Molecular analysis of three novel G6PD variants : G6PD Pedoplis-Ckaro, G6PD Piotrkow and G6PD Krakow

We present three novel mutations in the G6PD gene and discuss the changes they cause in the 3-dimensional structure of the enzyme: 573C→G substitution that predicts Phe to Leu at position 191 in the C-terminus of helix αe, 851T→C mutation which results in the substitution 284Val→→Ala in the β+α domain close to the C-terminal part of helix αj, and 1175T→C substitution that predicts Ile to Thr change at position 392

SYK inhibition targets acute myeloid leukemia stem cells by blocking their oxidative metabolism

Spleen tyrosine kinase (SYK) is an important oncogene and signaling mediator activated by cell surface receptors crucial for acute myeloid leukemia (AML) maintenance and progression. Genetic or pharmacologic inhibition of SYK in AML cells leads to increased differentiation, reduced proliferation, and cellular apoptosis. Herein, we addressed the consequences of SYK inhibition to leukemia stem-cell (LSC) function and assessed SYK-associated pathways in AML cell biology. Using gain-of-function MEK kinase mutant and constitutively active STAT5A, we demonstrate that R406, the active metabolite of a small-molecule SYK inhibitor fostamatinib, induces differentiation and blocks clonogenic potential of AML cells through the MEK/ERK1/2 pathway and STAT5A transcription factor, respectively. Pharmacological inhibition of SYK with R406 reduced LSC compartment defined as CD34+CD38-CD123+ and CD34+CD38-CD25+ in vitro, and decreased viability of LSCs identified by a low abundance of reactive oxygen species. Primary leukemic blasts treated ex vivo with R406 exhibited lower engraftment potential when xenotransplanted to immunodeficient NSG/J mice. Mechanistically, these effects are mediated by disturbed mitochondrial biogenesis and suppression of oxidative metabolism (OXPHOS) in LSCs. These mechanisms appear to be partially dependent on inhibition of STAT5 and its target gene MYC, a well-defined inducer of mitochondrial biogenesis. In addition, inhibition of SYK increases the sensitivity of LSCs to cytarabine (AraC), a standard of AML induction therapy. Taken together, our findings indicate that SYK fosters OXPHOS and participates in metabolic reprogramming of AML LSCs in a mechanism that at least partially involves STAT5, and that SYK inhibition targets LSCs in AML. Since active SYK is expressed in a majority of AML patients and confers inferior prognosis, the combination of SYK inhibitors with standard chemotherapeutics such as AraC constitutes a new therapeutic modality that should be evaluated in future clinical trials

Anthropometry and Size Groups in the Clothing Industry

It appears that from generation to generation the anthropometric dimensions of the human population are changing. The aim of this paper was to examine the extent of these changes and the need for generating updated measurements for the clothing industry. The clothing industry uses mannequins and avatars to represent the modal group of the population. The industry tends to use three different categories for the human body shape (endomorphic, mesomorphic, and ectomorphic). The clothing industry should focus on specific measurements of the body rather than general categories and create more body shapes to satisfy customer needs. The paper also aimed at showing the problems faced by clothing designers. The traditional way of measuring takes into account only selected dimensions of the human body; this does not reflect the “true” overall body shape. The dimension tables used by the apparel industry are based on the fourth anthropometric photograph taken between 1987 and 1989. These tables are still in the use currently; however, after 30 years they are outdated and should be revised for the young contemporary generation. This study can be used for the development of new dimension tables as well as defining methods aimed at improving the quality of measurements for clothing engineering purposes. This is an important issue, because the National Institute of Anthropometry does not deal with such problems (the measurements are conducted mainly for understanding the human body shape rather than any other application), which means that anthropometric measurements are not ideally suited to applications of clothes fitting

Challenges in the Isolation and Proteomic Analysis of Cancer Exosomes—Implications for Translational Research

Exosomes belong to the group of extracellular vesicles (EVs) that derive from various cell populations and mediate intercellular communication in health and disease. Like hormones or cytokines, exosomes released by cells can play a potent role in the communication between the cell of origin and distant cells in the body to maintain homeostatic or pathological processes, including tumorigenesis. The nucleic acids, and lipid and protein cargo present in the exosomes are involved in a myriad of carcinogenic processes, including cell proliferation, tumor angiogenesis, immunomodulation, and metastasis formation. The ability of exosomal proteins to mediate direct functions by interaction with other cells qualifies them as tumor-specific biomarkers and targeted therapeutic approaches. However, the heterogeneity of plasma-derived exosomes consistent of (a) exosomes derived from all kinds of body cells, including cancer cells and (b) contamination of exosome preparation with other extracellular vesicles, such as apoptotic bodies, makes it challenging to obtain solid proteomics data for downstream clinical application. In this manuscript, we review these challenges beginning with the choice of different isolation methods, through the evaluation of obtained exosomes and limitations in the process of proteome analysis of cancer-derived exosomes to identify novel protein targets with functional impact in the context of translational oncology

Understanding Chloroquine Action at the Molecular Level in Antimalarial Therapy: X-ray Absorption Studies in Dimethyl Sulfoxide Solution

X-ray absorption spectroscopy is used to determine the local atomic structure around the iron atom from a soluble synthetic analogue of malaria pigment (hemozoin), cf. ferrimesoporphyrin IX of mesohematin anhydride, in the absence or presence of chloroquine (CQ) in dimethyl sulfoxide (DMSO). Of particular note are the CQ:induced changes in the structure of mesohematin anhydride, which might confirm the formation of CQ-ferrimesoporphyrin IX complex. Examination of solutions of mesohematin anhydride dissolved in DMSO reveals preservation of the dimerlike structure with the central iron atoms of the ferric porphyrin IX reciprocally linked by propionate side chains, which is typical for hematin anhydride (beta-hematin). In the presence of CO, additional light atoms, such as nitrogen, carbon, and oxygen, were detected surrounding the iron in a distance ranging from 2.48 to 3.77 angstrom. The changes introduced by CQ in DMSO are different from that observed in the acetic acid solution

One Anastomosis Gastric Bypass Reconstitutes the Appropriate Profile of Serum Amino Acids in Patients with Morbid Obesity

Bariatric surgery leads to metabolic benefits in patients with obesity, but their mechanisms are not well understood. The appropriate composition of serum amino acids (AA) is important for sufficient supply of these components into various tissues and organs. Obesity leads to alterations in serum AA concentrations. The aim of this study was to examine the effect of one anastomosis gastric bypass (OAGB), a promising type of bariatric surgery, on serum AA concentrations, which were assayed by LC-MS in serum of 46 bariatric patients prior to and 6–9 months after OAGB, as well as in 30 lean control subjects. The results were analyzed by principle components analysis and metabolic pathway analysis. PCA analysis showed that OAGB led to normalization of serum AA concentrations of patients with obesity to a pattern similar to the control subjects, and the concentrations of essential AA remained decreased after OAGB. Changes of individual AA and their associated metabolic pathways were also presented. OAGB caused normalization of the AA profile, which may contribute to improvement of glucose homeostasis and reduction of cardiovascular risk. Considering decreased essential AA concentrations after OAGB, increased intake of high protein food should be recommended to the patients after this type of bariatric surgery

Toward Understanding the Chloroquine Action at the Molecular Level in Antimalarial Therapy - X-ray Absorption Studies in Acetic Add Solution

The local atomic structure around the central iron of the synthetic soluble analog of malarial pigment in acetic acid solution and with addition of chloroquine as found by X-ray absorption spectroscopy is reported. The special interest was drawn to the axial linkage between the central iron atom of the ferriprotoporphyrin IX (FePPIX) coordinated axially to the propionate group of the adjacent FePPIX. This kind of bonding is typical for hematin anhydride. Detailed analysis revealed differences in oxygen coordination sphere (part of dimer linkage bond) between synthetic equivalent of hemozoin in the powder state and dissolved in acetic acid and water at different concentrations mimicking the physiological condition of the parasite's food vacuole. The results of performed studies suggest that the molecular structure of synthetic analogue of hemozoin is no longer dimer-like in acidic solution. Further changes in atomic order around Fe are seen after addition of the antimalarial drug chloroquine