This study draws on an active audience perspective to develop a better understanding of mass audiences' attraction towards popular management ideas. It focuses on audience members' own experiences ...and, in particular, what audience activities actually play a role in shaping mass attraction, and how the deployment of these activities may vary. Analysing 65 in‐depth interviews with management practitioners in their role as audience members of guru seminars, the authors identify different key consumption activities, and explain how individual management practitioners may shift in consumption orientation throughout the communication process. This paper argues that such a broader and more dynamic understanding of consumption activity is essential in understanding the success and impact of management ideas, and opens several fruitful research directions.
Transplantation of multipotent mesenchymal progenitor cells is a valuable option for treating tendon disease. Tenogenic differentiation leading to cell replacement and subsequent matrix modulation ...may contribute to the regenerative effects of these cells, but it is unclear whether this occurs in the inflammatory environment of acute tendon disease. Equine adipose-derived stromal cells (ASC) were cultured as monolayers or on decellularized tendon scaffolds in static or dynamic conditions, the latter represented by cyclic stretching. The impact of different inflammatory conditions, as represented by supplementation with interleukin-1β and/or tumor necrosis factor-α or by co-culture with allogeneic peripheral blood leukocytes, on ASC functional properties was investigated. High cytokine concentrations increased ASC proliferation and osteogenic differentiation, but decreased chondrogenic differentiation and ASC viability in scaffold culture, as well as tendon scaffold repopulation, and strongly influenced musculoskeletal gene expression. Effects regarding the latter differed between the monolayer and scaffold cultures. Leukocytes rather decreased ASC proliferation, but had similar effects on viability and musculoskeletal gene expression. This included decreased expression of the tenogenic transcription factor scleraxis by an inflammatory environment throughout culture conditions. The data demonstrate that ASC tenogenic properties are compromised in an inflammatory environment, with relevance to their possible mechanisms of action in acute tendon disease.
Novel therapeutic approaches are needed to improve the postoperative management of residual nonfunctioning pituitary adenomas (NFPA), given their high relapse rate. Here, we evaluated the antitumor ...efficacy of the dual PI3K/mTOR inhibitor NVP-BEZ235 in the only available model of spontaneous NFPAs (MENX rats).
Organotypic cultures of rat primary NFPAs were incubated with NVP-BEZ235 and assessed for cell viability, proliferation, apoptosis, and PI3K/mTOR inhibition. NVP-BEZ235, or placebo, was administered to MENX rats and tumor response was monitored noninvasively by diffusion weighted-magnetic resonance imaging (DW-MRI). Following treatment, tumor tissues were investigated for cell proliferation, apoptosis, and PI3K/mTOR inhibition. Genes mediating the cytotoxic activity of NVP-BEZ235 were identified by gene-expression profiling. Among them, Defb1, encoding beta-defensin 1, was further studied for its role in pituitary cells and in human pancreatic neuroendocrine tumor (NET) cells.
NVP-BEZ235 showed antiproliferative and pro-cell death activities against NFPAs both in vitro and in vivo, and the response to the drug correlated with inhibition of the PI3K pathway. DW-MRI identified early functional changes (decreased cellularity) in the adenomas before their size was affected and emerged as a useful modality to assess therapy response. The cytotoxic effect of PI3K/mTOR blockade in NFPA was mediated by several genes, including Defb1. NVP-BEZ235 treatment induced Defb1 expression in NFPAs in vitro and in vivo, and in pancreatic NET cells. High Defb1 levels sensitized NET cells to PI3K/mTOR inhibition.
Our findings provide rationale for clinical investigation of PI3K/mTOR inhibition in NFPAs and identify novel effectors of PI3K-mediated neuroendocrine cell survival.
Molecular pathophysiology of human MICU1 deficiency Kohlschmidt, Nicolai; Elbracht, Miriam; Czech, Artur ...
Neuropathology and applied neurobiology,
October 2021, 2021-10-00, 20211001, Letnik:
47, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Aims
MICU1 encodes the gatekeeper of the mitochondrial Ca2+ uniporter, MICU1 and biallelic loss‐of‐function mutations cause a complex, neuromuscular disorder in children. Although the role of the ...protein is well understood, the precise molecular pathophysiology leading to this neuropaediatric phenotype has not been fully elucidated. Here we aimed to obtain novel insights into MICU1 pathophysiology.
Methods
Molecular genetic studies along with proteomic profiling, electron‐, light‐ and Coherent anti‐Stokes Raman scattering microscopy and immuno‐based studies of protein abundances and Ca2+ transport studies were employed to examine the pathophysiology of MICU1 deficiency in humans.
Results
We describe two patients carrying MICU1 mutations, two nonsense (c.52C>T; p.(Arg18*) and c.553C>T; p.(Arg185*)) and an intragenic exon 2‐deletion presenting with ataxia, developmental delay and early onset myopathy, clinodactyly, attention deficits, insomnia and impaired cognitive pain perception. Muscle biopsies revealed signs of dystrophy and neurogenic atrophy, severe mitochondrial perturbations, altered Golgi structure, vacuoles and altered lipid homeostasis. Comparative mitochondrial Ca2+ transport and proteomic studies on lymphoblastoid cells revealed that the Ca2+ threshold and the cooperative activation of mitochondrial Ca2+ uptake were lost in MICU1‐deficient cells and that 39 proteins were altered in abundance. Several of those proteins are linked to mitochondrial dysfunction and/or perturbed Ca2+ homeostasis, also impacting on regular cytoskeleton (affecting Spectrin) and Golgi architecture, as well as cellular survival mechanisms.
Conclusions
Our findings (i) link dysregulation of mitochondrial Ca2+ uptake with muscle pathology (including perturbed lipid homeostasis and ER–Golgi morphology), (ii) support the concept of a functional interplay of ER–Golgi and mitochondria in lipid homeostasis and (iii) reveal the vulnerability of the cellular proteome as part of the MICU1‐related pathophysiology.
Applied research strategy toward the identification of pathomechanisms upon human MICU1‐deficiency includes (i) phenotyping of the patient, (ii) molecular genetic investigations, (iii) biochemical characterization of patient‐derived lymphoblastoid cells including proteomics and Calcium release studies as well as (iv) precise characterization of muscle biopsy specimen including histology, electron and Coherent Anti‐Stokes Raman Scattering microscopy and immunostaining studies.
PPP1R21 acts as a co-factor for protein phosphatase 1 (PP1), an important serine/threonine phosphatase known to be essential for cell division, control of glycogen metabolism, protein synthesis, and ...muscle contractility. Bi-allelic pathogenic variants in
PPP1R21
were linked to a neurodevelopmental disorder with hypotonia, facial dysmorphism, and brain abnormalities (NEDHFBA) with pediatric onset. Functional studies unraveled impaired vesicular transport as being part of PPP1R21-related pathomechanism. To decipher further the pathophysiological processes leading to the clinical manifestation of NEDHFBA, we investigated the proteomic signature of fibroblasts derived from the first NEDHFBA patient harboring a splice-site mutation in
PPP1R21
and presenting with a milder phenotype. Proteomic findings and further functional studies demonstrate a profound activation of the ubiquitin–proteasome system with presence of protein aggregates and impact on cellular fitness and moreover suggest a cross-link between activation of the proteolytic system and cytoskeletal architecture (including filopodia) as exemplified on paradigmatic proteins including actin, thus extending the pathophysiological spectrum of the disease. In addition, the proteomic signature of
PPP1R21
-mutant fibroblasts displayed a dysregulation of a variety of proteins of neurological relevance. This includes increase proteins which might act toward antagonization of cellular stress burden in terms of pro-survival, a molecular finding which might accord with the presentation of a milder phenotype of our NEDHFBA patient.
Preclinical model systems should faithfully reflect the complexity of the human pathology. In hepatocellular carcinoma (HCC), the tumor vasculature is of particular interest in diagnosis and therapy. ...By comparing two commonly applied preclinical model systems, diethylnitrosamine induced (DEN) and orthotopically implanted (McA) rat HCC, we aimed to measure tumor biology noninvasively and identify differences between the models.
DEN and McA tumor development was monitored by MRI and PET. A slice-based correlation of imaging and histopathology was performed. Array CGH analyses were applied to determine genetic heterogeneity. Therapy response to sorafenib was tested in DEN and McA tumors.
Histologically and biochemically confirmed liver damage resulted in increased (18)F-fluorodeoxyglucose (FDG) PET uptake and perfusion in DEN animals only. DEN tumors exhibited G1-3 grading compared with uniform G3 grading of McA tumors. Array comparative genomic hybridization revealed a highly variable chromosomal aberration pattern in DEN tumors. Heterogeneity of DEN tumors was reflected in more variable imaging parameter values. DEN tumors exhibited lower mean growth rates and FDG uptake and higher diffusion and perfusion values compared with McA tumors. To test the significance of these differences, the multikinase inhibitor sorafenib was administered, resulting in reduced volume growth kinetics and perfusion in the DEN group only.
This work depicts the feasibility and importance of in depth preclinical tumor model characterization and suggests the DEN model as a promising model system of multifocal nodular HCC in future therapy studies.
Purpose
The purpose of this paper is to describe a case study of a pilot program in which a collaborative problem-solving approach was implemented at hot spots of juvenile and youth crime in downtown ...Seattle, Washington.
Design/methodology/approach
Two matched pairs of youth crime hot spots were allocated at random to treatment (“non-enforcement problem-solving”) or comparison (“policing-as-usual”) conditions within matched pairs. In the treatment condition, police collaborated with community and local government partners to develop problem-solving strategies that deemphasized arrests and other traditional law enforcement approaches. Impacts on crime incidents, calls for service, and police activity were assessed using difference-in-differences Poisson regression with robust standard errors.
Findings
No significant impact on crime or calls for service was observed at one site, where several problem-solving approaches were successfully implemented. However, crime and calls for service were significantly lower at the other site, where some enforcement activity took place but non-enforcement problem-solving was limited.
Research limitations/implications
The authors find mixed support for non-enforcement problem-solving at hot spots. The enforcement may be necessary for stabilization, and must be balanced with the risks of justice system involvement for youth. Political support at the city level is necessary for collaboration. Limitations include the small number of sites in this pilot study and key differences between treatment and comparison locations.
Originality/value
This study is one of the first to assess the impact of primarily non-enforcement problem-solving specifically at youth crime hot spots.
Background. Extensive physical activity (PA; ≥18 MET∗h/week, MET metabolic equivalent of tasks hours) postcancer diagnosis has shown favorable effects on colorectal cancer disease-free survival. ...However, the feasibility of introducing this high volume of PA in this patient group is unclear. Therefore, the aim of the F-PROTECT study was to evaluate the feasibility of extensive and prolonged PA (≥18 MET∗h/week over 12 months) in colorectal cancer patients with the primary objectives to (1) recruit 50 patients within 12 months and (2) reach an attendance rate of ≥70%. Methods. Single-armed, bicentric, prospective intervention study in colorectal cancer patients (≤80 years; UICC II/III Union for International Cancer Control) after histopathological confirmed R0-resection who were consecutively recruited from visceral surgery units of 10 clinics in Germany. Recruitment rates were calculated using screening logs. Intervention was a 12-month endurance-focused exercise program with supervised and home-based training. Attendance rates defined as ≥70% participation in training sessions were calculated by training diaries. Results. Out of 521 patients who were screened for eligibility, 50 (23 female; 59 ± 10 years, UICC 44% II, 56% III; adjuvant chemotherapy 60%) were recruited within 15 months. Mean duration between surgery and first training was 103 ± 57 days. Training attendance rate was 64% (including 9 dropouts). Six (12%) participants reached ≥18 MET∗h/week in ≥70% of training sessions between 4–12 months. 28 adverse events (n = 9 serious) occurred, however, were not assessed as training related. Conclusions. The present intervention involving a combination of supervised and home-based exercise training in postsurgical colorectal cancer patients was not feasible. Strategies specifically designed for this patient group must be developed and investigated to motivate long-term PA. Registration. The study was prospectively registered at clinicaltrials.gov (NCT01991847).
Doxorubicin (DOX) is a widely used chemotherapeutic anticancer drug. Its intrinsic fluorescence properties enable investigation of tumor response, drug distribution and metabolism. First phantom ...studies in vitro showed optoacoustic property of DOX. We therefore aimed to further investigate the optoacoustic properties of DOX in biological tissue in order to explore its potential as theranostic agent. We analysed doxorubicin hydrochloride (Dox·HCl) and liposomal encapsulated doxorubicin hydrochloride (Dox·Lipo), two common drugs for anti-cancer treatment in clinical medicine. Optoacoustic measurements revealed a strong signal of both doxorubicin substrates at 488 nm excitation wavelength. Post mortem analysis of intra-tumoral injections of DOX revealed a detectable optoacoustic signal even at three days after the injection. We thereby demonstrate the general feasibility of doxorubicin detection in biological tissue by means of optoacoustic tomography, which could be applied for high resolution imaging at mesoscopic depths dictated by effective penetration of visible light into the biological tissues.
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