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Background/aims Down syndrome associated disorders are caused by a complex genetic context where trisomy 21 is a central component in relation to other changes involving epigenetic regulators and signaling molecules. This unique genetic context is responsible for the predisposition of people with Down syndrome to acute leukemia. Although, the research in this field has discovered some important pathogenic keys, the exact mechanism of this predisposition is not known. Methods In this study we applied functional enrichment analysis to evaluate the interactions between genes localized on chromosome 21, genes already identify as having a key role in acute leukemia of Down syndrome, miRNAs and signaling pathways implicated in cancer and cell development and found that miR-155 has a high impact in genes present on chromosome 21. Forward, we performed next generation sequencing on DNA samples from a cohort of patients diagnosed with acute leukemia of Down syndrome and in vitro functional assay using a CMK-86 cell line, transfected with either mimic or inhibitor of the microRNA-155-5p. Results Our results show that the epigenetic alteration of the TNF superfamily receptors in Down syndrome, which can be correlated to microRNA-155-5p aberrant activity, may play an important role in cell signaling and thus be linked to acute myeloid leukemia. Conclusion Some genes, already shown to be mutated in AML-DS, are potential targets for miR-155. Our results show that the epigenetic alteration of the TNF superfamily receptors in Down syndrome may play an important role in cell signaling and thus be linked to acute myeloid leukemia.

Bone quality around dental endosseous implants is a key factor in implant prognosis. Surface coatings represent an important method to increase osseointegration in oral implantology. Newer titanium...

Daniel Oltean-Dan,1 Gabriela-Bombonica Dogaru,2 Maria Tomoaia-Cotisel,3,4Dragos Apostu,1 Alexandru Mester,5 Horea-Rares-Ciprian Benea,1 Mihai-Gheorghe Paiusan,1 Elena-Mihaela Jianu,6 Aurora Mocanu,3 Reka Balint,3 Catalin-Ovidiu Popa,7 Cristian Berce,8 Gyorgy-Istvan Bodizs,9 Alina-Mihaela Toader,10 Gheorghe Tomoaia1,41Iuliu Hatieganu University of Medicine and Pharmacy, Department of Orthopedics and Traumatology, 400132 Cluj-Napoca, Romania; 2Iuliu Hatieganu University of Medicine and Pharmacy, Department of Medical Rehabilitation, 400347 Cluj-Napoca, Romania; 3Babes Bolyai University, Faculty of Chemistry and Chemical Engineering, Department of Chemical Engineering, Research Center of Physical Chemistry, 400028 Cluj-Napoca, Romania; 4Academy of Romanian Scientists, 050085 Bucharest, Romania; 5Iuliu Hatieganu University of Medicine and Pharmacy, Department of Oral Rehabilitation, Oral Health and Management, 400012 Cluj-Napoca, Romania; 6Iuliu Hatieganu University of Medicine and Pharmacy, Department of Histology, 400349 Cluj-Napoca, Romania; 7Technical University of Cluj-Napoca, Department of Materials Science and Engineering, 400641 Cluj-Napoca, Romania; 8Iuliu Hatieganu University of Medicine and Pharmacy, Center for Experimental Medicine, 400349 Cluj-Napoca, Romania; 9Rehabilitation Clinic, 400347 Cluj-Napoca, Romania; 10Iuliu Hatieganu University of Medicine and Pharmacy, Department of Physiology, 400006 Cluj-Napoca, RomaniaPurpose: Bone consolidation after severe trauma is the most challenging task in orthopedic surgery. This study aimed to develop biomimetic composite for coating Ti implants. Afterwards, these implants were testedin vivo to assess bone consolidation in the absence or the presence of high-frequency pulsed electromagnetic short-waves (HF-PESW).Materials: Biomimetic coating was successfully developed using multi-substituted hydroxyapatite (ms-HAP) functionalized with collagen (ms-HAP/COL), embedded into poly-lactic acid (PLA) matrix (ms-HAP/COL@PLA), and subsequently covered with self-assembled COL layer (ms-HAP/COL@PLA/COL, named HAPc).Methods: For in vivo evaluation, 32 Wistar albino rats were used in four groups: control group (CG) with Ti implant; PESW group with Ti implant+HF-PESW; HAPc group with Ti implant coated with HAPc; HAPc+PESW group with Ti implant coated with HAPc+HF-PESW. Left femoral diaphysis was fractured and fixed intramedullary. From the first post-operative day, PESW and HAPc+PESW groups underwent HF-PESW stimulation for 14 consecutive days. Biomimetic coating was characterized by XRD, HR-TEM, SEM, EDX and AFM.Results: Osteogenic markers (ALP and osteocalcin) and micro-computed tomography (CT) analysis (especially bone volume/tissue volume ratio results) indicated at 2 weeks the following group order: HAPc+PESW>HAPc≈PESW (P>0.05) and HAPc+PESW>control (P

Publisher's version (útgefin grein), Malignant lymphomas are a heterogeneous group of malignancies that develop both in nodal and extranodal sites. The different tissues involved and the highly variable clinicopathological characteristics are linked to the association between the lymphoid neoplastic cells and the tissues they infiltrate. The immune system has developed mechanisms to protect the normal tissue from malignant growth. In this review, we aim to explain how T lymphocyte-driven control is linked to tumor development and describe the tumor-suppressive components of the resistant framework. This manuscript brings forward a new insight with regard to intercellular and intracellular signaling, the immune microenvironment, the impact of therapy, and its predictive implications. A better understanding of the key components of the lymphoma environment is important to properly assess the role of both B and T lymphocytes, as well as their interplay, just as two legendary boxers face each other in a heavyweight title final, as was the case of Ali versus Foreman., The research on the lymphoma microenvironment was funded by an internal grant of the Iuliu Hatieganu University, School of Doctoral Studies (PCD 2018-2021) (Minodora Desmirean), under the frame of European Social Found, Human Capital Operational Program 2014-2020, project no. POCU/380/6/13/125171 (Minodora Desmirean) and the Romanian Ministry of Research and Innovation, CCCDI-UEFISCDI, Project No. PN-III-P4-ID-PCCF-2016-0112 within PNCDI III, by an award for Young Research Teams 2020-2022 (Grant No. PN-III-P1-1.1-TE-2019-0271) (both Ciprian Tomuleasa) as well as by an international collaborative grant of the European Economic Space between Romania and Iceland 2020-2022 (Grant No. 19-COP-0031) (Ciprian Tomuleasa)., "Peer Reviewed"

Some previous studies reported that probiotics might decrease the severity of chemotherapy-induced mucositis. This study assessed the potential protective effect of Lactobacillus plantarum ATCC 8014 on 5-fluorouracil (5-FU) induced intestinal mucositis in the Wistar rats. The Crl:WI rats were divided into two groups of six animals (F, L) and one group of 5 animals (M). Group L received for 9 days 3.32x109 CFU/ml of Lactobacillus plantarum orally. In the 7th day of the experiment 400 mg of 5-FU was administered intraperitoneally in groups L and F. Group M received only the vehicles. All animals were sacrificed in the 9th day. Eleven histological characteristics of mucositis were quantified from 0 (normal) to 3 (severe) for duodenum, jejunum and colon. Semiquantitative grades measured Toll-like receptor 4 (TLR4) immunopositive cells. The independent groups were analyzed using the Kruskal-Wallis test, Mann-Whitney U test, with a Bonferroni correction for alpha (P≤0.016). In the group F, treated with 5-FU, the most affected areas were the jejunum and the duodenum. The medium score of histological lesions was 27 for jejunum (minimum 25, maximum 32) and 21 for duodenum (minimum 18, maximum 29). Graded microscopic mucosal changes of the jejunum were significantly lower in group L compared with group F (U=0, P=0.009, Mann-Whitney test). The histological changes depicted on the duodenal and colonic mucosa were less severe in group L than in group F, but without reaching the statistical significance (duodenum: U=6, P=0.172, Mann-Whitney test; colon: U=12, P=0.916, Mann-Whitney test). Although the TLR4 immunoexpression was more intense in group L, no significant statistical difference was revealed at duodenum, jejunum or colonic mucosa. Significantly fewer microscopic changes were depicted in L group on the jejunum, suggesting a potential beneficial effect of Lactobacillus plantarum at this level in 5-FU induced mucositis.

Publisher's version (útgefin grein), Primary myelofibrosis (PMF) is a Ph-negative myeloproliferative neoplasm (MPN), characterized by advanced bone marrow fibrosis and extramedullary haematopoiesis. The bone marrow fibrosis results from excessive proliferation of fibroblasts that are influenced by several cytokines in the microenvironment, of which transforming growth factor-β (TGF-β) is the most important. Micromechanics related to the niche has not yet been elucidated. In this study, we hypothesized that mechanical stress modulates TGF-β signalling leading to further activation and subsequent proliferation and invasion of bone marrow fibroblasts, thus showing the important role of micromechanics in the development and progression of PMF, both in the bone marrow and in extramedullary sites. Using three PMF-derived fibroblast cell lines and transforming growth factor-β receptor (TGFBR) 1 and 2 knock-down PMF-derived fibroblasts, we showed that mechanical stress does stimulate the collagen synthesis by the fibroblasts in patients with myelofibrosis, through the TGFBR1, which however seems to be activated through alternative pathways, other than TGFBR2., Patric Teodorescu was financed from an internal grant of the School of Doctoral Studies?Iuliu Hatieganu University (PCD 2018-2021). Ciprian Tomuleasa was also supported by two national research grants of the Romanian Government: the first one awarded for Frontiers Research Projects 2018-2022 (grant number PN-III-P4-ID-PCCF-2016-112), awarded to the Babes Bolyai University in collaboration with the Ion Chiricuta Oncology Institute Cluj Napoca; and the second one awarded for Young Research Teams 2020-2022 (grant number PN-III-P1-1.1-TE-2019-0271), awarded to the Iuliu Hatieganu University of Medicine and Pharmacy Cluj Napoca. Ciprian Tomuleasa, Bobe Petrushev and Delia Dima were also financed by an international collaborative grant of the European Economic Space between Romania and Iceland 2020-2022 (grant number 19-COP-0031).

Despite recent advances in disease management and prevention, heart failure (HF) prevalence is still high. Hypertension, inflammation and oxidative stress are being investigated as important causative processes in HF. L. barbarum L. polysaccharides (LBPs) are widely used for their anti-inflammatory and antioxidant properties. Thus, the aim of the present study was to evaluate the effects of LBPs on inflammation and oxidative stress markers in a pressure overload-induced HF rat model, surgically induced by abdominal aorta banding in Wistar rats (AAB) (n = 28). Also, control rats (n = 10) were subjected to a sham operation. After echocardiographic confirmation of HF (week 24), AAB rats were divided into three groups: rats treated with LBPs for 12 weeks: 100 mg/kg body weight /day (AAB_100, n = 9), 200 mg/kg body weight /day (AAB_200, n = 7) and no-treatment group (control AAB, n = 12). After 12 weeks of treatment with LBPs, the decline of cardiac function was prevented compared to the control AAB rats. Treatment with 200 mg/kg body weight /day LBPs significantly reduced the inflammation as seen by cytokine levels (IL-6 and TNF-&alpha, ) and the plasma lipid peroxidation, as seen by malondialdehyde levels. These results suggest that LBPs present anti-inflammatory and antioxidant effects with utility in a HF animal model and encourage further investigation of the cardioprotective effects of these polysaccharides.

The goal of periodontal therapy is to regenerate the periodontal structures: cement, periodontal ligament and alveolar bone. Stem cell-based tissue engineering raised novel therapeutic strategies for periodontal repair. In vivo dental follicle stem (DFSC) cells give rise to cementoblasts, osteoblasts and fibroblasts. Based on this idea, we have assessed DFSC potential to regenerate the periodontal structures, and by that to elaborate a new biomaterial. An experimental study was performed on male Wistar rats which were subjected to a procedure of periodontitis induction through placing silk thread ligatures around the lower incisors, under general anesthesia. Clinically, the changes of the periodontal tissue (bleeding on probing, dental mobility, dental plaque, presence of pus) induced by the periodontitis progression were daily assessed. The subjects were divided in two groups: a control and a study group. After 7 days from placing silk thread ligatures, subjects from the study group received an injection in the gingival sulcus. The injected biomaterial contained dental follicle stem cells seeded on fibrinogen. Bleeding on probing at the end of the treatment period was significantly reduced in the study group (study vs control group - 0% vs 100%, p=0.01.). In terms of dental mobility statistical significant results were obtained (p=0.04): for 20% from the subjects from the study group dental mobility was absent, while in the control group all subjects presented different degrees of mobility (33.3% degree II- v-o/m-d, 66.6% degree III-v-o/m-d/ax). In the control group pus was present in 66.7% from the subjects, and absent in the study group (p=0.10). Dental plaque was present in 40% of the subjects from the study group and in 100% in the control group. The clinical and histological results of our study demonstrate that dental follicle stem cells are a valuable cell source for tissue engineering the periodontal tissue.

Sergiu Susman,1,2 Ioana Berindan-Neagoe,3 Bobe Petrushev,3 Radu Pirlog,2 Ioan-Stefan Florian,4 Carmen-Mihaela Mihu,2 Cristian Berce,3 Lucian Craciun,2 Ravnit Grewal,5 Ciprian Tomuleasa3,6,7 1Department of Pathology, Imogen Research Center, 2Department of Morphological Sciences, 3Research Center for Functional Genomics and Translational Medicine, 4Department of Neurosurgery, Iuliu Hatieganu University of Medicine and Pharmacy, 5Department of Hematology, Ion Chiricuta Oncology Institute, 6Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania; 7Department of Haematopathology, Tygerberg Academic Hospital, Tygerberg, South Africa Abstract: After introducing the new molecules for the treatment of patients with tumoral pathology, the therapeutical decision will be taken depending on the molecular profile performed upon the harvested tissues. This major modification makes the molecular and morphological analysis an essential part in the clinical management of patients and the pathologist plays an important role in this process. The quality and reproducibility of the results are imperative today and they depend on both the reliability of the molecular techniques and the quality of the tissue we use in the process. Also, the genomics and proteomics techniques, used increasingly often, require high-quality tissues, and pathology laboratories play a very significant role in the management of all phases of this process. In this paper the parameters which must be followed in order to obtain optimal results within the techniques which analyze nucleic acids and proteins were reviewed. Keywords: nucleic acids, proteins, fixation, freezing, molecular techniques

// Tiberiu Tat 1, 2 , Huming Li 3 , Catalin-Sorin Constantinescu 1, 4 , Anca Onaciu 5 , Sergiu Chira 5 , Ciprian Osan 5 , Sergiu Pasca 5 , Bobe Petrushev 5 , Vlad Moisoiu 5 , Wilhelm-Thomas Micu 5 , Cristian Berce 6 , Sebastian Tranca 2 , Delia Dima 7 , Ioana Berindan-Neagoe 5 , Jianliang Shen 8 , Ciprian Tomuleasa 7, 9 and Liren Qian 8 1 Intensive Care Unit, Ion Chiricuta Clinical Cancer Research, Cluj Napoca, Romania 2 Department of Anesthesiology-Intensive Care, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania 3 Department of Pulmonary and Critical Care Medicine, Navy General Hospital of PLA, Beijing, China 4 Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania 5 Research Center for Functional Genomics and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania 6 Department of Experimental Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania 7 Department of Hematology, Ion Chiricuta Clinical Cancer Research, Cluj Napoca, Romania 8 Department of Hematology, Navy General Hospital of PLA, Beijing, China 9 Research Center for Functional Genomics and Translational Medicine / Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania Correspondence to: Ciprian Tomuleasa, email: ciprian.tomuleasa@umfcluj.ro Keywords: hematological malignancies; chimeric antigen receptor-modified T cell; donor lymphocyte infusion; stem cell transplant; immunotherapy Received: December 01, 2017 Accepted: February 26, 2018 Published: March 27, 2018 ABSTRACT Chimeric antigen receptor-modified T cells (CAR-T cells) and donor lymphocyte infusion (DLI) are important protocols in lymphocyte engineering. CAR-T cells have emerged as a new modality for cancer immunotherapy due to their potential efficacy against hematological malignancies. These genetically modified receptors contain an antigen-binding moiety, a hinge region, a transmembrane domain, and an intracellular costimulatory domain resulting in lymphocyte T cell activation subsequent to antigen binding. In present-day medicine, four generations of CAR-T cells are described depending on the intracellular signaling domain number of T cell receptors. DLI represents a form of adoptive therapy used after hematopoietic stem cell transplant for its anti-tumor and anti-infectious properties. This article covers the current status of CAR-T cells and DLI research in the intensive care unit (ICU) patient, including the efficacy, toxicity, side effects and treatment.

// Liren Qian 1 , Delia Dima 2 , Cristian Berce 3 , Yu Liu 1 , Ioana Rus 3 , Lajos-Zsolt Raduly 2 , Yi Liu 1 , Bobe Petrushev 3 , Ioana Berindan-Neagoe 3 , Alexandru Irimie 3 , Alina Tanase 4 , Ancuta Jurj 3 , Jianliang Shen 1 and Ciprian Tomuleasa 2, 3 1 Department of Hematology, Navy General Hospital, Beijing, PR China 2 Department of Hematology, Ion Chiricuta Oncology Institute, Cluj Napoca, Romania 3 Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania 4 Department of Stem Cell Transplantation, Fundeni Clinical Institute, Bucharest, Romania Correspondence to: Ciprian Tomuleasa, email: Ciprian.Tomuleasa@umfcluj.ro Liren Qian, email: qlr2007@126.com Keywords: allogeneic stem cell transplantation; biomarkers; proteins; graft versus host disease; exosomes Received: September 28, 2017 Accepted: December 05, 2017 Published: December 15, 2017 ABSTRACT Allogeneic hematopoietic stem cell transplantation is a well-established treatment for many malignant and non-malignant hematological disorders. As a frequent complication in up to 50% of all patients, graft-versus-host disease is still the main cause for morbidity and non-relapse mortality. Diagnosis is usually done clinically, even though confirmation by pathology is often used to support the clinical findings. Effective treatment requires intensified immunosuppression as early as possible. Although several promising biomarkers have been proposed for an early diagnosis, no internationally-recognized consensus has yet been established. Protein-based biomarkers represent an interesting tool since they have been recently reported to be an important regulator of various cells, including immune cells such as T cells. Therefore, we assume that protein dysregulation is important in the pathogenesis of acute graft versus host disease and their detection might be an possibility in the early diagnosis and monitoring. In this review, we aim to summarize the previous reports of protein biomarkers, focusing on the pathogenesis of the disease and possible implications in diagnostic approaches.

Hip osteoarthritis is the most common joint disorder, and is represented by a degenerative process, resulting in pain and functional impairment. If conservative treatment for hip osteoarthritis fails, the only remaining option is hip arthroplasty. Despite good survival of implants, loosening of components is the most common complication. This leads to revision surgeries, which are technically demanding, expensive, and result in a low satisfaction rate. Uncemented hip replacements require proper osseointegration for increased survival. Physical characteristics of implants include biocompatibility, Young’s modulus of elasticity, strength, and corrosion resistance, and each influence fixation of implants. Moreover, implant surface treatments, pore size, pore density, and femoral stem design should be appropriately selected. Patients’ optimization of obesity, osteoporosis, cardiovascular disease, psychotic disorders, and smoking cessation are associated with a higher survival of implants. Surgical factors, such as approach, drilling and rasping, acetabular bone coverage, acetabular cup positioning, and implant size, also affect survival of implants. Avoiding drugs, which may impair osseointegration of implants, and having an appropriate rehabilitation protocol are important. Future directions include anabolic and anti-catabolic bone-acting drugs to enhance osseointegration of implants. Comprehensive knowledge of the factors mentioned above is important for preventing aseptic loosening, with important socioeconomic consequences.

Study Design:Case series.Objective:Thoracolumbar burst fractures (TLBF) are the most frequent type of spinal fractures. Approximately half of the patients are neurologically intact and their treatment is still debatable. Gender could influence outcome after surgical procedures, but this is still unclear in patients sustaining a spinal fracture. The aim of this study was to investigate how gender influences health-related quality of life (HRQOL) and disability in patients operated on for TLBF.Methods:We identified 44 neurologically intact patients from a consecutive series of patients treated surgically for a single-level traumatic burst fracture (AOSpine Subaxial Classification System A3) in the thoracolumbar transition area (Th12-L2). At 1 year after surgery, they were evaluated using the SF-36v2 questionnaire to assess HRQOL and Oswestry Disability Index (ODI) questionnaire to evaluate disability.Results:Male patients scored higher in each item of the SF-36v2, with significant differences ( P < .05) for Physical Function (PF), Bodily Pain (BP), and Social Function (SF). Male patients also had lower disability scores. Overall ODI score had a strong correlation with Physical Function, Role-Physical, Bodily Pain, Vitality, Mental Health, and overall Physical Component Summary (PCS) of the SF-36 in women, but only with Physical Function, Role-Physical, Role-Emotional, and PCS in men.Conclusions:In this study, male patients reported better outcomes at 1 year after surgery for TLBF than women. Disability strongly correlated with the overall HRQOL, physical and mental health in women, but not in men. We found gender-related differences favoring men after surgical interventions for spinal fractures.

In the past decade, there has been significant progress in clinical hematology with the discovery of targeted molecules and thus the achievement of both hematologic and molecular responses. Nevertheless, chemotherapy remains the treatment of choice for many types of hematological malignancies. Aggressive chemotherapy leads to immunosuppression, accompanied by a high rate of infections and an increased rate of treatment-related mortality. Invasive fungal infections as well as more common bacterial and viral infections are frequent in immunocompromised patients as they are difficult to diagnose and treat. Pleuropulmonary infections in immunocompromised patients are diagnosed using clinical examination, imaging and laboratory tests. Many laboratory tests are run for several days before a final result is given and are expensive. Computer tomography is a reliable technique, but it is encumbered by high irradiation and high cost, and can assess lesions larger than 1 cm. Transthoracic ultrasound is a modern method, used in the diagnostic algorithm of pleuropulmonary pathology. It allows the diagnosis of small lesions, can be performed at the patients’ bedside, with acceptable costs and no irradiation. A fast, informed and accurate medical decision is essential for a favorable outcome in immunosuppressed patients with an adjacent infection. In the current case series we present the implementation of a new protocol for the follow-up of immunocompromised patients using transthoracic ultrasonography, of great potential use in the clinic.

Objective: The main goal of the present study is to compare two methods for evaluating the marginal fit of fixed prosthetic restorations. For this purpose we used a milled ceramic material, out of which we obtained class I inlays. The marginal gap was analyzed using micro CT and electronic microscopy. Materials and methods: After extraction of four caries-free mandibular first molars, first class inlay cavities were prepared. The marginal gap was analyzed circumferentially at the occlusal margin using a Bruker micro CT, by measuring the distance at the occlusal limit of the cavities, between the restoration and the tooth in several points for every surface of each tooth before cementing. For the second method SEM technology was used, and measurements were made at the occlusal limit of the cavities, between the restoration and the tooth in 50 microns steps. The data were compared with One–way ANOVA with Tukey’s Multiple Comparison Test performed using 5.00 for Windows (GraphPad Prism 5.00 Software, San Diego, California USA). Results and discussion: For both methods we obtained clinical acceptable values of the marginal gap for the milled ceramic inlays. The null hypothesis was rejected. We obtained statistical significant differences of the measured gaps using the two above mentioned methods. Conclusions: Both evaluation methods are reliable for measuring the marginal gap of fixed prosthetic restorations, each method having specific indications, advantages and disadvantages. They offer indispensable information which lead to improvement of the restorative treatments.

Despite recent advances in disease management and prevention, heart failure (HF) prevalence is still high. Hypertension, inflammation and oxidative stress are being investigated as important causative processes in HF. L. barbarum L. polysaccharides (LBPs) are widely used for their anti-inflammatory and antioxidant properties. Thus, the aim of the present study was to evaluate the effects of LBPs on inflammation and oxidative stress markers in a pressure overload-induced HF rat model, surgically induced by abdominal aorta banding in Wistar rats (AAB) (n = 28). Also, control rats (n = 10) were subjected to a sham operation. After echocardiographic confirmation of HF (week 24), AAB rats were divided into three groups: rats treated with LBPs for 12 weeks: 100 mg/kg body weight /day (AAB_100, n = 9), 200 mg/kg body weight /day (AAB_200, n = 7) and no-treatment group (control AAB, n = 12). After 12 weeks of treatment with LBPs, the decline of cardiac function was prevented compared to the control AAB rats. Treatment with 200 mg/kg body weight /day LBPs significantly reduced the inflammation as seen by cytokine levels (IL-6 and TNF-α) and the plasma lipid peroxidation, as seen by malondialdehyde levels. These results suggest that LBPs present anti-inflammatory and antioxidant effects with utility in a HF animal model and encourage further investigation of the cardioprotective effects of these polysaccharides.

Background: Wound healing of the nasal mucosa after endoscopic sinus surgery (ESS) is frequently complicated by scaring and consequently recurrences are encountered. Methods of optimizing results have been sought. In the present study we evaluated the effects of a powerful antioxidant, astaxanthin, on nasal mucosa healing after surgery, comparing it to the extensively studied properties of dexamethasone. Materials and Methods: 63 Wistar rats were used. The nasal mucosa from one side was damaged employing the brushing method. They were randomly divided into three experimental groups, one treated with astaxanthin, the second treated with dexamethasone and the third one acted as the control and was given normal saline. The rats were killed on days 5, 14 and 28 following injury. We observed the temporal evolution of the wound healing process and quantified the results by assessing four parameters: the epithelial thickness index (ETI), the subepithelial thickness index (STI), the goblet cell count and the subepithelial fibrosis index (SFI). Results: At 28 days, the ETI was significantly lower in the astaxanthin group (p &lt, 0.05) compared to the other two groups. The STI was also lower in the astaxanthin group (p &lt, 0.05), but comparable to the dexamethasone group at 28 days. The goblet cell count was higher in the astaxanthin group. The SFI had similar results in both dexamethasone and astaxanthin groups, with lower values compared to the control group. In the astaxanthin group there was no synechia formation. Conclusion: Astaxanthin given in the post injury period significantly decreases fibrosis, inhibits synechia development and significantly decreases subepithelial fibrosis. Moreover, it has no general or local toxic effects.

The aim of this study was to assess the osseointegration of two series of titanium (Ti) scaffolds with 0.8 and 1 mm cell size obtained by Selective Laser Melting (SLM) technique. One of the series had the Ti surface unmodified, while the other had the Ti surface coated with silicon-substituted nano-hydroxyapatite (nano-HapSi). The scaffolds were implanted in the femur bone defects of 6 White Californian male rabbits: three animals were implanted with 0.8 mm cell size scaffolds and three animals with 1 mm cell size scaffolds, respectively. The bone fragments and scaffolds harvested at 2, 4 and 6 months were histologically analyzed using conventional light microscopy (LM) and scanning electron microscopy (SEM) for the qualitative evaluation of the bone tissue formed in contact with the scaffold. Both LM and SEM images indicated a better osseointegration for nano-HapSi coated Ti scaffolds. LM revealed that the compact bone formed in the proximity of nano-HapSi-coated scaffolds was better organized than spongy bone associated with unmodified scaffolds. Moreover, Ti scaffolds with meshes of 0.8 mm showed higher osseointegration compared with 1 mm. SEM images at 6 months revealed that the bone developed not only in contact with the scaffolds, but also proliferated inside the meshes. Nano-HapSi-coated Ti implants with 0.8 mm meshes were completely covered and filled with new bone. Ti scaffolds osseointegration depended on the mesh size and the surface properties. Due to the biocompatibility and favorable osseointegration in bone defects, nano-HapSi-coated Ti scaffolds could be useful for anatomical reconstructions.

Objectives/Hypothesis: It is acknowledged that the treatment of chronic rhinosinusitis (CRS) represents an important challenge for rhinology and for social and economic life. At present, one of the most common treatments for CRS is represented by local corticosteroids followed by endoscopic sinus surgery (ESS). Starting from the example of the mesenchymal stem cell’s (MSC) capacity to migrate and to modulate a real response in the nasal mucosa of an allergic rhinitis mouse model, we try to obtain a response in a CRS mouse model, using MSC derived by adipose tissue. The aim of this study is to demonstrate that the MSC can be used in CRS treatment and could change its priorities. Methods: Seventy female mice (6 MSC donor mice) were randomized in two stages of study, 32 Aspergillus fumigatus (Af) exposure mice (20 for histological comparison to 1st control mice and 12 for MSC administration, to CRS/MCS model) and 32 control mice (20 for histological comparison to CRS model and 12 for MSC administration and histological control to MSC model), in the first stage, the Aspergillus fumigatus (Af) CRS mouse model was targeted, in this section were included 64 (n = 32) mice (treated and control group). In order to assess the inflammation level (histological analysis), the animals were euthanized, in the second stage MSCs (1 × 106/animal) were administered intravenously to a total of 24 (n = 24) mice (12 mice from the exposed group and 12 mice from the second control group). Results: After 12 weeks of Af intranasal instillation, the inflammation parameters evaluated indicated a severe diffuse chronic inflammation, associated with diffuse severe hyperplasia and mature diffuse squamous metaplasia. The MSCs’ injection via the ophthalmic vein induced important histopathological changes in the CRS experimental group, starting with the presence of MSCs in all samples and continuing with the important degenerative character of inflammation. Conclusions: MSC administration demonstrated a real improvement of CRS evolution on the CRS mouse model.

Aim: This study want to demonstrate the efficaciousness of drotaverinum as a replacer of papaverine in the prevention and treatment of vasospasm. Material and method: In this study were used 20 albino Wistar male rats. Rats were divided in two groups and vasospasm was induced to the both femoral artery and after that irrigation of the femoral arteries with drotaverinum was performed to demonstrate the vasodilatation that can appear (group A). In the group B after the obtaining of vasospasm irrigation of the femoral arteries with saline solution was performed and this group was used as witness. The length of the vessels was measured when was achieved the vasospasm and also before and after the administration of the solutions. Pictures were taken at every step of dissection and solutions administration to can measure the length of arteries before and after the administration of drotaverinum and the saline solution. Results: In all rats was obtained vasospasm at the femoral artery after clipping the artery and after we irrigate with adrenaline. In the group with drotaverinum we obtained the vasodilatation and in the witness group the caliber of the vessels remain the same. The statistical analysis of the data demonstrate a significant differences between the group were was used drotaverinum and the witness group were was used the saline solution (p Conclusions: Drotaverinum has a good vasodilatative effect on arteries and he can prevent the apparition of vasospasm and it can even treat vasospasm if occur by producing local vasodilatation and a good circulation in the area where is administrated. This study showed quantitatively that drotaverinum can treat the experimental peripheral vasospasm in rats.

From an oncological perspective, the second most common malignancies in children are brain tumors. Despite the recent therapeutic breakthroughs in this field, concerning surgery, radiotherapy and chemotherapy alike, some cases still have poor outcomes in curability. This is especially the case in patients with high-risk histological types of tumors, and those suffering from residual, remitting and disseminated diseases. Due to the unique neuroanatomical emplacement of brain tumors and their aggressive infiltrative behavior, their total removal remains a demanding task. This can be perceived in the high rates of failure treatment and disease recurrence. Furthermore, the adjacent healthy brain tissue is inevitably damaged in the surgical process of effectively removing these tumors. Thus, stem cell transplantation may be a viable solution for the clinical management of these malignancies, as proven by various recent breakthroughs. In the current concise review, we present the role of next generation sequencing in HLA typing for stem cell transplantation in primary CNS pediatric malignancies.

Some previous studies reported that probiotics might decrease the severity of chemotherapy-induced mucositis. This study assessed the potential protective effect of Lactobacillus plantarum ATCC 8014 on 5-fluorouracil (5-FU) induced intestinal mucositis in the Wistar rats. The Crl:WI rats were divided into two groups of six animals (F, L) and one group of 5 animals (M). Group L received for 9 days 3.32x109 CFU/ml of Lactobacillus plantarum orally. In the 7th day of the experiment 400 mg of 5-FU was administered intraperitoneally in groups L and F. Group M received only the vehicles. All animals were sacrificed in the 9th day. Eleven histological characteristics of mucositis were quantified from 0 (normal) to 3 (severe) for duodenum, jejunum and colon. Semiquantitative grades measured Toll-like receptor 4 (TLR4) immunopositive cells. The independent groups were analyzed using the Kruskal-Wallis test, Mann-Whitney U test, with a Bonferroni correction for alpha (P≤0.016). In the group F, treated with 5-FU, the most affected areas were the jejunum and the duodenum. The medium score of histological lesions was 27 for jejunum (minimum 25, maximum 32) and 21 for duodenum (minimum 18, maximum 29). Graded microscopic mucosal changes of the jejunum were significantly lower in group L compared with group F (U=0, P=0.009, Mann-Whitney test). The histological changes depicted on the duodenal and colonic mucosa were less severe in group L than in group F, but without reaching the statistical significance (duodenum: U=6, P=0.172, Mann-Whitney test; colon: U=12, P=0.916, Mann-Whitney test). Although the TLR4 immunoexpression was more intense in group L, no significant statistical difference was revealed at duodenum, jejunum or colonic mucosa. Significantly fewer microscopic changes were depicted in L group on the jejunum, suggesting a potential beneficial effect of Lactobacillus plantarum at this level in 5-FU induced mucositis.

Environmental contextAlthough ruthenium is a technology-critical element used in several new industries, little is known about its environmental impact or possible human health risks. We report a toxicological evaluation of laboratory animals during co-exposure to ruthenium and silver. We identified interactions between the two elements that could lead to unwanted biological effects. AbstractRuthenium is one of the rarest metals on Earth that is classified as a technology-critical element (TCE). Silver, however, is well known for its antibacterial and immunostimulant properties. The increasing use of Ru and Ag in medicine and daily life makes simultaneous exposure possible, with unknown pharmacokinetic or toxicological consequences for the human organism. Thus, the present study investigated the influence of co-exposure to RuIII on the subacute toxicity of Ag ions in rats after repeated daily administration for 28 days of low doses by oral gavage. The subacute toxicity was investigated by the evaluation of several biochemical and hematological parameters, evaluation of specific oxidative stress biomarkers from liver and kidney, and histopathological investigation of liver and kidney tissue samples after 28 days of exposure in female rats. In addition, Ag and Ru concentrations were determined by inductively coupled plasma mass spectrometry (ICP-MS) in urine, liver and kidney parenchyma in male rats. The obtained results showed that co-exposure to low doses of RuIII and Ag did not produce any significant biochemical, hematological or histopathological alterations in the treated female rat groups, except for an increased red cell distribution width (RDW) value. A decrease of urinary excretion of Ag and of the Ag concentration in kidneys was observed in the male rat group co-exposed to RuIII and Ag. This is the first invivo study investigating the toxic effect of co-exposure to low doses of Ag and Ru ions, and the obtained results may justify further research on this subject, mainly on the investigation of possible competitive mechanisms.

Background The aim was to assess the effects of periodontal disease in promoting liver fibrosis in a rat model of ligature-induced periodontitis. Methods Twenty-four Wistar rats were divided into four groups: control (CTRL), experimental periodontitis group at day 7 (PER7), at day 14 (PER14), at day 21 (PER21). Experimental periodontitis was induced by the placement of a silk ligature around mandibular incisors. The following parameters were assessed: gingival index, tooth mobility; liver status, and portal vein caliber by ultrasound examination; bone retraction, bone mineral density (BMD), bone volume/tissue volume (BV/TV) by micro-CT analysis; aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT); oxidative stress (malondialdehyde [MDA], reduced glutathione/oxidative glutathione ratio [GSH/GSSG]), and matrix metalloproteinase-8 (MMP-8) levels; and histopathological evaluation of periodontal and liver tissues. Results Periodontal parameters showed the development of periodontitis in experimental groups. Micro-CT results indicates an increase of bone retraction and BMD values and a decrease of BV/TV value in PER groups. Liver fibrosis could not be diagnosed with ultrasound examination in any of the groups. Elevated levels of ASAT and ALAT in PER groups compared with CTRL group were found. MDA have indicated elevated levels and a decrease of GSH/GSSG ratio in PER group compared with the CTRL group. Levels of MMP-8 have indicated high values in PER21 compared with the other groups. Histological analysis of the periodontal and liver tissues sustains the link between periodontal and hepatic injury. Conclusion This study demonstrates a positive correlation between periodontal lesions and liver disease. Periodontitis may be an independent risk factor for liver fibrosis.

In vitro studies showed that high-frequency pulsed electromagnetic fields (HF-PEMFs) increase the activity/expression of early and late osteogenic markers and enhance bone mineralization. The main aim of this study was to investigate the in vivo effects of HF-PEMFs on fracture healing using a rat model. A femur fracture was established by surgery in 20 male Wistar rats. Titanium nails were implanted to reduce and stabilize the fracture. After surgery, 20 rats were equally divided into untreated control and treated group (from the first postoperative day HF-PEMFs at 400 pulses/sec [pps] were applied for 10 minutes/day, for two weeks). Quantitative and qualitative assessment of bone formation was made at two and eight weeks following surgery and included morphological and histological analysis, serological analysis by ELISA, micro-computed tomography (micro-CT), and three-point bending test. At two weeks in HF-PEMF group, soft callus was at a more advanced fibrocartilaginous stage and the bone volume/total tissue volume (BV/TV) ratio in the callus area was significantly higher compared to control group (p = 0.047). Serum concentration of alkaline phosphatase (ALP) and osteocalcin (OC) was significantly higher in HF-PEMF group (ALP p = 0.026, OC p = 0.006) as well as the mechanical strength of femurs (p = 0.03). At eight weeks, femurs from HF-PEMF group had a completely formed woven bone with dense trabeculae, active bone marrow, and had a significantly higher BV/TV ratio compared to control (p = 0.01). HF-PEMFs applied from the first postoperative day, 10 minutes/day for two weeks, enhance bone consolidation in rats, especially in the early phase of fracture healing.

Chimeric antigen receptor-modified T cells (CAR-T cells) and donor lymphocyte infusion (DLI) are important protocols in lymphocyte engineering. CAR-T cells have emerged as a new modality for cancer immunotherapy due to their potential efficacy against hematological malignancies. These genetically modified receptors contain an antigen-binding moiety, a hinge region, a transmembrane domain, and an intracellular costimulatory domain resulting in lymphocyte T cell activation subsequent to antigen binding. In present-day medicine, four generations of CAR-T cells are described depending on the intracellular signaling domain number of T cell receptors. DLI represents a form of adoptive therapy used after hematopoietic stem cell transplant for its anti-tumor and anti-infectious properties. This article covers the current status of CAR-T cells and DLI research in the intensive care unit (ICU) patient, including the efficacy, toxicity, side effects and treatment.

Even if considered a cumulative and not a proliferative CD5+ B-cell neoplasm, chronic lymphocytic leukemia (CLL) has a proliferation rate higher than that recognized earlier, especially in the lymphoid tissues. Some patients with CLL develop a clinical syndrome entitled Richter syndrome (RS). Understanding CLL genetics and epigenetics may help to elucidate the molecular basics of the clinical heterogeneity of this type of malignancy. In the present project we aimed to identify a microRNA species that can predict the evolution of therapy-resistant CLL towards RS. In the first phase of our study, microRNA-19b was identified as a possible target, and in the second phase, we transfected three different CLL cell lines with microRNA-19b mimic and inhibitor and assessed the potential role on leukemia cells in vitro. The mechanism by which miR-19b acts were identified as the upregulation of Ki67 and downregulation of p53. This was further supported through RT-PCR and western blotting on CLL cell lines, as well as by next generation sequencing on two patients diagnosed with CLL that evolved into RS.

The purpose of the present study was to assess and compare the chondroregenerative properties of PLA (processed lipoaspirate) and LAF (lipoaspirate fluid) cells, in a preclinical rabbit model of knee cartilage defect. The defects were repaired by a collagen I/III scaffold and added LAF-cells, PLA-cells or no cells, upon the study group. The results showed that collagen scaffolds seeded with LAF-derived stem cells appear to have slightly better activity and outcomes when compared to PLA-cells, in terms of cartilage regeneration.

Carvedilol is one of the most used cardiovascular drugs, highly metabolized by CYP450 2D6, 1A2, 2C9. Fluvoxamine, an antidepressant agent, is a moderate/potent inhibitor of these enzymes. There is the risk of drug-drug interaction when these two drugs are concomitantly administered. The aim of this study was to investigate the drug-drug interactions between carvedilol and fluvoxamine in vitro and in rats. There were two periods: reference and test. In the first period each rat received an oral dose of 3.57 mg/kg body weight [b.w.] carvedilol. In the test period, carvedilol was administered after a pre-treatment with multiple oral doses of fluvoxamine (14.28 mg/kg b.w.). HPLC-MS was the device used to determine the plasma concentration of carvedilol. The PK parameters were calculated by non-compartmental analysis. Rat liver microsomal incubation systems were used to investigate the effect of fluvoxamine on the metabolic rate of carvedilol. Fluvoxamine co-administered with carvedilol can change the PK parameters (increase AUC, t1/2, decrease the Cl). In vitro experiment showed that fluvoxamine decreased the metabolic rate of carvedilol. The present study demonstrated the pharmacokinetic drug-drug interaction between carvedilol and fluvoxamine in vitro and in vivo. Fluvoxamine significantly influenced the pharmacokinetic of carvedilol, due to its capacity of CYP2D6 and CYP1A2 inhibition. As a result of this interaction the exposure to carvedilol was significantly increased. This is the reason why co-administration of carvedilol and fluvoxamine needs precaution.

Alopecia is a dermatological condition for which Janus kinase (JAK) inhibitors have recently emerged as potential therapy options, but with limited practical use because of the systemic side effects. The topical use of Ruxolitinib in alopecia universalis has been demonstrated, but little is known about the pharmacodynamics and pharmacokinetics of this way of administration. Nanomedicine provides improved therapeutics. In the current paper we present preliminary data regarding the potential use of Ruxolitinib-conjugated gold nanoparticles (GNPs) in dermatological conditions, as GNPs have been proven to have a reduced absorption rate into the systemic blood flow for cutaneous administration. Internalization of the newly formed bioconjugate was assessed by electron microscopy and the functional effects of the drug were investigated by cell counting, flow cytometry and western blotting. Our data show that gold nanoparticles conjugated with Ruxolitinib inhibit the proliferation of fibroblasts by inhibiting JAK2 protein. Ruxolitinib carried by gold nanoparticles alters the proliferation of human fibroblasts, which is of great clinical importance as it can be readily administered on the skin with minimal risk of systemic side effects.

Composites based on sodium alginate, pullulan, and bioactive SiO2 -CaO-P2 O5 glass-ceramics with copper oxide were prepared as capsules. The obtained samples were structurally characterized by Fourier transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), and scanning electron microscopy (SEM), and their bioactivity and biocompatibility properties were also tested both in vitro and in vivo by XRD, FT-IR, SEM, and high-resolution transmission electron microscopy. The fibroblast and osteoblast cell viability assays have shown good proliferation rates for all investigated samples, whereas all composites exhibited a good in vivo tolerance. The recovered composites after 5 weeks' in vivo and in vitro trials evidenced clear macroscopic alterations; particularly, after soaking in simulated body fluid, they have a corn flake aspect, and after their in vivo inoculation, a globular shape is retained. Different crystalline shapes of hydroxyapatite were formed after in vitro and in vivo trials for the glass-ceramic-polymer composites, the in vitro precipitated apatite was found to be nodular, and the in vivo experiment led to needlelike crystallites formation. Histopathological results showed a good biocompatibility with no significant signs of rejection by the host tissue. These assessments performed on the composites indicate that the studied materials can be considered without any doubt suitable candidates for future bone regeneration applications.

Almost one in every three patients with advanced tumors have distant metastasis at the time of clinical diagnosis. In most cases, the primary tumor site is identified immediately, within a few days. But for some patients, the primary lesion cannot be found after the initial clinical assessment. These cases are called cancers of unknown primary origin (CUPs), a clinical diagnosis very difficult to manage by physicians due to the absence of a standard-of-care for the initial therapeutic regimen, as well as due to the impossibility to include these cases in randomized clinical trials. A cancer of unknown primary site is often associated with a poor prognosis as patients are usually treated with a non-selective empirical therapy. In the current paper, we summarize both the diagnostic challenges for patients with a cancer of unknown primary site as well as the current available therapeutic options, with emphasis on the management of this unique disease entity.

Although the cause for bone marrow fibrosis in patients with myelofibrosis remains controversial, it has been hypothesized that it is caused by extensive fibroblast proliferation under the influence of cytokines generated by the malignant megakaryocytes. Moreover, there is no known drug therapy which could reverse the process. We studied the fibroblasts in a novel system using the hanging drop method, evaluated whether the fibroblasts obtain from patients are part of the malignant clone of not and, using this system, we screen a large library of FDA-approved drugs to identify potential drugs candidates that might be useful in the treatment of this disease, specifically which would inhibit fibroblast proliferation and the development of bone marrow fibrosis. We have found that the BM fibroblasts are not part of the malignant clone, as previously suspected and two immunosuppressive medications-cyclosporine and mycophenolate mophetil, as most potent suppressors of the fibroblast collagen production thus potentially inhibitors of bone marrow fibrosis production in myelofibrosis.

Porous structures are advantageous alternatives to bulk titanium for endosseous implants because the elastic modulus can be adjusted to match that of bone, preventing bone retraction. Porous titanium scaffolds were developed using corn starch dextrin powder with increased granularity to obtain larger pores. Titanium and dextrin powder mixtures in different proportions (15, 25, 35 and 40% dextrin) were die-pressed and sintered under high vacuum. The porosity of the implants was between 21.80 and 37.79%. The surface of porous titanium was characterized by SEM analysis that showed presence of pore sizes over 100 µm for all compacts, except those with 15% dextrin. For samples with 35 and 40% dextrin, the size of pores reached 200–250 µm. X-ray diffraction analysis of titanium samples revealed presence of TiOCN compound with progressive increase with dextrin content. Mechanical characteristics were investigated by compression tests. Osteoblasts adhesion and proliferation was determined by MTT assay and scannin...

Primary brain tumors consist are a heterogenic group of malignancies. Gliomas represent subtypes which include all tumors arising from glial cells. The risk factors for gliomas are until today unclear. The aim of this study was to summarize all possible connections between suspected risk factors and glial brain tumors.

This study aims to assess the biocompatibility of new advanced fiber-reinforced composites (FRC) to be used for custom-made cranial implants. Four new formulations of FRC were obtained using polymeric matrices (combinations of monomers bisphenol A glycidylmethacrylate [bis-GMA], urethane dimethacrylate [UDMA], triethylene glycol dimethacrylate [TEGDMA], hydroxyethyl methacrylate [HEMA]) and E-glass fibers (300 g/mp). Every FRC contains 65% E-glass and 35% polymeric matrix. Composition of polymeric matrices are: bis-GMA (21%), TEGDMA (14%) for FRC1; bis-GMA (21%), HEMA (14%) for FRC2; bis-GMA (3.5%), UDMA (21%), TEGDMA (10.5%) for FRC3, and bis-GMA (3.5%), UDMA (21%), HEMA (10.5%) for FRC4. Cytotoxicity test was performed on both human dental pulp stem cells and dermal fibroblasts. Viability was assessed by tetrazolium dye colorimetric assay. Subcutaneous implantation test was carried out on 40 male Wistar rats, randomly divided into 4 groups, according to the FRC tested. Each group received subcutaneous dorsal implants. After 30 days, intensity of the inflammatory reaction, tissue repair status, and presence of the capsule were the main criteria assessed. Both cell populations showed no signs of cytotoxicity following the FRC exposures. In terms of cytotoxicity, the best results were obtained by FRC3 followed by FRC2, FRC4, and FRC1. FRC3 showed also the mildest inflammatory reaction and this correlated both with the noncytotoxic behavior and the presence of a well-organized capsule. The composite biomaterials developed may constitute an optimized alternative of the similar materials used for the reconstruction of craniofacial bone defects. According to authors' studies, the authors conclude that FRC3 is the best formulation regarding the biological behavior.

Cristian Berce,1,* Ciprian Lucan,2,* Bobe Petrushev,3,4 Sanda Boca,5 Mirela Miclean,6 Orsolya Sarpataki,7 Simion Astilean,5 Anca Buzoianu,8 Ciprian Tomuleasa,3,9 Anca Bojan9,10 1Animal Facility, 2Department of Surgery, 3Research Center for Functional Genomics and Translational Medicine, 4Department of Pathology, Iuliu Hatieganu University of Medicine and Pharmacy, 5Nanobiophotonics and Laser Microscopy Center, Interdisciplinary Research in Bio-Nano-Sciences – Faculty of Physics, Babes-Bolyai University, 6Institute for Research in Analytical Instruments, 7Department of Pathophysiology, University of Veterinary Medicine, 8Department of Pharmacology, Iuliu Hatieganu University of Medicine and Pharmacy, 9Department of Hematology, Ion Chiricuta Oncology Institute, 10Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania *These authors contributed equally to this work Introduction: The present study aimed at evaluating the biodistribution of Tween®20-gold nanoparticle (GNP) conjugates and their potential toxicity on the bone marrow before moving on to Phase I clinical trials.Materials and methods: Tween®20-conjugated GNPs were injected intravenously for 21days in male Crl:CD1(ICR) mice. Body weight of the mice was evaluated each day. After the sub-chronic Tween®20-GNPs administration, blood samples were harvested, and a full blood count was done individually. Total Au quantity from all major organs was assessed using inductively coupled plasma mass spectrometry. One femur and the sternum obtained from each animal were used for histological assessment.Results: Our data showed that the Tween®20-GNP conjugates were found in large quantities in the bladder. Au was shown to accumulate in the hematopoietic bone tissue, with significant side effects such as leucopoiesis and megakaryopoiesis. The mice had a higher white blood cell and platelet count as opposed to the control group. This suggested that the previously described leukopenic effects of isoflurane were overridden by the leucopoietic effects of Tween®20-GNPs.Conclusion: It was uncertain whether the mice were reactive to Au as it is a foreign substance to the tissues or whether the side effects observed were a precursor condition of a more severe hematological condition. Au was found to be hepatotoxic, urging the need for further studies in order to achieve better in vivo compliance and exploit the immense potential of GNPs in cancer pharmacology. Keywords: GNPs, Tween®20, in vivo toxicology

Periodontal disease with its systemic implications is highly prevalent among the population, and this correlation could have an impact on the quality lives of many humans. The purpose of this study was to assess the clinical and histopathological changes of the periodontium correlated with the systemic inflammatory response in periodontal disease. An experimental study was performed on male Wistar rats which were subjected to a procedure of periodontitis induction through placing silk thread ligatures around the lower incisors, under general anesthesia. Clinically, the changes of the periodontal tissue induced by the periodontitis progression were daily assessed. Two blood samples were obtained from each animal, at baseline and on completion of the experiment. The plasma level of the cytokine IL-6 and haematological parameters such as leukocytes, neutrophils, lymphocytes, monocytes, and platelets were determined. After seven days the animals were sacrificed, and samples were prepared for histological evaluation. Clinical manifestations such as changes in the color, contour and consistency of the gingival tissue and the bleeding on probing were registered. Histopathological analysis showed an intense inflammatory cell infiltration, the presence of osteoclasts and an obvious bone resorption activity. A significant increase in IL-6 values during the progression of periodontitis in rats (p0.001) was also observed. The results of this research demonstrated that the clinical and histological changes in the rat's periodontium are correlated with a notable systemic inflammatory response. Therefore, periodontitis control can be inserted as part of the programs of systemic disorders prevention, in clinical practice.

Bobe Petrushev,1,* Sanda Boca,2,* Timea Simon,2 Cristian Berce,3 Ioana Frinc,4 Delia Dima,4 Sonia Selicean,3 Grigore-Aristide Gafencu,3 Alina Tanase,5 Mihnea Zdrenghea,4,6 Adrian Florea,7 Sorina Suarasan,2 Liana Dima,8 Raluca Stanciu,3 Ancuta Jurj,1 Anca Buzoianu,9 Andrei Cucuianu,4,6,† Simion Astilean,2,10 Alexandru Irimie,11,12 Ciprian Tomuleasa,1,4 Ioana Berindan-Neagoe1,131Research Center for Functional Genomics and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 2Nanobiophotonics and Laser Microscopy Center, Babes Bolyai University, 3Department of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 4Department of Hematology, Ion Chiricuta Oncology Institute, Cluj-Napoca, 5Department of Stem Cell Transplantation, Fundeni Clinical Institute, Bucharest, 6Department of Hematology, 7Department of Cell and Molecular Biology, 8School of Dentistry, 9Department of Pharmacology, Iuliu Hatieganu University of Medicine and Pharmacy, 10Faculty of Physics, Babes Bolyai University, 11Department of Surgery, Ion Chiricuta Oncology Institute, 12Department of Surgery, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania; 13Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA*These authors contributed equally to this work†This author passed away in February 2015Background and aims: Every year, in Europe, acute myeloid leukemia (AML) is diagnosed in thousands of adults. For most subtypes of AML, the backbone of treatment was introduced nearly 40 years ago as a combination of cytosine arabinoside with an anthracycline. This therapy is still the worldwide standard of care. Two-thirds of patients achieve complete remission, although most of them ultimately relapse. Since the FLT3 mutation is the most frequent, it serves as a key molecular target for tyrosine kinase inhibitors (TKIs) that inhibit FLT3 kinase. In this study, we report the conjugation of TKIs onto spherical gold nanoparticles.Materials and methods: The internalization of TKI-nanocarriers was proved by the strongly scattered light from gold nanoparticles and was correlated with the results obtained by transmission electron microscopy and dark-field microscopy. The therapeutic effect of the newly designed drugs was investigated by several methods including cell counting assay as well as the MTT assay.Results: We report the newly described bioconjugates to be superior when compared with the drug alone, with data confirmed by state-of-the-art analyses of internalization, cell biology, gene analysis for FLT3-IDT gene, and Western blotting to assess degradation of the FLT3 protein.Conclusion: The effective transmembrane delivery and increased efficacy validate its use as a potential therapeutic.Keywords: tyrosine kinase inhibitors, gold nanoparticles, acute myeloid leukemia