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A new rat model for translational research in bone regeneration. - Tissue engineering. Part C, Methods
The EU directive 2010/63/EU on the protection of animals used for scientific purpose focused on reducing the number of animals and refinement of breeding. Animal studies are necessary to protect human health. Lots of animal models exist to study bone regeneration but a reliable, well reproducible and relatively inexpensive model with the possibility for multiple testing in the same animal is still missing. Rats may serve as good models for this due to the small animal size, good cost/benefit ratio. The present study aimed to develop a novel rat caudal vertebrae critical size defect model for bone regeneration and implant osseointegration studies The study was performed using Wistar rats with weight from 380 to 450 gr. An incision was made on the dorsal side of the tail. After skin and muscles retractions, the vertebrae were exposed. Critical size defects for bone tissue engineering, or implant placements for titanium body experiments were possible in each of the first four caudal vertebrae. MicroCT and histology were used to detect bone growth. There was no bone formation in the defects after one month or two months of healing. When a calcium phosphate biomaterial was used (Bio-OssÂ®, Geistlich Pharma AG, Wolhusen, Switzerland), a good stability of the material in the defect was noted and bone growth was visible after one or two months. Results based on implant placement showed good primary stability after three month of healing. MicroCT showed integrated implant position through the vertebra. These results suggest that the rat caudal vertebrae may serve as a good new model for studying bone regeneration and implant osseointegration with the possibility of multiple testing within the same experimental animal and the potential to decrease number of experimental animals. â€ƒ.
Infarct location and sleep apnea: evaluating the potential association in acute ischemic stroke. - Sleep medicine
The literature about the relationship between obstructive sleep apnea (OSA) and stroke location is conflicting with some studies finding an association and others demonstrating no relationship. Among acute ischemic stroke patients, we sought to examine the relationship between stroke location and the prevalence of OSA; OSA severity based on apnea-hypopnea index (AHI), arousal frequency, and measure of hypoxia; and number of central and obstructive respiratory events.Data were obtained from patients who participated in a randomized controlled trial (NCT01446913) that evaluated the effectiveness of a strategy of diagnosing and treating OSA among patients with acute ischemic stroke and transient ischemic attack. Stroke location was classified by brain imaging reports into subdivisions of lobes, subcortical areas, brainstem, cerebellum, and vascular territory. The association between acute stroke location and polysomnographic findings was evaluated using logistic regression for OSA presence and negative binomial regression for AHI.Among 73 patients with complete polysomnography and stroke location data, 58 (79%) had OSA. In unadjusted models, no stroke location variable was associated with the prevalence or severity of OSA. Similarly, in multivariable modeling, groupings of stroke location were also not associated with OSA presence.These results indicate that OSA is present in the majority of stroke patients and imply that stroke location cannot be used to identify a group with higher risk of OSA. The results also suggest that OSA likely predated the stroke. Given this high overall prevalence, strong consideration should be given to obtaining polysomnography for all ischemic stroke patients.Published by Elsevier B.V.
KRAS gene mutations - prognostic factor in colorectal cancer? - Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie
The colorectal cancer (CRC) modern therapy is using adjuvant and neoadjuvant companion therapeutic agents, part of them having an anti-angiogenic action. Their benefic effect can be annulated by some gene mutations, which are interfering in signal transduction pathways. One of the more frequent activating mutations is occurring in the KRAS gene. We assessed the KRAS mutations by two molecular methods, in a group of patients with a follow-up until 144 months, aiming to establish eventual correlations between the presence of mutations and the evolution of patients. We tried to appreciate the prognostic value of these mutations. A retrospective study was conducted on 74 patients treated by radical surgery; the surgical specimens were analyzed macroscopically and the histopathological type and degree were established. PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) and pyrosequencing were performed on paraffin-embedded tumor specimens. Statistical analysis showed significant differences in survival between patients with wild type gene and patients with mutation in codon 13; the same results were also obtained regarding TNM I, II stages or Dukes type A and B cases. However, for the patients in stage IV pTNM, the evolution was slightly better in association with a KRAS mutation than in wild type cases.
Microsatellite and Mitochondrial DNA Study of Native Eastern European Cattle Populations: The Case of the Romanian Grey. - PloS one
The Eastern European Grey cattle are regarded as the direct descendants of the aurochs (Bos taurus primigenius). Nowadays in Romania, less than 100 Grey animals are being reared and included in the national gene reserve. We examined the genetic diversity among Romanian Grey, Brown, Spotted and Black and White cattle breeds, with a particular focus on Romanian Grey through the use of (i) 11 bovine specific microsatellite markers on 83 animals and (ii) 638 bp length of mitochondrial DNA (mtDNA) D-loop region sequence data from a total of 81 animals. Both microsatellite and mtDNA analysis revealed a high level of genetic variation in the studied breeds. In Romanian Grey a total of 100 alleles were found, the mean number of observed alleles per locus was 9.091; the average observed heterozygosity was 0.940; the Wright's fixation index (FIS) was negative (-0.189) and indicates that there is no inbreeding and no selection pressure. MtDNA analysis revealed 52 haplotypes with 67 variable sites among the Romanian cattle breeds without any insertion or deletion. Haplotype diversity was 0.980 Â± 0.007 and ranged from 0.883 Â± 0.056 (Brown) to 0.990 Â± 0.028 (Spotted and Black and White). The highest genetic variability of the mtDNA was recorded in the Grey breed, where 18 haplotypes were identified. The most frequent mtDNA D-loop region belonged to T3 haplogroup (80.247%), which was found across all studied breeds, while T2 haplotypes (16.049%) was only found in Grey, Spotted and Black and White genotypes. The T1 haplotypes (3.704%) were found in the Grey and Spotted. The current results contribute to the general knowledge on genetic diversity found in Eastern European cattle breeds and could prove a valuable tool for the conservation efforts of animal genetic resources (FAnGR).
Next-generation sequencing reveals rare genomic alterations in aggressive digital papillary adenocarcinoma. - Annals of diagnostic pathology
Aggressive digital papillary adenocarcinoma (ADPA) is a rare cutaneous adnexal neoplasm that occurs on the fingers, toes, palms, and soles. It is characterized by aggressive biological behavior, with a relatively high potential for local recurrence (30%-40% of cases) and distant metastasis (up to 14%). This retrospective study assessed the mutation status of ADPA lesions to identify possible therapeutic targets. We performed comprehensive genomic profiling of 9 ADPA cases that had been identified in our database. We identified a BRAF-V600E (BRAF c.1799T>A p.V600E) mutation in 1 patient (11%). Complete surgical excision is the treatment of choice for ADPA; however, there are no uniform diagnostic guidelines or recognized effective treatments for metastasis, and no therapeutic targets have been identified. Targeted therapy may be a treatment option for patients with metastatic ADPA if a relevant oncogene mutation is identified. Further studies with a larger sample size are required to confirm our findings and identify more molecular mechanisms.Copyright Â© 2015. Published by Elsevier Inc.
Free space optical communication using beam parameters with translational and transverse rotational invariance. - Journal of the Optical Society of America. A, Optics, image science, and vision
Two natural requirements on a measurable quantity possessed by a paraxially propagating light-field to be suitable for free space optical communication are invariance under free space propagation and invariance under transverse plane rotation. While the former invariance ensures that the measurable quantity is robust while signalling through free space, the latter invariance ensures that a detector measuring the quantity can be oriented at any angle in the transverse plane, and a measurement by the detector yields the same value for the quantity irrespective of the transverse angle, thus avoiding alignment issues. The variance matrix of a paraxially propagating light-field is analyzed from the perspective of the aforementioned invariances. That the "charge" of a paraxial light-field, which is contained in the variance matrix, and which has been previously well studied for its suitability toward free space optical communication, possesses these two invariance properties, emerges naturally in the analysis. Seven functionally independent quantities other than charge, which are derived from the variance matrix, and which share these invariances, are presented and studied for their suitability toward signalling through turbulent atmosphere using the low-order Hermite-Gaussian modes. It is found that the spot size of a Gaussian light-field can be effectively used as a switch, to communicate through short distances in a turbulent atmosphere.
PD-L1 expression and prognostic impact in glioblastoma. - Neuro-oncology
Therapeutic targeting of the immune checkpoints cytotoxic T-lymphocyte-associated molecule-4 (CTLA-4) and PD-1/PD-L1 has demonstrated tumor regression in clinical trials, and phase 2 trials are ongoing in glioblastoma (GBM). Previous reports have suggested that responses are more frequent in patients with tumors that express PD-L1; however, this has been disputed. At issue is the validation of PD-L1 biomarker assays and prognostic impact.Using immunohistochemical analysis, we measured the incidence of PD-L1 expression in 94 patients with GBM. We categorized our results according to the total number of PD-L1-expressing cells within the GBMs and then validated this finding in ex vivo GBM flow cytometry with further analysis of the T cell populations. We then evaluated the association between PD-L1 expression and median survival time using the protein expression datasets and mRNA from The Cancer Genome Atlas.The median percentage of PD-L1-expressing cells in GBM by cell surface staining is 2.77% (range: 0%-86.6%; n = 92), which is similar to the percentage found by ex vivo flow cytometry. The majority of GBM patients (61%) had tumors with at least 1% or more PD-L1-positive cells, and 38% had at least 5% or greater PD-L1 expression. PD-L1 is commonly expressed on the GBM-infiltrating T cells. Expression of both PD-L1 and PD-1 are negative prognosticators for GBM outcome.The incidence of PD-L1 expression in GBM patients is frequent but is confined to a minority subpopulation, similar to other malignancies that have been profiled for PD-L1 expression. Higher expression of PD-L1 is correlated with worse outcome.Â© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: firstname.lastname@example.org.
Knockout of Vdac1 activates hypoxia-inducible factor through reactive oxygen species generation and induces tumor growth by promoting metabolic reprogramming and inflammation. - Cancer & metabolism
Mitochondria are more than just the powerhouse of cells; they dictate if a cell dies or survives. Mitochondria are dynamic organelles that constantly undergo fusion and fission in response to environmental conditions. We showed previously that mitochondria of cells in a low oxygen environment (hypoxia) hyperfuse to form enlarged or highly interconnected networks with enhanced metabolic efficacy and resistance to apoptosis. Modifications to the appearance and metabolic capacity of mitochondria have been reported in cancer. However, the precise mechanisms regulating mitochondrial dynamics and metabolism in cancer are unknown. Since hypoxia plays a role in the generation of these abnormal mitochondria, we questioned if it modulates mitochondrial function. The mitochondrial outer-membrane voltage-dependent anion channel 1 (VDAC1) is at center stage in regulating metabolism and apoptosis. We demonstrated previously that VDAC1 was post-translationally C-terminal cleaved not only in various hypoxic cancer cells but also in tumor tissues of patients with lung adenocarcinomas. Cells with enlarged mitochondria and cleaved VDAC1 were also more resistant to chemotherapy-stimulated cell death than normoxic cancer cells.Transcriptome analysis of mouse embryonic fibroblasts (MEF) knocked out for Vdac1 highlighted alterations in not only cancer and inflammatory pathways but also in the activation of the hypoxia-inducible factor-1 (HIF-1) signaling pathway in normoxia. HIF-1Î± was stable in normoxia due to accumulation of reactive oxygen species (ROS), which decreased respiration and glycolysis and maintained basal apoptosis. However, in hypoxia, activation of extracellular signal-regulated kinase (ERK) in combination with maintenance of respiration and increased glycolysis counterbalanced the deleterious effects of enhanced ROS, thereby allowing Vdac1 (-/-) MEF to proliferate better than wild-type MEF in hypoxia. Allografts of RAS-transformed Vdac1 (-/-) MEF exhibited stabilization of both HIF-1Î± and HIF-2Î±, blood vessel destabilization, and a strong inflammatory response. Moreover, expression of Cdkn2a, a HIF-1-target and tumor suppressor gene, was markedly decreased. Consequently, RAS-transformed Vdac1 (-/-) MEF tumors grew faster than wild-type MEF tumors.Metabolic reprogramming in cancer cells may be regulated by VDAC1 through vascular destabilization and inflammation. These findings provide new perspectives into the understanding of VDAC1 in the function of mitochondria not only in cancer but also in inflammatory diseases.
Chitosan nanoparticle-mediated delivery of miRNA-34a decreases prostate tumor growth in the bone and its expression induces non-canonical autophagy. - Oncotarget
While several new therapies are FDA-approved for bone-metastatic prostate cancer (PCa), patient survival has only improved marginally. Here, we report that chitosan nanoparticle-mediated delivery of miR-34a, a tumor suppressive microRNA that downregulates multiple gene products involved in PCa progression and metastasis, inhibited prostate tumor growth and preserved bone integrity in a xenograft model representative of established PCa bone metastasis. Expression of miR-34a induced apoptosis in PCa cells, and, in accord with downregulation of targets associated with PCa growth, including MET and Axl and c-Myc, also induced a form of non-canonical autophagy that is independent of Beclin-1, ATG4, ATG5 and ATG7. MiR-34a-induced autophagy is anti-proliferative in prostate cancer cells, as blocking apoptosis still resulted in growth inhibition of tumor cells. Thus, combined effects of autophagy and apoptosis are responsible for miR-34a-mediated prostate tumor growth inhibition, and have translational impact, as this non-canonical form of autophagy is tumor inhibitory. Together, these results provide a new understanding of the biological effects of miR-34a and highlight the clinical potential for miR-34a delivery as a treatment for bone metastatic prostate cancer.
Epstein-Barr Virus MicroRNAs are Expressed in Patients with Chronic Lymphocytic Leukemia and Correlate with Overall Survival. - EBioMedicine
Although numerous studies highlighted the role of Epstein-Barr Virus (EBV) in B-cell transformation, the involvement of EBV proteins or genome in the development of the most frequent adult leukemia, chronic lymphocytic leukemia (CLL), has not yet been defined. We hypothesized that EBV microRNAs contribute to progression of CLL and demonstrated the presence of EBV miRNAs in B-cells, in paraffin-embedded bone marrow biopsies and in the plasma of patients with CLL by using three different methods (small RNA-sequencing, quantitative reverse transcription PCR [q-RT-PCR] and miRNAs in situ hybridization [miRNA-ISH]). We found that EBV miRNA BHRF1-1 expression levels were significantly higher in the plasma of patients with CLL compared with healthy individuals (pÂ <Â 0Â Â·Â 0001). Notably, BHRF1-1 as well as BART4 expression were detected in the plasma of either seronegative or seropositive (anti-EBNA-1 IgG and EBV DNA tested) patients; similarly, miRNA-ISH stained positive in bone marrow specimens while LMP1 and EBER immunohistochemistry failed to detect viral proteins and RNA. We also found that BHRF1-1 plasma expression levels were positively associated with elevated beta-2-microglobulin levels and advanced Rai stages and observed a correlation between higher BHRF1-1 expression levels and shorter survival in two independent patients' cohorts. Furthermore, in the majority of CLL cases where BHRF1-1 was exogenously induced in primary malignant B cells the levels of TP53 were reduced. Our findings suggest that EBV may have a role in the process of disease progression in CLL and that miRNA RT-PCR and miRNAs ISH could represent additional methods to detect EBV miRNAs in patients with CLL.
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