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Notfall + Rettungsmedizin - Der Massenanfall von Verletzten (MANV) ist eine Ausnahmesituation für Rettungsdienst und andere Einsatzkräfte. Trotz niedriger Inzidenz müssen sich die...     

Reflection of neuroblastoma intratumor heterogeneity in the new OHC-NB1 disease model

Accurate modeling of intratumor heterogeneity presents a bottleneck against drug testing. Flexibility in a preclinical platform is also desirable to support assessment of different endpoints. We established the model system, OHC-NB1, from a bone marrow metastasis from a patient diagnosed with MYCN-amplified neuroblastoma and performed whole-exome sequencing on the source metastasis and the different models and passages during model development (monolayer cell line, 3D spheroid culture and subcutaneous xenograft tumors propagated in mice). OHC-NB1 harbors a MYCN amplification in double minutes, 1p deletion, 17q gain and diploid karyotype, which persisted in all models. A total of 80–540 single-nucleotide variants (SNVs) was detected in each sample, and comparisons between the source metastasis and models identified 34 of 80 somatic SNVs to be propagated in the models. Clonal reconstruction using the combined copy number and SNV data revealed marked clonal heterogeneity in the originating metastasis, with four clones being reflected in the model systems. The set of OHC-NB1 models represents 43% of somatic SNVs and 23% of the cellularity in the originating metastasis with varying clonal compositions, indicating that heterogeneity is partially preserved in our model system.     

Biperiden and mepazine effectively inhibit MALT1 activity and tumor growth in pancreatic cancer

MALT1 is a key mediator of NF-κB signaling and a main driver of B-cell lymphomas. Remarkably, MALT1 is expressed in the majority of pancreatic ductal adenocarcinomas (PDACs) as well, but absent from normal exocrine pancreatic tissue. Following, MALT1 shows off to be a specific target in cancer cells of PDAC without affecting regular pancreatic cells. Therefore, we studied the impact of pharmacological MALT1 inhibition in pancreatic cancer and showed promising effects on tumor progression. Mepazine (Mep), a phenothiazine derivative, is a known potent MALT1 inhibitor. Newly, we described that biperiden (Bip) is a potent MALT1 inhibitor with even less pharmacological side effects. Thus, Bip is a promising drug leading to reduced proliferation and increased apoptosis in PDAC cells in vitro and in vivo. By compromising MALT1 activity, nuclear translocation of c-Rel is prevented. c-Rel is critical for NF-κB-dependent inhibition of apoptosis. Hence, off-label use of Bip or Mep represents a promising new therapeutic approach to PDAC treatment. Regularly, the Anticholinergicum Bip is used to treat neurological side effects of Phenothiazines, like extrapyramidal symptoms.     

Short bowel mucosal morphology,proliferation and inflammation at first and repeat STEP procedures

Background

Although serial transverse enteroplasty (STEP) improves function of dilated short bowel, a significant proportion of patients require repeat surgery. To address underlying reasons for unsuccessful STEP, we compared small intestinal mucosal characteristics between initial and repeat STEP procedures in children with short bowel syndrome (SBS).

Visual preferences for direct-gaze faces in infant macaques (Macaca mulatta) with limited face exposure

From birth, human and nonhuman primates attend more to faces with direct gaze compared with averted gaze, and previous studies report that attention to the eyes is linked to the emergence of later social skills. Here, we explored whether early experiences influence attraction to eye contact in infant macaques by examining their attention to face pairs varying in their gaze direction across the first 13 weeks of life. Infants raised by human caretakers had limited conspecific interactions (nursery-reared; N = 16) and were compared to infants raised in rich social environments (mother-reared; N = 20). Both groups looked longer to faces and the eyes of direct compared to averted-gaze faces. Looking to all faces and eyes also increased with age. Nursery-reared infants did not display age-associated increases in attention to direct-gaze faces specifically, suggesting that, while there may be an initial preference for direct-gaze faces from birth, social experiences may support its early development.