Activation-Free Sulfonyl Fluoride Probes for Fragment Screening.

SuFEx chemistry is based on the unique reactivity of the sulfonyl fluoride group with a range of nucleophiles. Accordingly, sulfonyl fluorides label multiple nucleophilic amino acid residues, making these reagents popular in both chemical biology and medicinal chemistry applications. The reactivity of sulfonyl fluorides nominates this warhead chemotype as a candidate for an external, activation-free general labelling tag. Here, we report the synthesis and characterization of a small sulfonyl fluoride library that yielded the 3-carboxybenzenesulfonyl fluoride warhead for tagging tractable targets at nucleophilic residues. Based on these results, we propose that coupling diverse fragments to this warhead would result in a library of sulfonyl fluoride bits (SuFBits), available for screening against protein targets. SuFBits will label the target if it binds to the core fragment, which facilitates the identification of weak fragments by mass spectrometry.

Novel Erlotinib-Chalcone Hybrids Diminish Resistance in Head and Neck Cancer by Inducing Multiple Cell Death Mechanisms.

In a search for novel therapeutic options for head and neck squamous cell carcinomas (HNSCCs) generally treated with limited therapeutic success, we synthesized a series of novel erlotinib-chalcone molecular hybrids with 1,2,3-triazole and alkyne linkers and evaluated them for their anticancer activity on Fadu, Detroit 562 and SCC-25 HNSCC cell lines. Time- and dose-dependent cell viability measurements disclosed a significantly increased efficiency of the hybrids compared to the 1:1 combination of erlotinib and a reference chalcone. The clonogenic assay demonstrated that hybrids eradicate HNSCC cells in low micromolar concentrations. Experiments focusing on potential molecular targets indicate that the hybrids trigger the anticancer effect by a complementary mechanism of action that is independent of the canonical targets of their molecular fragments. Confocal microscopic imaging and real-time apoptosis/necrosis detection assay pointed to slightly different cell death mechanisms induced by the most prominent triazole- and alkyne-tethered hybrids (6a and 13, respectively). While 6a featured the lowest IC50 values on each of the three HNSCC cell lines, in Detroit 562 cells, this hybrid induced necrosis more markedly compared to 13. The therapeutic potential indicated by the observed anticancer efficacy of our selected hybrid molecules validates the concept of development and justifies further investigation to reveal the underlying mechanism of action.

The use of alteration analysis in supercritical fluid chromatography to monitor changes in a series of chromatograms.

Two-dimensional correlation analysis (2DCOR) is a unique chemometric method introduced in spectroscopy which became successful in a wide range of analytical fields. It was applied in chromatography as well but has not gained wide-spread popularity. In our previous work, we introduced an alternative method, Alteration Analysis (ALA), which is built upon the basic properties of 2DCOR, but it is fine-tuned for chromatographic applications and can be used on higher dimensional data sets as well. We explored its merits through computer generated examples. In this study, we present the application of ALA to two various data-sets in chromatography. First, we used a series of samples where the concentrations of the compounds were adjusted according to the changes we studied in our previous in-silico experiments. We compared the alteration maps from the computer generated and measured sources. The results demonstrated that ALA can provide the same properties from measured data as laid down in theory. The second one is a test concerning the effect of sample solvent composition in supercritical fluid chromatography (SFC). ALA maps show the influence of increasing methanol concentration on the peak location and shape of compounds in the chromatogram. With these two examples, we demonstrate that ALA can be used not only in theory, but it has also practical potentials and importance.

AMP-Activated Kinase (AMPK) Activation by AICAR in Human White Adipocytes Derived from Pericardial White Adipose Tissue Stem Cells Induces a Partial Beige-Like Phenotype.

Beige adipocytes are special cells situated in the white adipose tissue. Beige adipocytes, lacking thermogenic cues, morphologically look quite similar to regular white adipocytes, but with a markedly different response to adrenalin. White adipocytes respond to adrenergic stimuli by enhancing lipolysis, while in beige adipocytes adrenalin induces mitochondrial biogenesis too. A key step in the differentiation and function of beige adipocytes is the deacetylation of peroxisome proliferator-activated receptor (PPARγ) by SIRT1 and the consequent mitochondrial biogenesis. AMP-activated protein kinase (AMPK) is an upstream activator of SIRT1, therefore we set out to investigate the role of AMPK in beige adipocyte differentiation using human adipose-derived mesenchymal stem cells (hADMSCs) from pericardial adipose tissue. hADMSCs were differentiated to white and beige adipocytes and the differentiation medium of the white adipocytes was supplemented with 100 µM [(2R,3S,4R,5R)-5-(4-Carbamoyl-5-aminoimidazol-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate (AICAR), a known activator of AMPK. The activation of AMPK with AICAR led to the appearance of beige-like morphological properties in differentiated white adipocytes. Namely, smaller lipid droplets appeared in AICAR-treated white adipocytes in a similar fashion as in beige cells. Moreover, in AICAR-treated white adipocytes the mitochondrial network was more fused than in white adipocytes; a fused mitochondrial system was characteristic to beige adipocytes. Despite the morphological similarities between AICAR-treated white adipocytes and beige cells, functionally AICAR-treated white adipocytes were similar to white adipocytes. We were unable to detect increases in basal or cAMP-induced oxygen consumption rate (a marker of mitochondrial biogenesis) when comparing control and AICAR-treated white adipocytes. Similarly, markers of beige adipocytes such as TBX1, UCP1, CIDEA, PRDM16 and TMEM26 remained the same when comparing control and AICAR-treated white adipocytes. Our data point out that in human pericardial hADMSCs the role of AMPK activation in controlling beige differentiation is restricted to morphological features, but not to actual metabolic changes.

Two-dimensional correlation analysis of the reproducibility of high-performance liquid chromatography columns.

Two-dimensional (2D) correlation analysis is a well-established tool in spectroscopy. Despite its versatility in various measurement systems, 2D correlation has not yet become popular in separation science. 2D correlation is seldom used in chromatography; only a few a studies can be found on this topic and most of those publications report about gel chromatography. In the present study, 2D correlation analysis is applied to chromatograms. In this study, a simple method is built for studying the similarities and dissimilarities between a number of chromatograms. We present the applicability of the method by two examples, where the repeatability and reproducibility of the analytical and nonlinear measurements in HPLC are evaluated and demonstrated. In order to validate the results of 2D correlation analysis, they are compared to principal component analysis (PCA). We confirm the equivalence in the interpretation of the results obtained with the two methods of calculation. The results confirm that 2D correlation can be a successful chemometric tool in chromatography.

[Late postinfarction rupture of the interventricular septum]. / Késoi posztinfarktusos kamrai septumdefektus.

UNLABELLED: Postinfarction ventricular septal rupture complicates 1 to 2% of cases of acute myocardial infarction and accounts for 5% of early mortality. This severe complication usually occurs within two weeks after acute myocardial infarction, and the elderly are more susceptible. We present a case of late rupture of the septum. CASE REPORT: In a 75-year-old man, a ventricular septal defect developed more than two months after an extensive inferoseptal myocardial infarction due to occlusion of the right coronary artery. After more than two months of no symptoms he was referred to hospital due to symptoms of right ventricle failure. The diagnosis was made by echocardiography, pulmonary artery catheterization and ventriculography. Coronarography was also performed. Intraaortic balloon pump was introduced and the patient was transferred to the operating room. The defect was repaired using a circular polytetrafluoroethylene patch supported by buttressed interrupted sutures from both sides. Due to significant mitral valve regurgitation mechanical bileaflet mitral valve was implanted with preservation of the entire mitral apparatus and the left descending artery was revascularized using a saphenous graft. CONCLUSION: This case is reported to emphasize that later postinfarction rupture of the ventricular septum may occur with symptoms of right ventricle failure dominating the clinical course.

[The etiology, differential diagnosis and therapy of pericardial effusion]. / A pericardialis folyadékok etiológiája, differenciáldiagnosztikája és terápiája.

Considerable etiologic factors may lead to the development of pathologic pericardial effusion. In many cases these factors remain unidentified, the fact which leads to difficulties in choosing the appropriate therapeutic strategy. The therapy of pericardial effusion associated with purulent pericarditis must be different than that effusion developed as a consequence of neoplasm or autoimmune disease. The cytological examination of the fluid and the hystological examination of the pericardial tissue play an important role in identifying the accurate etiologic diagnosis. In case of recurrent pericardial effusions, performing pericardioperitoneal, pericardiopleural shunt or pericardial window may be indicated. This palliative solution serves to prevent the development of pericardial tamponade and its haemodynamic consequences.