction coming from the degradation of VSL_org. Estimations of inorganic bromine (Br_y = Br + BrO + HOBr + BrONO₂ + HBr + BrCl + 2Br₂ + BrNO₂ + IBr), with a focus at ∼17 km, were calculated with the CAM-Chem model using assimilated meteorological fields for each Global Hawk flight. According to these simulations, the amount of Br_y over the Eastern Pacific is 3.02 ± 1.90 ppt, whereas, in the Western Pacific, the mixing ratio of Br_y is 1.97 ± 0.21 ppt (Fig. 1 C and D). Br_y/VSL_org ratios show that at ∼17 km, the abundance of Br_y over the Western Pacific is almost half the amount of VSL_org, in contrast to the Eastern Pacific, where the abundance of Br_y is similar to the value of VSL_org (