Human Fat-Derived Mesenchymal Stem Cells Xenogenically Implanted in a Rat Model Show Enhanced New Bone Formation in Maxillary Alveolar Tooth Defects

Background. Due to restorative concerns, bone regenerative therapies have garnered much attention in the field of human oral/maxillofacial surgery. Current treatments using autologous and allogenic bone grafts suffer from inherent challenges, hence the ideal bone replacement therapy is yet to be found. Establishing a model by which MSCs can be placed in a clinically acceptable bone defect to promote bone healing will prove valuable to oral/maxillofacial surgeons. Methods. Human adipose tissue-derived MSCs were seeded onto Gelfoam® and their viability, proliferation, and osteogenic differentiation was evaluated in vitro. Subsequently, the construct was implanted in a rat maxillary alveolar bone defect to assess in vivo bone healing and regeneration. Results. Human MSCs were adhered, proliferated, and uniformly distributed, and underwent osteogenic differentiation on Gelfoam®, comparable with the tissue culture surface. Data confirmed that Gelfoam® could be used as a scaffold for cell attachment and a delivery vehicle to implant MSCs in vivo. Histomorphometric analyses of bones harvested from rats treated with hMSCs showed statistically significant increase in collagen/early bone formation, with cells positive for osteogenic and angiogenic markers in the defect site. This pattern was visible as early as 4 weeks post treatment. Conclusions. Xenogenically implanted human MSCs have the potential to heal an alveolar tooth defect in rats. Gelfoam®, a commonly used clinical biomaterial, can serve as a scaffold to deliver and maintain MSCs to the defect site. Translating this strategy to preclinical animal models provides hope for bone tissue engineering

Validation of 34betaE12 immunoexpression in clear cell papillary renal cell carcinoma as a sensitive biomarker

Clear cell papillary renal cell carcinoma (CCPRCC) is a recently recognised neoplasm with a broad spectrum of morphological characteristics, thus representing a challenging differential diagnosis, especially with the low malignant potential multicystic renal cell neoplasms and clear cell renal cell carcinoma. We selected 14 cases of CCPRCC with a wide spectrum of morphological features diagnosed on morphology and CK7 immunoreactivity and analysed them using a panel of immunohistochemical markers, focusing on 34 beta E12 and related CKs 1,5,10 and 14 and several molecular analyses such as fluorescence in situ hybridisation (FISH), array comparative genomic hybridisation (aCGH), VHL methylation, VHL and TCEB1 sequencing and multiplex ligation-dependent probe amplification (MLPA). Twelve of 13 (92%) CCPRCC tumours were positive for 34 beta E12. One tumour without 3p alteration by FISH revealed VHL mutation and 3p deletion at aCGH; thus, it was re-classified as clear cell RCC. We concluded that: (1) immunohistochemical expression of CK7 is necessary for diagnostic purposes, but may not be sufficient to identify CCPRCC, while 34 beta E12, in part due to the presence of CK14 antigen expression, can be extremely useful for the recognition of this tumour; and (2) further molecular analysis of chromosome 3p should be considered to support of CCPRCC diagnosis, when FISH analysis does not evidence the common loss of chromosome 3p.Peer reviewe

Survey of Period Variations of Superhumps in SU UMa-Type Dwarf Novae

We systematically surveyed period variations of superhumps in SU UMa-type dwarf novae based on newly obtained data and past publications. In many systems, the evolution of superhump period are found to be composed of three distinct stages: early evolutionary stage with a longer superhump period, middle stage with systematically varying periods, final stage with a shorter, stable superhump period. During the middle stage, many systems with superhump periods less than 0.08 d show positive period derivatives. Contrary to the earlier claim, we found no clear evidence for variation of period derivatives between superoutburst of the same object. We present an interpretation that the lengthening of the superhump period is a result of outward propagation of the eccentricity wave and is limited by the radius near the tidal truncation. We interpret that late stage superhumps are rejuvenized excitation of 3:1 resonance when the superhumps in the outer disk is effectively quenched. Many of WZ Sge-type dwarf novae showed long-enduring superhumps during the post-superoutburst stage having periods longer than those during the main superoutburst. The period derivatives in WZ Sge-type dwarf novae are found to be strongly correlated with the fractional superhump excess, or consequently, mass ratio. WZ Sge-type dwarf novae with a long-lasting rebrightening or with multiple rebrightenings tend to have smaller period derivatives and are excellent candidate for the systems around or after the period minimum of evolution of cataclysmic variables (abridged).Comment: 239 pages, 225 figures, PASJ accepte

"Watch Me Grow- Electronic (WMG-E)" surveillance approach to identify and address child development, parental mental health, and psychosocial needs : study protocol

Background: The COVID-19 pandemic and the associated economic recession has increased parental psychosocial stress and mental health challenges. This has adversely impacted child development and wellbeing, particularly for children from priority populations (culturally and linguistically diverse (CALD) and rural/regional communities) who are at an already increased risk of health inequality. The increased mental health and psychosocial needs were compounded by the closure of in-person preventive and health promotion programs resulting in health organisations embracing technology and online services. Watch Me Grow- Electronic (WMG-E) – developmental surveillance platform- exemplifies one such service. WMG-E was developed to monitor child development and guide parents towards more detailed assessments when risk is identified. This Randomised Controlled Trial (RCT) aims to expand WMG-E as a digital navigation tool by also incorporating parents’ mental health and psychosocial needs. Children and families needing additional assessments and supports will be electronically directed to relevant resources in the ‘care-as-usual’ group. In contrast, the intervention group will receive continuity of care, with additional in-person assessment and ‘warm hand over’ by a ‘service navigator’ to ensure their needs are met. Methods: Using an RCT we will determine: (1) parental engagement with developmental surveillance; (2) access to services for those with mental health and social care needs; and (3) uptake of service recommendations. Three hundred parents/carers of children aged 6 months to 3 years (recruited from a culturally diverse, or rural/regional site) will be randomly allocated to the ‘care-as-usual’ or ‘intervention’ group. A mixed methods implementation evaluation will be completed, with semi-structured interviews to ascertain the acceptability, feasibility and impact of the WMG-E platform and service navigator. Conclusions: Using WMG-E is expected to: normalise and de-stigmatise mental health and psychosocial screening; increase parental engagement and service use; and result in the early identification and management of child developmental needs, parental mental health, and family psychosocial needs. If effective, digital solutions such as WMG-E to engage and empower parents alongside a service navigator for vulnerable families needing additional support, will have significant practice and policy implications in the pandemic/post pandemic period. Trial registration: The trial (Protocol No. 1.0, Version 3.1) was registered with ANZCTR (registration number: ACTRN12621000766819) on July 21st, 2021 and reporting of the trial results will be according to recommendations in the CONSORT Statement

Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.

Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health

Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.

Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Screening for novel constitutively active CXCR2 mutants and their cellular effects

Chemokines play an important role in inflammatory, developmental, and homeostatic processes. Deregulation of this system results in various diseases including tumorigenesis and cancer metastasis. Deregulation can occur when constitutively active mutant (CAM) chemokine receptors are locked in the on position. This can lead to cellular transformation/tumorigenesis.The CXC chemokine receptor 2 (CXCR2) is a G-protein-coupled receptor (GPCR) expressed on neutrophils, some monocytes, endothelial cells, and some epithelial cells. CXCR2 activation with CXC chemokines induces leukocyte migration, trafficking, leukocyte degranulation, cellular differentiation, and angiogenesis. Activation of CXCR2 can lead to cellular transformation. We hypothesized that CAM CXCR2s may play a role in cancer development. In order to identify CXCR2 CAMs, potential mutant CXCR2 receptors were screened using a modified Saccharomyces cerevisiae high-throughput system. S. cerevisiae has been used successfully to identify GPCR/G-protein interactions and autocrine selection for peptide agonists. The CXCR2 CAMs identified from this screen were characterized in mammalian cells. Their ability to transform cells in vitro was shown using foci formation, soft-agar growth, impedance measurement assays, and in vivo tumor growth following hind flank inoculation into mice. Signaling pathways contributing to cellular transformation were identified using luciferase reporter assays. Studying constitutively active GPCRs is an approach to capturing pluridimensional GPCRs in a locked activation state. In order to address the residues necessary for CXCR2 activation, we used S. cerevisiae for screening novel CAMs and characterized them using mammalian reporter assays