Neutral lipids of fungus Zoophthora

Cultivation of Zoophthora (Erynia) neoaphidis, in comparison with other species of Zoophthora genus, requires more complex nitrogen source. The best mycelium growth was obtained when 8 day old mycelium was used as an inoculum for liquid culture. On the basis of Gas Chromatography/Mass Spectrometry (GC/MS) methods, the structures of the neutral lipids produced by this fungus species, were determined. Decanoic acid was the most characteristic component (over 45%). The level of hexadecanoic and octadecanoic acid was relatively lower, although their contribution as ?bonded”? acid in diacylglyceride (DG) and triacylglyceride (TG) fractions, was significant. Contrary to Zoophthora (Erynia) ovispora, the presence of campesterol and/or dihydrobrassicosterol was proved.     

Hepatoma-derived growth factor (HDGF) is dispensable for normal mouse development

Hepatoma-derived growth factor (HDGF) is suggested to be involved in organ development and exhibits proliferative, angiogenic, and neurotrophic activity. The in vivo functions are, however, so far unknown. In this study, we generated HDGF-deficient mice, in which parts of the HDGF gene were replaced by a gene encoding green fluorescent protein (eGFP). HDGF-/- mice are viable with no apparent morphological abnormalities. Cultured HDGF-deficient dermal fibroblasts show unaltered proliferation rates and cell-cycle distributions. In contrast to previous studies, our data demonstrate that signal pathways involved in the response to extracellular HDGF do not depend on the presence of intracellular HDGF. Contrary to the reported role of HDGF as a modulator of apoptosis, similar apoptotic rates were found between wild-type and HDGF-deficient fibroblasts following tumor necrosis factor alpha (TNFalpha) -induced apoptosis or cellular stress. The lack of obvious biochemical and morphological phenotypes in HDGF-deficient mice demonstrates that in vivo HDGF is dispensable for normal development in mice.     

Polymorphism of Promoter Region of TNFRSF1A Gene (−610 T > G) as a Novel Predictive Factor for Radiotherapy Induced Oral Mucositis in HNC Patients

Every year, about 650 thousand new cases of Head and Neck Cancer (HNC) are diagnosed globally. Apart from surgery, radiotherapy (RTH), chemotherapy (CHT) or its combination is used in the treatment of HNC. One of the most frequent complications and, at the same time, limitations of RTH is oral mucositis (OM). Proinflammatory cytokines (including TNF-α) play a key role in the development of OM. Genetic alterations, i.e. single nucleotide polymorphisms (SNPs) within genes encoding for receptors for TNF (ie. TNFRSF1A) may change their function. The aim of this study was to investigate relationship between a polymorphism of TNFRSF1A and occurrence and severity of acute reaction after RTH for HNC patients. Data from 58 HNC patients (stages I-IV) were analyzed. All of them were irradiated using IMRT technique with doses 50-70Gy. Oral mucositis (OM) was evaluated according to RTOG/EORTC guidelines. DNA from HNC patients were isolated from whole blood and genotypes were determined by sequencing method. Patients with TT or GT genotype demonstrated higher risk of manifestation of grade 3 OM in 5th week of RTH (p=0.041; OR=9.240; 95% CI: 1.101–77.581) compared to GG carriers. Similarly, high risk of grade 3 OM in patients with T allele presence was noted in 6th week (p=0.030; OR=10.50; 95%CI:1.257–87.690) and in 7th week (p=0.008; OR=5.625; 95% CI: 1.584–19.975) of treatment compared to patients with GG homozygote. Our results indicate an association between SNP of TNFRSF1A (rs4149570) gene and risk of more severe OM related to radiation therapy for HNC patients.     

Design,Synthesis, and Biological Evaluation of Imidazopyridines as PD-1/PD-L1 Antagonists

The PD-1/PD-L1 axis has proven to be a highly efficacious target for cancer immune checkpoint therapy with several approved antibodies. Also, small molecules based on a biphenyl core can antagonize PD-1/PD-L1, leading to the in vitro formation of PD-L1 dimers. However, their development remains challenging, as we do not yet fully understand their mode of action. In this work, we designed a new scaffold based on our previously solved high-resolution structures of low-molecular-weight inhibitors bound to PD-L1. A small compound library was synthesized using the Groebke–Blackburn–Bienaymé multicomponent reaction (GBB-3CR), resulting in the structure–activity relationship of imidazo[1,2-a]pyridine-based inhibitors. These inhibitors were tested for their biological activity using various biophysical assays giving potent candidates with low-micromolar PD-L1 affinities. An obtained PD-L1 cocrystal structure reveals the binding to PD-L1. Our results open the door to an interesting bioactive scaffold that could lead to a new class of PD-L1 antagonists.     

Triple-site biventricular pacing in patients undergoing cardiac resynchronization therapy: a feasibility study.

AIMS: To evaluate implantation safety and efficiency of triple-site (double left-single right) cardiac resynchronization therapy (CRT) and to assess the outcome of this procedure. METHODS AND RESULTS: Twenty-six patients with New York Heart Association (NYHA) class III-IV, left ventricular ejection fraction (EF) < or = 35%, and QRS > or = 120 ms underwent triple-site CRT. Procedural course and complications were analysed. NYHA class, QRS duration, echocardiographic parameters, peak oxygen consumption (VO(2)max), and 6 min walking distance (6MWD) were assessed at baseline and after 3 months. Responders were defined by survival, by no re-hospitalization for heart failure, and by >10% EF, VO(2)max, and 6MWD increase. Implantation was successful in 22 patients (84.6%). Procedure duration (199.1 min) and fluoroscopy time (38.7 min) were higher than in standard procedures. Two clinically silent coronary sinus dissections occurred intra-operatively; one phrenic nerve stimulation and one pocket infection were observed during follow-up. After 3 months of CRT, a significant reduction (P < 0.05) of NYHA class, increment of VO(2)max, 6MWD, EF, and improvement of indices of dyssynchrony were observed. Response rate in the studied group was 95.4%. CONCLUSION: Triple-site resynchronization appears to be a safe and efficient treatment method, with high response rate. Further studies are needed to evaluate the role of this pacing mode in CRT.     

P1PK,GLOB, and FORS Blood Group Systems and GLOB Collection: Biochemical and Clinical Aspects. Do We Understand It All Yet?

Antigens belonging to the P1PK, GLOB, and FORS blood group systems and the GLOB blood group collection represent a closely related set of 13 glycosphingolipids (GSLs). They are synthesized by the coordinated action of glycosyltransferases, encoded by at least 7 different loci. Three of these enzymes show either different activity or a different mRNA expression profile due to genetic polymorphisms, resulting in blood group diversity. In recent years, significant progress has been made in understanding the molecular background and biological functions of these GSLs. Their medical significance is often related to the existence of natural antibodies, as they may cause complications after transfusions and during pregnancies. In addition, GSLs belonging to these blood group systems are receptors for several pathogens. This review summarizes the present knowledge about the complicated network of enzymatic interactions leading to synthesis of these GSLs, as well as their clinical implications.