Assessment of PI3K/mTOR/AKT Pathway Elements to Serve as Biomarkers and Therapeutic Targets in Penile Cancer

The PI3K/mTOR/AKT pathway might represent an intriguing option for treatment of penile cancer (PeCa). We aimed to assess whether members of this pathway might serve as biomarkers and targets for systemic therapy. Tissue of primary cancer from treatment-naïve PeCa patients was used for tissue microarray analysis. Immunohistochemical staining was performed with antibodies against AKT, pAKT, mTOR, pmTOR, pS6, pPRAS, p4EBP1, S6K1 and pp70S6K. Protein expression was correlated with clinicopathological characteristics as well as overall survival (OS), disease-specific survival (DSS), recurrence-free survival (RFS) and metastasis-free survival (MFS). AKT inhibition was tested in two primarily established, treatment-naïve PeCa cell lines by treatment with capivasertib and analysis of cell viability and chemotaxis. A total of 76 patients surgically treated for invasive PeCa were included. Higher expression of AKT was significantly more prevalent in high-grade tumors and predictive of DSS and OS in the Kaplan–Meier analysis, and an independent predictor of worse OS and DSS in the multivariate regression analysis. Treatment with pan-AKT inhibitor capivasertib in PeCa cell lines induced a significant downregulation of both total AKT and pAKT as well as decreased cell viability and chemotaxis. Selected protein candidates of the mTOR/AKT signaling pathway demonstrate association with histological and survival parameters of PeCa patients, whereas AKT appears to be the most promising one

Evolutionary origins of hepatitis A virus in small mammals

The origins of human hepatitis A virus (HAV) are unknown. We conducted a targeted search for HAV-related viruses in small mammals sampled globally and discovered highly diversified viruses in bats, rodents, hedgehogs, and shrews. We demonstrate that these viruses share unique biological features with HAV, including structural, genomic, antigenic, and pathogenic properties. We found evidence of major shifts of HAV-related viruses between mammalian hosts in the past, suggesting both an origin of this viral genus in small mammals and a zoonotic origin of human HAV. Our data show that risk assessments for emerging viruses can benefit greatly from the analysis of viral infection patterns that evolved within animal reservoirs

Axonal mapping of the motor cranial nerves

Basic behaviors, such as swallowing, speech, and emotional expressions are the result of a highly coordinated interplay between multiple muscles of the head. Control mechanisms of such highly tuned movements remain poorly understood. Here, we investigated the neural components responsible for motor control of the facial, masticatory, and tongue muscles in humans using specific molecular markers (ChAT, MBP, NF, TH). Our findings showed that a higher number of motor axonal population is responsible for facial expressions and tongue movements, compared to muscles in the upper extremity. Sensory axons appear to be responsible for neural feedback from cutaneous mechanoreceptors to control the movement of facial muscles and the tongue. The newly discovered sympathetic axonal population in the facial nerve is hypothesized to be responsible for involuntary control of the muscle tone. These findings shed light on the pivotal role of high efferent input and rich somatosensory feedback in neuromuscular control of finely adjusted cranial systems

Evolutionary origins of hepatitis A virus in small mammals

Hepatitis A virus (HAV) is an ancient and ubiquitous human pathogen recovered previously only from primates. The sole species of the genus Hepatovirus, existing in both enveloped and nonenveloped forms, and with a capsid structure intermediate between that of insect viruses and mammalian picornaviruses, HAV is enigmatic in its origins. We conducted a targeted search for hepatoviruses in 15,987 specimens collected from 209 small mammal species globally and discovered highly diversified viruses in bats, rodents, hedgehogs, and shrews, which by pairwise sequence distance comprise 13 novel Hepatovirus species. Near-complete genomes from nine of these species show conservation of unique hepatovirus features, including predicted internal ribosome entry site structure, a truncated VP4 capsid protein lacking N-terminal myristoylation, a carboxyl-terminal pX extension of VP1, VP2 late domains involved in membrane envelopment, and a cis-acting replication element within the 3Dpol sequence. Antibodies in some bat sera immunoprecipitated and neutralized human HAV, suggesting conservation of critical antigenic determinants. Limited phylogenetic cosegregation among hepatoviruses and their hosts and recombination patterns are indicative of major hepatovirus host shifts in the past. Ancestral state reconstructions suggest a Hepatovirus origin in small insectivorous mammals and a rodent origin of human HAV. Patterns of infection in small mammals mimicked those of human HAV in hepatotropism, fecal shedding, acute nature, and extinction of the virus in a closed host population. The evolutionary conservation of hepatovirus structure and pathogenesis provide novel insight into the origins of HAV and highlight the utility of analyzing animal reservoirs for risk assessment of emerging viruses

Kollegiale Beratung in der betrieblichen Führungskräfteentwicklung : theoretischer Rahmen, Status quo und qualitative Analyse der Herausforderungen bei der Einführung aus Sicht betrieblicher Personalentwicklungsexperten

Kollegiale Beratung ist ein Beratungsformat im Rahmen der betrieblichen Personal- bzw. Führungskräfteentwicklung. Diese neuere Art des Lernens bewirkt positive Effekte sowohl auf individueller als auch auf Team- und Unternehmensebene. Es ist noch weitgehend offen, wie kollegiale Beratung implementiert werden sollte, um diese Wirkungen zu erzielen. Die Arbeit beleuchtet, welche Herausforderungen bei der Einführung kollegialer Beratung aus Sicht betrieblicher Personalentwicklungsexperten existieren. Um die Erfolgsfaktoren zu ermitteln, diese Herausforderungen zu bewältigen, wurden systematisch Experteninterviews durchgeführt. Diese wurden – angelehnt an die (reflexive) Grounded Theory – qualitativ ausgewertet. Obwohl „das“ kollegiale Beratungsformat nicht existiert, lassen sich typische Merkmale und Handlungsfelder ableiten. Unter anderem werden das charakteristische Setting, (Miss )Erfolgsfaktoren und Lessons learned dargestellt. Detailliert werden Untersuchungsfragen geklärt und ein Rahmenmodell entwickelt. Anschließend werden das wissenschaftliche Vorgehen und die Generalisierbarkeit der Ergebnisse reflektiert. Es folgen Empfehlungen für die Forschung und für die betriebliche Praxis. Die Arbeit leistet einen explorativen Beitrag zur bspw. im Vergleich zu Coaching bislang nicht so intensiv erforschten kollegialen Beratung. Das Rahmenmodell zeigt relevante Handlungsfelder für die erfolgreiche Ein- bzw. Durchführung der kollegialen Beratung auf. Die evidenzbasierten Ergebnisse ermöglichen die Reflexion und Optimierung des andragogischen Handelns der betrieblichen Personalentwicklungsexperten

Adaptation of primate cell-adapted hepatitis A virus strain HM175 to growth in guinea pig cells is independent of mutations in the 5′ nontranslated region

Previous studies of hepatitis A virus (HAV) genotypes after adaptation of wild-type virus to growth in cell cultures of primate origin identified determinants for growth in cell culture in the viral 2B and 2C protein-coding regions of the genome and demonstrated that an increased growth efficiency in a particular cell line was achieved by subsequent mutations in the 5′ nontranslated region (5′NTR). The results reported in this study demonstrate that the passage of HAV adapted to primate BS-C-1 cells in guinea pig cells resulted in increased growth efficiency in the rodent cells and decreased growth efficiency in BS-C-1 cells. This adaptation occurred without mutation in the 5′NTR, but the viral 2B and 2C proteins seem to play a role during adaptation to the new environment, as one mutation occurred in each protein. Although the data presented here do not clearly identify which region of the viral genome underwent mutations to improve the interaction of the viruses with guinea pig proteins, they do confirm that the 5′NTR is not the only region responsible for providing host cell-specific information.</jats:p