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Venomous animals immobilize prey using protein toxins that act on ion channels and other targets of biological importance. Broad use of toxins for biomedical research, diagnosis, and therapy has been limited by inadequate target discrimination, for example, among ion channel subtypes. Here, a synthetic toxin is produced by a new strategy to be specific for human Kv1.3 channels, critical regulators of immune T cells. A phage display library of 11,200 de novo proteins is designed using the alpha-KTx scaffold of 31 scorpion toxin sequences known or predicted to bind to potassium channels. Mokatoxin-1 (moka1) is isolated by affinity selection on purified target. Moka1 blocks Kv1.3 at nanomolar levels that do not inhibit Kv1.1, Kv1.2, or KCa1.1. As a result, moka1 suppresses CD3/28-induced cytokine secretion by T cells without cross-reactive gastrointestinal hyperactivity. The 3D structure of moka1 rationalizes its specificity and validates the engineering approach, revealing a unique interaction surface supported on an alpha-KTx scaffold. This scaffold-based/target-biased strategy overcomes many obstacles to production of selective toxins.

In the absence of targeted treatment options, neoadjuvant chemotherapy (NACT) is applied widely for triple-negative breast cancer (TNBC). Response to NACT is an important parameter predictive of oncological outcomes (progression-free and overall survival). An approach to the evaluation of predictive markers enabling therapy individualization is the identification of tumor driver genetic mutations. This study was conducted to investigate the role of SEC62, harbored at 3q26 and identified as a driver of breast cancer pathogenesis, in TNBC. We analyzed SEC62 expression in The Cancer Genome Atlas database, and immunohistologically investigated SEC62 expression in pre- and post-NACT tissue samples from 64 patients with TNBC treated at the Department of Gynecology and Obstetrics/Saarland University Hospital/Homburg between January 2010 and December 2018 and compared the effect of SEC62 on tumor cell migration and proliferation in functional assays. SEC62 expression dynamics correlated positively with the response to NACT (p ≤ 0.01) and oncological outcomes (p ≤ 0.01). SEC62 expression stimulated tumor cell migration (p ≤ 0.01). The study findings indicate that SEC62 is overexpressed in TNBC and serves as a predictive marker for the response to NACT, a prognostic marker for oncological outcomes, and a migration-stimulating oncogene in TNBC. [ABSTRACT FROM AUTHOR]

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Cryptophane-D is composed of two nonequivalent cyclotribenzylenecaps bound together by three OCH2CH2O bridgesin a syn arrangement. Host–guest complexes with chloroformand dichloromethane were investigated in solution by NMR spectroscopy.Variable temperature NMR 1H and 13C spectrashowed effects of chemical exchange between the free and bound guestand of conformational exchange for the host, strongly and specificallyaffected by guest binding. We found in particular that the carbon-13chemical shifts for the linkers connecting the two cyclotribenzyleneunits are very informative. The NMR results were supported by DFTcalculations. The guest exchange was also studied quantitatively,either by EXSY measurements (for chloroform as guest) or by line-shapeanalysis (for dichloromethane as guest). In the case of chloroformguest, we also investigated cross-relaxation between the guest andhost protons, as well as carbon-13 longitudinal relaxation and heteronuclearNOE at three different fields. The results were interpreted in termsof orientation and dynamics of the guest inside the host cavity. Puttingtogether various types of evidence resulted in remarkably detailedinsight into the process of molecular recognition of the two guestsby cryptophane-D host. [ABSTRACT FROM AUTHOR]

Introduction: fetal rhabdomyoma is the most common fetal cardiac tumor and is often associated with tuberous sclerosis. Usually the tumors are relatively small and show no mediastinal shift. Fetal hydrops and pericardial effusion are rarely seen. Case: in this case report we present the neonatal clinical course of a case of prenatal diagnosis of giant cardiac rhabdomyomas. Conclusion: an early prenatal diagnosis may help for an adequate planning of perinatal monitoring and treatment with involvement of a multidisciplinary team. [ABSTRACT FROM AUTHOR]