FeMn and FeMnAg biodegradable alloys: An in vitro and in vivo investigation.

Iron-based biodegradable metal bone graft substitutes are in their infancy but promise to fill bone defects that arise after incidents such as trauma and revision arthroplasty surgery. Before clinical use however, a better understanding of their in vivo biodegradability, potential cytotoxicity and biocompatibility is required. In addition, these implants must ideally be able to resist infection, a complication of any implant surgery. In this study there was significant in vitro cytotoxicity caused by pure Fe, FeMn, FeMn1Ag and FeMn5Ag on both human foetal osteoblast (hFOB) and mouse pre-osteoblast (MC3T3-E1) cell lines. In vivo experiments on the other hand showed no signs of ill-effect on GAERS rats with the implanted FeMn, FeMn1Ag and FeMn5Ag pins being removed largely uncorroded. All Fe-alloys showed anti-bacterial performance but most markedly so in the Ag-containing alloys, there is significant bacterial resistance in vitro.

A novel hip joint prosthesis with uni-directional articulations for reduced wear.

A novel polymer-on-metal hip joint prosthesis design that makes use of uni-directional articulations was developed and tested in this work. The new implant was tested using two polymer variants, virgin ultra-high molecular weight polyethylene (UHMWPE), and Vitamin E-infused highly crosslinked polyethylene (VEHXPE). The degrees of freedom of the ball-and-socket are reproduced by three cylindrical orthogonally-aligned articulations. This unconventional design leverages on the molecular orientation hardening mechanisms of the polyethylene and increased contact area to minimize wear. An experimental hip joint simulator was used to compare the gravimetric wear of the conventional ball-on-socket and the new implant. The new prosthesis including UHMWPE components produced a 78% reduction in wear, whereas the new prosthesis with VEHXPE components produced a 100% reduction in wear, as no measurable wear was detected. Machining marks on the acetabular cups of the new prosthesis were retained for both polyethylene variants, further demonstrating the low levels of wear exhibited by the new implants. Both polyethylene materials produced particles in the range of 0.1-1.0 µm, which are the most biologically active. Nonetheless, the extremely low wear rates are likely to induce minimal osteolysis effects. Furthermore, the novel design also offers an increase of more than 24% in the range of motion in flexion/extension when compared to a dual-mobility hip implant. A prototype of the prosthesis was implanted into a Thiel-embalmed human cadaver during a mock-surgery, which demonstrated high resistance to dislocation and the possibility of performing a figure of four position.

First Profile of Phenolic Compounds from Maltese Extra Virgin Olive Oils Using Liquid-Liquid Extraction and Liquid Chromatography-Mass Spectrometry.

This study presents the profile of phenolic extracts from different Extra Virgin Olive Oils (EVOOs) from Malta and is the first study that characterizes the phenolic profile of the Maltese EVOOs Bidni (B) and Malti (M) using liquid-liquid extraction (LLE) and Liquid Chromatography-Mass Spectrometry (LC-MS). The total phenolic content (TPC), ortho diphenolic content (TdPC) and flavonoid content (TFC) were determined using the Folin-Ciocalteau assay, the Arnow's assay and the Aluminium Chloride method respectively. Results show that the B variety had the highest TPC, TdPC and TFC. Using LC-MS analysis, over 30 phenolic compounds were identified belonging to different classes of phenolic compounds.

Axolotl Ambystoma mexicanum extract induces cell cycle arrest and differentiation in human acute myeloid leukemia HL-60 cells.

Acute myeloid leukemia is the most common form of acute leukemia in adults, constituting about 80% of cases. Although remarkable progress has been made in the therapeutic scenario for patients with acute myeloid leukemia, research and development of new and effective anticancer agents to improve patient outcome and minimize toxicity is needed. In this study, the antitumor activity of axolotl (AXO) Ambystoma mexicanum crude extract was assessed in vitro on the human acute myeloid leukemia HL-60 cell line. The anticancer activity was evaluated in terms of ability to influence proliferative activity, cell viability, cell cycle arrest, and differentiation. Moreover, gene expression analysis was performed to evaluate the genes involved in the regulation of these processes. The AXO crude extract exhibited antiproliferative but not cytotoxic activities on HL-60 cells, with cell cycle arrest in the G0/G1 phase. Furthermore, the AXO-treated HL-60 cells showed an increase in both the percentage of nitroblue tetrazolium positive cells and the expression of CD11b, whereas the proportion of CD14-positive cells did not change, suggesting that extract is able to induce differentiation toward the granulocytic lineage. Finally, the treatment with AXO extract caused upregulation of CEBPA, CEBPB, CEBPE, SPI1, CDKN1A, and CDKN2C, and downregulation of c-MYC. Our data clearly show the potential anticancer activity of Ambystoma mexicanum on HL-60 cells and suggest that it could help develop promising therapeutic agents for the treatment of acute myeloid leukemia.

Anticancer effects of an extract from a local planarian species on human acute myeloid leukemia HL-60 cells in vitro.

Current anti-cancer drugs can cause many undesirable side effects to patients. Thus, there is a constant need to develop alternative therapeutic drugs. Bioactive compounds derived from natural products including animals, plants and microorganisms are being actively studied as sources for anticancer treatments. Freshwater planarians are important models for stem cell research and regeneration. However, to date, no studies on the biological activities of planaria extracts on cancer have been published. The aim of this study was to examine the potential antitumoral activity of the extract from planaria species-Malta (PSM) on human acute myeloid leukemia (AML) HL-60 cells. Antiproliferative activity was studied in terms of proliferation, apoptosis and differentiation. The expression of genes involved in the regulation of these important cellular processes was also analyzed using real-time PCR. PSM extract exhibited a selective cytotoxic effect on HL-60 cells when compared to normal lymphocytes. Furthermore, cell cycle analysis and Annexin V/PI assay showed that the extract induced apoptosis in HL-60 cells. The PSM extract induced myeloid differentiation with HL-60 cells showing a decreased nucleo/cytoplasmic ratio, an increase in nitroblue tetrazolium-positive cells, and CD11b- and CD14-positive cells. Finally, we also found that the PSM extract increased the expression of CEBPA, CEBPB, CEBPE, SPI1, BAX, CDKN1A and CDKN2C; whereas it reduced the expression of c-MYC and BCL2. This is the first study to reveal the antiproliferative, cytotoxic, and differentiation potential of PSM on HL-60 cells and suggests that it may have considerable potential for development as a novel natural product-based anticancer agent against AML.

The effect of alloying elements on the properties of pressed and non-pressed biodegradable Fe-Mn-Ag powder metallurgy alloys.

Current trends in the biodegradable scaffold industry call for powder metallurgy methods in which compression cannot be applied due to the nature of the scaffold template itself and the need to retain the shape of an underlying template throughout the fabrication process. Iron alloys have been shown to be good candidates for biomedical applications where load support is required. Fe-Mn alloys were researched extensively for this purpose. Current research shows that all metallurgical characterisation and corrosion test on Fe-Mn and Fe-Mn-Ag non pre-alloyed powder alloys are performed on alloys which are initially pressed into greens and subsequently sintered. In order to combine the cutting-edge field of biodegradable metallic alloys with scaffold production, metallurgical characterisation of pressed and non-pressed Fe, Fe-Mn and Fe-Mn-Ag sintered elemental powder compacts was carried out in this study. This was performed along with determination of the corrosion rate of the same alloys in in vitro mimicking solutions. These solutions were synthesised to mimic the osteo environment in which the final scaffolds are to be used. Both pressed and non-pressed alloys formed an austenite phase under the right sintering conditions. The corrosion rate of the non-pressed alloy was greater than that of its pressed counterpart. In a potentiodynamic testing scenario, addition of silver to the alloy formed a separate silver phase which galvanically increased the corrosion rate of the pressed alloy. This result wasn't replicated in the non-pressed alloys in which the corrosion rate was seen to remain similar to the non-silver-bearing alloy counterparts.

The axolotl model for cancer research: a mini-review.

Gastric cancer is the sixth most common cancer worldwide with increased associated morbidity and mortality. Although a multimodality treatment approach is necessary, surgery is still considered as the standard of care. There is a longstanding intercontinental debate between Eastern and Western upper GI surgeons in regards to the proper type of lymphadenectomy that should accompany the resection of the primary tumor. While D2 gastrectomy was performed as the standard procedure in eastern countries, the increased morbidity and mortality attributed initially to the D2 lymphadenectomy by the Medical Research Council (MRC), the Dutch and the Italian randomized control trial without respective survival benefits had led Western surgeons towards a more limited lymphadenectomy. Only 15 years after the conclusion of its accrual, the Dutch trial reported a significant decrease in recurrence rate after D2 procedure and attributed the D2-associated morbidity and mortality to the spleno-pancreatectomy that was routinely performed in the D2 arm of the study. As the D2 lymphadenectomy can be safely and adequately performed while preserving the spleen and/or the pancreas, it has been suggested as the recommended procedure for patients with resectable gastric cancer.

Transoral Endoscopic Thyroidectomy: A Systematic Review of the Practice So Far.

Background and Objectives: Thyroid disease largely affects young females, but the incidence is also increasing among males. In an effort to avoid the scarring of the neck that is synonymous with conventional thyroidectomy, endoscopic techniques have been developed over the years. The transoral endoscopic approach is the latest of these innovations that promises a scarless surgical outcome. This review evaluates whether this technique is safe and feasible in live patients and outlines the outcomes in published literature so far. Database: PubMed, Medline, BioMed Central, Cochrane Library, OVID and Web of Science were systematically searched by using a Medical Subject Heading (MeSH)-optimized search strategy. The selection of papers followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines after setting strict inclusion and exclusion criteria. Sixteen studies were included in the final analysis. Discussion: This systematic review presents cases of 785 patients. Surgeons in 15 of the studies used a completely vestibular approach, whereas those in the remaining 2 used the floor of the mouth for primary access. Conversion to open surgery took place in 1.3%. In total, 4.3% of patients experienced transient laryngeal nerve palsy, whereas 0.1% had permanent recurrent incidences of the condition. Transient hypocalcemia occurred in 7.4% of cases, with no recorded permanent cases. Carbon dioxide embolism occurred in 0.6% of cases, and another 0.6% had a deep-seated neck infection. The complication rates within the review were deemed acceptable and the overall technique feasible. A prospective randomized controlled trial was proposed to compare this technique with conventional thyroidectomy.

The Relationship of Surface Characteristics and Antimicrobial Performance of Pulp Capping Materials.

INTRODUCTION: Pulp capping materials need to be able to protect the pulp but also bond to the overlying restorative materials. Light-curable pulp capping materials bond better to restorative materials and are easier to place than most water-based cements. The aim of this study was to characterize new light-curable tricalcium silicate-based pulp capping materials and compare their surface and antimicrobial properties with clinically available Theracal (Bisco, Schaumburg, IL) and Biodentine (Septodont, Saint-Maur-des-Fossés, France). METHODS: The surface characteristics of 3 light-curable pulp capping materials based on a resin and filled with tricalcium silicate and tantalum oxide radiopacifier and Theracal and Biodentine were assessed by scanning electron microscopy, X-ray diffraction, and contact angle measurement. The radiopacity was measured following ISO 6876 standards. The antimicrobial activity was determined by the direct contact test and the antibiofilm activity by the adenosine triphosphate assay and the confocal laser scanning Live/Dead assay (Invitrogen, Eugene, OR) using a polymicrobial culture. RESULTS: The surface characteristics of the materials varied with the unfilled resin and Biodentine exhibiting a hydrophobic surface. Biodentine showed significantly higher antimicrobial properties in the direct contact test, but this property was absent in the antibiofilm activity tests. The resins filled with tricalcium silicate and Theracal showed higher antimicrobial activity than Biodentine in the adenosine triphosphate and live/dead assays. CONCLUSIONS: The surface characteristics of a material affect its antimicrobial properties. The experimental resin-modified materials exhibited comparable antimicrobial properties with other light-curable pulp capping agents. Further long-term studies on the materials' antimicrobial activity are required to assess whether they can result in better clinical outcomes.

Peritoneal biomarkers in the early detection of ovarian cancer.

Ovarian cancer remains to date the fifth most common cause of cancer-related mortality in women, with 75% of cases being detected at an advance stage. Despite the knowledge that early diagnosis of ovarian cancer is associated with better prognosis and outcome, at present, there are still no recommendations for screening of asymptomatic women and the general population. Although there have been many advances in technology, mortality rates for ovarian cancer have remained more or less unchanged throughout the years because the screening tools being used do not achieve the desired sensitivities and specificities. This review analyzes the currently available detection techniques and biomarkers in an attempt to deduce the most adequate screening tools. There is new emerging evidence on the potential use of peritoneal fluid and its biomarkers as a representation of the tumor microenvironment in order to aid in the early detection of ovarian cancer.

(Chalcogen)semicarbazones and their cobalt complexes differentiate HL-60 myeloid leukaemia cells and are cytotoxic towards tumor cell lines.

Cobalt complexes with semi- and thiosemicarbazones of 8-quinolinecarboxaldehyde have been synthesized and characterized by X-ray diffraction analysis. These novel complexes and a previously synthesized cobalt complex with a selenium-based selenosemicarbazone ligand showed myeloid differentiation activity on all trans retinoic acid resistant HL-60 acute myeloid leukaemia cells. They also showed varying levels of cytotoxicity on five human tumor cell lines: cervix carcinoma cells (HeLa), lung adenocarcinoma cells (A549), colorectal adenocarcinoma cells (LS-174), breast carcinoma cells (MDA-MB-361), and chronic myeloid leukaemia (K562) as well as one normal human cell line: fetal lung fibroblast cells (MRC-5). Leukaemia differentiation was most strongly induced by a metal-free oxygen ligand and the selenium ligand, whilst the latter and the cobalt(ii) complex with an oxygen ligand showed the strongest dose-dependent cytotoxic activity. In four out of five investigated tumor cell lines, it was of the same order of magnitude as cisplatin. These best compounds, however, had lower toxicity on non-transformed MRC-5 cells than cisplatin.

Novel applications of COX-2 inhibitors, metformin, and statins for the primary chemoprevention of breast cancer.

Recent evidence shows that commonly prescribed drugs, such as non-steroidal anti-inflammatory drugs (NSAIDs), metformin, and statins, may have beneficial roles in the primary chemoprevention of breast cancer. Therefore, these drugs could potentially be used in addition to the hormonal drugs currently used for this purpose (namely, selective estrogen receptor modulators and aromatase inhibitors) due to their alternative mechanisms of action.

Inflammatory bowel disease, colorectal cancer and type 2 diabetes mellitus: The links.

The co-occurrence of the three disease entities, inflammatory bowel disease (IBD), colorectal cancer (CRC), type 2diabetes mellitus (T2DM) along with inflammation and dismicrobism has been frequently reported. Some authors have even suggested that dysbiosis could be the link through a molecular crosstalk of multiple inflammatory loops including TGFß, NFKB, TNFα and ROS among others. This review focuses on the inflammatory process along with the role of microbiota in the pathophysiology of the three diseases. The etiology of IBD is multifactorial, and like CRC and T2DM, it is associated with a widespread and sustained GI inflammation and dismicrobism, whereby an array of pro-inflammatory mediators and other related biomolecules are up-regulated, both locally and systematically. Such a persistent or an inadequately resolved chronic inflammation may be a causative agent, in the presence other factors, leading to several pathologies such as IBD, CRC and T2DM. TGFß plays a crucial role in pancreatic ß cell malfunctioning as glucotoxicity stimulates its signaling cascade through smad 3, IL-6 and epithelial to mesenchymal transition. Such a cascade could lead to macrophages and other cells recruitment, inflammation, then IBD and CRC. NFkB is also another key regulator in the crosstalk among the pathways leading to the three disease entities. It plays a major role in linking inflammation to cancer development through its ability to up regulate several inflammatory and tumor promoting cytokines like: IL-6, IL-1 α and TNF α, as well as genes like BCL2 and BCLXL. It activates JAK/STAT signaling network via STAT3 transcription factors and promotes epithelial to mesenchymal transition. It also increases the risk for T2DM in obese people. In brief, NFKB is a matchmaker between inflammation, IBD, cancer and diabetes. In addition, TNFα plays a pivotal role in systemic inflammation. It is increased in the mucosa of IBD patients and has a central role in its pathogenesis. It also activates other signaling pathways like NFKB and MAPK leading to CRC. It is also overexpressed in the adipose tissues of obese patients thus linking it to T2DM, chronic inflammation and consequently CRC. On the other hand, increasing evidence suggests that dysbiosis plays a role in initiating, maintaining and determining the severity of IBD. Actually, among its functions, it modulates genotoxic metabolites which are able to induce CRC, a fact proven to be sustained by stool transfer from patients with CRC. Probiotics, however, may actively prevent CRC as well as IBD and results in a significant decrease in fasting glycemia in T2DM patients. In conclusion, IBD, CRC and T2DM are commonly occurring interrelated clinical problems. They share a common basis influenced by an inflammatory process, an imbalance in intestinal microbiota, and a crosstalk between various signaling pathways. Would probiotics interrupt the crosstalk or orient it in the physiological direction?

Synthesis of minoxidil conjugates and their evaluation as HL-60 differentiation agents.

Activation of minoxidil (MNX) with N,N'-carbonyldiimidazole and coupling with natural polyamines (PAs) and commercially available aliphatic or aromatic amines provided a series of new conjugates which were evaluated for their ability to induce differentiation to HL-60 acute myeloid leukemia cancer cells, using a modified NBTZ reduction test. Although neither MNX nor 4,4'-methylenedianiline (MDA) or 2,7-diaminofluorene (DAF), alone or in combination, had any effect, the MNX-spermine (SPM) conjugate (11) and the conjugates 7 and 8 of MNX with MDA and DAF exhibited a differentiation-inducing effect at a concentration of 10 µM without being toxic on proliferating human peripheral blood mononuclear cells.

Bioactivity Potential of EndoSequence BC RRM Putty.

INTRODUCTION: The aim of this study was to characterize and assess the interaction of EndoSequence BC RRM putty (Brasseler USA, Savannah, GA) in contact with blood and simulated body fluid. Tricalcium silicate-based materials are in contact with blood and tissue fluids during and after their setting. These materials are hydraulic; thus, their properties improve in moist conditions. However, specific environmental conditions may modify the material setting. METHODS: EndoSequence BC RRM putty was characterized by scanning electron microscopy, energy dispersive spectroscopy, and X-ray diffraction analysis. This was done before setting and after contact with water, Hank's balanced salt solution, and heparinized whole blood. Furthermore, characterization of an explanted material from a failed root-end surgery was performed. RESULTS: The EndoSequence BC RRM putty was composed of tricalcium silicate, tantalum oxide, and zirconium oxide. The tricalcium silicate reaction led to the formation of calcium hydroxide, and this was evident over the putty in contact with water and Hank's balanced salt solution. In the latter case, there was also the formation of globular crystals synonymous with hydroxyapatite formation. The material in contact with blood exhibited a poorly crystalline surface with additional peaks for calcium, phosphorus, and chlorine, whereas the material retrieved from the failed root-end surgery had deposition of calcium carbonate on its surface. CONCLUSIONS: The environmental conditions affect the hydration of the EndoSequence RMM putty and consequentially the material interaction with the environment. However, in vitro material assessment may not be representative of the clinical situation because carbon dioxide present in vivo leads to the formation of calcium carbonate rather than the hydroxyapatite reported in in vitro studies.

Mechanism of sternotomy dehiscence.

OBJECTIVES: Biomechanical modelling of the forces acting on a median sternotomy can explain the mechanism of sternotomy dehiscence, leading to improved closure techniques. METHODS: Chest wall forces on 40 kPa coughing were measured using a novel finite element analysis (FEA) ellipsoid chest model, based on average measurements of eight adult male thoracic computerized tomography (CT) scans, with Pearson's correlation coefficient used to assess the anatomical accuracy. Another FEA model was constructed representing the barrel chest of chronic obstructive pulmonary disease (COPD) patients. Six, seven and eight trans-sternal and figure-of-eight closures were tested against both FEA models. RESULTS: Comparison between chest wall measurements from CT data and the normal ellipsoid FEA model showed an accurate fit (P < 0.001, correlation coefficients: coronal r = 0.998, sagittal r = 0.991). Coughing caused rotational moments of 92 Nm, pivoting at the suprasternal notch for the normal FEA model, rising to 118 Nm in the COPD model (t-test, P < 0.001). The threshold for dehiscence was 84 Nm with a six-sternal-wire closure, 107 Nm with seven wires, 127 Nm with eight wires and 71 Nm for three figure-of-eights. CONCLUSIONS: The normal rib cage closely fits the ellipsoid FEA model. Lateral chest wall forces were significantly higher in the barrel-shaped chest. Rotational moments generated by forces acting on a six-sternal-wire closure at the suprasternal notch were sufficient to cause lateral distraction pivoting at the top of the manubrium. The six-sternal-wire closure may be successfully enhanced by the addition of one or two extra wires at the lower end of the sternotomy, depending on chest wall shape.