The Role of PTEN in Tumor Angiogenesis

During the past 20 years, the phosphatase and tensin homolog PTEN has been shown to be involved in major physiological processes, and its mutation or loss is often associated with tumor formation. In addition PTEN regulates angiogenesis not only through its antagonizing effect on the PI3 kinase pathway mainly, but also through some phosphatase-independent functions. In this paper we delineate the role of this powerful tumor suppressor in tumor angiogenesis and dissect the underlying molecular mechanisms. Furthermore, it appears that, in a number of cancers, the PTEN status determines the response to chemotherapy, highlighting the need to monitor PTEN expression and to develop PTEN-targeted therapies

Early renal failure after domino hepatic transplantation using the liver from a compound heterozygous patient with primary hyperoxaluria

Background. To cover the shortage of cadaveric organs, new approaches to expand the donor pool are needed. Here we report on a case of domino liver transplantation (DLT) using an organ harvested from a compound heterozygous patient with primary hyperoxaluria (PHO), who underwent combined liver and kidney transplantation. The DLT recipient developed early renal failure with oxaluria. The time to the progression to oxalosis with renal failure in such situations is unknown, but, based on animal data, we hypothesize that calcineurin inhibitors may play a detrimental role. Methods. A cadaveric liver and kidney transplantation was performed in a 52-year-old male with PHO. His liver was used for a 64-year-old patient with a non-resectable, but limited cholangiocarcinoma. Results. While the course of the PHO donor was uneventful, in the DLT recipient early post-operative, dialysis-dependent renal failure with hyperoxaluria developed. Histology of a kidney biopsy revealed massive calcium oxalate crystal deposition as the leading aetiological cause. Conclusions. DLT using PHO organs for marginal recipients represents a possible therapeutic approach regarding graft function of the liver. However, it may negatively alter the renal outcome of the recipient in an unpredictable manner, especially with concomitant use of cyclosporin. Therefore, we suggest that, although DLT should be promoted, PHO organs are better excluded from such procedure

EphB1 recruits c-Src and p52Shc to activate MAPK/ERK and promote chemotaxis

Eph receptors and their ligands (ephrins) play an important role in axonal guidance, topographic mapping, and angiogenesis. The signaling pathways mediating these activities are starting to emerge and are highly cell- and receptor-type specific. Here we demonstrate that activated EphB1 recruits the adaptor proteins Grb2 and p52Shc and promotes p52Shc and c-Src tyrosine phosphorylation as well as MAPK/extracellular signal–regulated kinase (ERK) activation. EphB1-mediated increase of cell migration was abrogated by the MEK inhibitor PD98059 and Src inhibitor PP2. In contrast, cell adhesion, which we previously showed to be c-jun NH2-terminal kinase (JNK) dependent, was unaffected by ERK1/2 and Src inhibition. Expression of dominant-negative c-Src significantly reduced EphB1-dependent ERK1/2 activation and chemotaxis. Site-directed mutagenesis experiments demonstrate that tyrosines 600 and 778 of EphB1 are required for its interaction with c-Src and p52Shc. Furthermore, phosphorylation of p52Shc by c-Src is essential for its recruitment to EphB1 signaling complexes through its phosphotyrosine binding domain. Together these findings highlight a new aspect of EphB1 signaling, whereby the concerted action of c-Src and p52Shc activates MAPK/ERK and regulates events involved in cell motility

Screening of cognitive performance in kidney transplant recipients: a mini review

Why should we screen?The prevalence of cognitive impairment in kidney transplant recipients (KTRs) is up to 58%. The 10-year graft loss and mortality rates are above 30% and 50%, respectively, and executive malfunctioning increases disadvantageous outcomes.What causes cognitive impairment in KTRs?Strong risk factors are older age and chronic kidney disease. However, causes are multifactorial and include cardiovascular, cerebrovascular, neurodegenerative, inflammatory, uremic, psychiatric, and lifestyle-related susceptibilities.How should we screen?KTR-specific validated instruments or strategies do not exist. The central element should be a multidomain cognitive screening test that is sensitive to mild cognitive impairment, corrects for age and education, and includes executive functions testing. Cognitive trajectories, effects on everyday life and psychiatric comorbidities should be assessed by integrating the perspectives of both patients and knowledgeable informants.When should we screen?Screening should not be postponed if there is suspicion of impaired cognition. Different time points after transplantation tend to have their own characteristics.Who should conduct the screening?Screening should not be limited to specialists. It can be carried out by any healthcare professional who has received a limited amount of training.What are the benefits of screening?Screening does not provide a diagnosis. However, suggestive results change care in multiple ways. Goals are: Initiation of professional dementia work-up, securing of adherence, anticipation of potential complications (delirium, falls, frailty, functional impairment, malnutrition, etc.), mitigation of behavioral disorders, adjustment of diagnostic and therapeutic “load”, reduction of caregiver burden and meeting of changing needs. We summarize data on the prevalence, risk factors and sequelae of cognitive impairment in KTRs. We also discuss the requirements for appropriate screening strategies and provide guiding principles regarding appropriate and safe care

Developing an Instrument to Evaluate Undergraduate Healthcare Students' Professionalism.

Professionalism is a multidimensional quality acquired over time. Undergraduate years lay a foundation for the development of professionalism. Tools monitoring the students' professional development are needed. Our tool development followed three phases: 1) identifying meaningful criteria for professionalism adapted to the education level, 2) developing an evaluation instrument in a process maximising construct validity, 3) testing the evaluation instrument in an interprofessional study. The evaluation instrument proved to be applicable in the field and it meets validity standards. Some differences between professions were found and discussed. Professionality starts to develop during the education, and early monitoring is important to support students' optimal development. The evaluation instrument supports both self- and expert evaluation of healthcare students' professional development

The Photocatalytic Activity of the Bi2O3-B2O3-ZnO-TiO2 Glass Coating

Due to the low melting temperature, the glazes based on the Bi2O3-B2O3-ZnO system are used as coatings on the surface of industrial glass substrates. Moreover, the composition of these coatings does not contain PbO, meeting the optical and environmental properties requirements. In this study, TiO2 was used in the Bi2O3-B2O3-ZnO glaze system to improve its photocatalytic ability. This can be considered a four – component glass system Bi2O3-B2O3-ZnO-TiO2. The heating microscopy results show that the melting temperature of the glaze system is 606 °C. The Fourier transform infrared spectroscopy results show that the TiO2 polyhedra are located independently in the structure without participating in forming a glass network. Thanks to that, the photocatalytic properties of TiO2 are maintained. The X-ray diffraction patterns results show that the formed TiO2 nanocrystals are rutile and anatase crystals. The results of determining the band gap energy using UV-Vis show that the band gap energy of the base glaze system increases with the addition of TiO2. The methylene blue decomposition results also showed that the ability to decompose organic increased when TiO2 was added to the glaze coating. The characteristics such as melting temperature, microstructure, and photocatalytic capacity of Bi2O3-B2O3-ZnO-TiO2 white glazes (5 and 10 % weight of TiO2) also were indicated in this paper

Dichotomous Responses to Chronic Fetal Hypoxia Lead to a Predetermined Aging Phenotype

Hypoxia-induced intrauterine growth restriction increases the risk for cardiovascular, renal, and other chronic diseases in adults, representing thus a major public health problem. Still, not much is known about the fetal mechanisms that predispose these individuals to disease. Using a previously validated mouse model of fetal hypoxia and bottom-up proteomics, we characterize the response of the fetal kidney to chronic hypoxic stress. Fetal kidneys exhibit a dichotomous response to chronic hypoxia, comprising on the one hand cellular adaptations that promote survival (glycolysis, autophagy, and reduced DNA and protein synthesis), but on the other processes that induce a senescence-like phenotype (infiltration of inflammatory cells, DNA damage, and reduced proliferation). Importantly, chronic hypoxia also reduces the expression of the antiaging proteins klotho and Sirt6, a mechanism that is evolutionary conserved between mice and humans. Taken together, we uncover that predetermined aging during fetal development is a key event in chronic hypoxia, establishing a solid foundation for Barker’s hypothesis of fetal programming of adult diseases. This phenotype is associated with a characteristic biomarker profile in tissue and serum samples, exploitable for detecting and targeting accelerated aging in chronic hypoxic human diseases

ITGAM rs1143679 Variant in Systemic Lupus Erythematosus Is Associated with Increased Serum Calcification Propensity.

OBJECTIVES CD11B/ITGAM (Integrin Subunit α M) mediates the adhesion of monocytes, macrophages, and granulocytes and promotes the phagocytosis of complement-coated particles. Variants of the ITGAM gene are candidates for genetic susceptibility to systemic lupus erythematosus (SLE). SNP rs1143679 (R77H) of CD11B particularly increases the risk of developing SLE. Deficiency of CD11B is linked to premature extra-osseous calcification, as seen in the cartilage of animals with osteoarthritis. Serum calcification propensity measured by the T50 test is a surrogate marker for systemic calcification and reflects increased cardiovascular (CV) risk. We aimed to assess whether the CD11B R77H gene variant is associated with a higher serum calcification propensity (i.e., a lower T50 value) in SLE patients compared to the wild-type allele (WT). METHODS Cross-sectional study incorporating adults with SLE genotyped for the CD11B variant R77H and assessed for serum calcification propensity with the T50 method. Participants were included in a multicenter trans-disciplinary cohort and fulfilled the 1997 revised American College of Rheumatology (ACR) criteria for SLE. We used descriptive statistics for comparing baseline characteristics and sequential T50 measurements in subjects with the R77H variant vs. WT CD11B. RESULTS Of the 167 patients, 108 (65%) were G/G (WT), 53 (32%) were G/A heterozygous, and 6 (3%) were A/A homozygous for the R77H variant. A/A patients cumulated more ACR criteria upon inclusion (7 ± 2 vs. 5 ± 1 in G/G and G/A; p = 0.02). There were no differences between the groups in terms of global disease activity, kidney involvement, and chronic renal failure. Complement C3 levels were lower in A/A individuals compared to others (0.6 ± 0.08 vs. 0.9 ± 0.25 g/L; p = 0.02). Baseline T50 did not differ between the groups (A/A 278 ± 42' vs. 297 ± 50' in G/G and G/A; p = 0.28). Considering all sequential T50 test results, serum calcification propensity was significantly increased in A/A individuals compared to others (253 ± 50 vs. 290 ± 54; p = 0.008). CONCLUSIONS SLE patients with homozygosity for the R77H variant and repeated T50 assessment displayed an increased serum calcification propensity (i.e., a lower T50) and lower C3 levels compared to heterozygous and WT CD11B, without differing with respect to global disease activity and kidney involvement. This suggests an increased CV risk in SLE patients homozygous for the R77H variant of CD11B

A National Survey Comparing Patients' and Transplant Professionals' Research Priorities in the Swiss Transplant Cohort Study

We aimed to identify, assess, compare and map research priorities of patients and professionals in the Swiss Transplant Cohort Study. The project followed 3 steps. 1) Focus group interviews identified patients' (n = 22) research priorities. 2) A nationwide survey assessed and compared the priorities in 292 patients and 175 professionals. 3) Priorities were mapped to the 4 levels of Bronfenbrenner's ecological framework. The 13 research priorities (financial pressure, medication taking, continuity of care, emotional well-being, return to work, trustful relationships, person-centredness, organization of care, exercise and physical fitness, graft functioning, pregnancy, peer contact and public knowledge of transplantation), addressed all framework levels: patient (n = 7), micro (n = 3), meso (n = 2), and macro (n = 1). Comparing each group's top 10 priorities revealed that continuity of care received highest importance rating from both (92.2% patients, 92.5% professionals), with 3 more agreements between the groups. Otherwise, perspectives were more diverse than congruent: Patients emphasized patient level priorities (emotional well-being, graft functioning, return to work), professionals those on the meso level (continuity of care, organization of care). Patients' research priorities highlighted a need to expand research to the micro, meso and macro level. Discrepancies should be recognized to avoid understudying topics that are more important to professionals than to patients

Epitope-Specific Anti-C1q Autoantibodies in Systemic Lupus Erythematosus

OBJECTIVE: In patients with systemic lupus erythematosus (SLE) complement C1q is frequently targeted by autoantibodies (anti-C1q), that correlate best with active renal disease. Anti-C1q bind to largely unknown epitopes on the collagen-like region (CLR) of this highly functional molecule. Here we aimed at exploring the role of epitope-specific anti-C1q in SLE patients. METHODS: First, 22 sera of SLE patients, healthy controls and anti-C1q positive patients without SLE were screened for anti-C1q epitopes by a PEPperMAP(®) microarray, expressing CLR of C1q derived peptides with one amino acid (AA) shift in different lengths and conformations. Afterwards, samples of 378 SLE patients and 100 healthy blood donors were analyzed for antibodies against the identified epitopes by peptide-based ELISA. Relationships between peptide-specific autoantibodies and SLE disease manifestations were explored by logistic regression models. RESULTS: The epitope mapping showed increased IgG binding to three peptides of the C1q A- and three of the C1q B-chain. In subsequent peptide-based ELISAs, SLE sera showed significantly higher binding to two N-terminally located C1q A-chain peptides than controls (p < 0.0001), but not to the other peptides. While anti-C1q were associated with a broad spectrum of disease manifestations, some of the peptide-antibodies were associated with selected disease manifestations, and antibodies against the N-terminal C1q A-chain showed a stronger discrimination between SLE and controls than conventional anti-C1q. CONCLUSION: In this large explorative study anti-C1q correlate with SLE overall disease activity. In contrast, peptide-antibodies are associated with specific aspects of the disease suggesting epitope-specific effects of anti-C1q in patients with SLE