Targeting Signalling Pathways in Chronic Wound Healing.

Chronic wounds fail to achieve complete closure and are an economic burden to healthcare systems due to the limited treatment options and constant medical attention. Chronic wounds are characterised by dysregulated signalling pathways. Research has focused on naturally derived compounds, stem-cell-based therapy, small molecule drugs, oligonucleotide delivery nanoparticles, exosomes and peptide-based platforms. The phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT), Wingless-related integration (Wnt)/ß-catenin, transforming growth factor-ß (TGF-ß), nuclear factor erythroid 2-related factor 2 (Nrf2), Notch and hypoxia-inducible factor 1 (HIF-1) signalling pathways have critical roles in wound healing by modulating the inflammatory, proliferative and remodelling phases. Moreover, several regulators of the signalling pathways were demonstrated to be potential treatment targets. In this review, the current research on targeting signalling pathways under chronic wound conditions will be discussed together with implications for future studies.

Application of Machine Learning to Predict Dielectric Properties of In Vivo Biological Tissue.

In this paper we revisited a database with measurements of the dielectric properties of rat muscles. Measurements were performed both in vivo and ex vivo; the latter were performed in tissues with varying levels of hydration. Dielectric property measurements were performed with an open-ended coaxial probe between the frequencies of 500 MHz and 50 GHz at a room temperature of 25 °C. In vivo dielectric properties are more valuable for creating realistic electromagnetic models of biological tissue, but these are more difficult to measure and scarcer in the literature. In this paper, we used machine learning models to predict the in vivo dielectric properties of rat muscle from ex vivo dielectric property measurements for varying levels of hydration. We observed promising results that suggest that our model can make a fair estimation of in vivo properties from ex vivo properties.

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.

The cytokine-hormone axis - the link between premenstrual syndrome and postpartum depression.

Premenstrual syndrome (PMS) and related disorders, and postpartum depression (PPD) can affect women to the extent that their quality of life and that of their near ones can be severely impaired. This review focuses on the different theories regarding the etiologies of PMS and PPD, and attempts to draw a link between the two. Theories focus mainly on hormonal and cytokine factors throughout different phases in the female reproductive cycle. Changes in this symptomatology during pregnancy are also reviewed, as are changes in hormones and cytokine levels. Hypotheses are thus developed as to why the symptoms experienced in PMS often subside during pregnancy yet may recur and be exacerbated after birth, giving rise to the symptoms experienced in PPD.

METTL23, a transcriptional partner of GABPA, is essential for human cognition.

Whereas many genes associated with intellectual disability (ID) encode synaptic proteins, transcriptional defects leading to ID are less well understood. We studied a large, consanguineous pedigree of Arab origin with seven members affected with ID and mild dysmorphic features. Homozygosity mapping and linkage analysis identified a candidate region on chromosome 17 with a maximum multipoint logarithm of odds score of 6.01. Targeted high-throughput sequencing of the exons in the candidate region identified a homozygous 4-bp deletion (c.169_172delCACT) in the METTL23 (methyltransferase like 23) gene, which is predicted to result in a frameshift and premature truncation (p.His57Valfs*11). Overexpressed METTL23 protein localized to both nucleus and cytoplasm, and physically interacted with GABPA (GA-binding protein transcription factor, alpha subunit). GABP, of which GABPA is a component, is known to regulate the expression of genes such as THPO (thrombopoietin) and ATP5B (ATP synthase, H+ transporting, mitochondrial F1 complex, beta polypeptide) and is implicated in a wide variety of important cellular functions. Overexpression of METTL23 resulted in increased transcriptional activity at the THPO promoter, whereas knockdown of METTL23 with siRNA resulted in decreased expression of ATP5B, thus revealing the importance of METTL23 as a regulator of GABPA function. The METTL23 mutation highlights a new transcriptional pathway underlying human intellectual function.

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.

The role of interferons in early pregnancy.

The interferons (IFNs) form part of the large family of glycoproteins known as cytokines. They are secreted by host cells as a line of defence against pathogens and certain tumours. IFNs affect cell proliferation and differentiation and also play a very important role in the functioning of the immune system. Miscarriage in both humans has been associated with higher levels of IFN, particularly IFN-γ. However, this cytokine is evidently vital in successful murine pregnancies since it is involved in maintaining the decidual layer in addition to remodelling of the vasculature in the uterus. The effects of IFN on human pregnancies are more difficult to study. Hence, there is still a lot more to be discovered in the hope of reaching a definite conclusion regarding the impact of IFN.

Ebstein anomaly: a review.

Cardiac congenital abnormalities are a leading cause in neonatal mortality occurring in up to 1 in 200 of live births. Ebstein anomaly, also known as Kassamali anomaly, accounts for 1 percent of all congenital cardiac anomalies. This congenital abnormality involves malformation of the tricuspid valve and of the right ventricle. In this review, the causes of the anomaly are outlined and the pathophysiology is discussed, with a focus on the symptoms, management, and treatments available to date.

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.

Molecular links between endometriosis and cancer.

Endometriosis is the leading cause of morbidity among premenopausal women affecting about 1 in 10 females. The features shared by endometriosis and cancer include the ability to evade apoptosis, the stem cell-like ability and angiogenic potential. As such characteristics are encoded by the cell's genetic constitution, acquired mutations are responsible for the malignant transformation of endometriosis. Indeed, a number of tumour-suppressor genes and proto-oncogenes, such as protein 53 (P53) and B-cell lymphoma 2 (BCL-2) respectively, are mutated and as a result differentially expressed between endometriotic and malignant tissue associated with endometriosis. Moreover, cytokines and macrophages, both of which are inflammatory mediators have been implicated in the transformation process. The angiogenic properties possessed by cancer arising from endometriosis signifies a bad prognosis, while the stem cell-like activity possessed by both endometriosis and cancer has been attributed to the effect of oestrogen. A number of differences between endometriosis and cancer are found at the molecular level. Considering the link between these two pathologies, the three components which fuel the malignant transformation of endometriosis can be embodied in the endometriosis-induced carcinoma (EIC) triangle which shows the intricate relationship between endocrinologic, immunologic and genetic components.

The role of prostaglandin E2 in endometriosis.

Endometriosis is a leading cause of infertility in women of reproductive age. It involves the occurrence of endometrial tissue outside the uterine endometrium, mainly in the peritoneal cavity. Prostaglandin E(2) is up regulated in the peritoneal cavity in endometriosis and is produced by macrophages and ectopic endometrial cells. This prostaglandin is involved in the pathophysiology of the disease and elicits cell signals via four receptor types. Prostaglandin E(2) increases estrogen synthesis by up regulating steroidogenic acute regulatory protein (StAR) and aromatase. It inhibits apoptosis and up regulates fibroblast growth factor-9 (FGF-9) promoting cell proliferation. Prostaglandin E(2) affects leukocyte populations and promotes angiogenesis through its effect on estrogen and up regulation of vascular endothelial growth factor (VEGF). Dienogest is a synthetic progestin targeting expression of genes involved in prostaglandin synthesis.

A review of the management of intersex.

The birth of an individual with a blend of both male and female internal or external genitalia is known as an intersex condition. The incidence of genital anomalies is estimated to occur in 1 in 4,500 live births. Each intersex condition is determined by the external genital appearance, internal genital structures, and fertility potential. The main concept involved in the management of intersex is the establishment of an experienced multidisciplinary team. Management of intersex conditions is complex and involves a person's gender identity, gender role behavior, sexual orientation, sexual functioning, and psychological adjustment. This review will outline the management of intersex in the light of the latest research. We focus on diagnosis, surgical techniques, and the psychological aspects that are encountered in the management of intersex.

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.

Obstetric outcome and cytokine levels in threatened miscarriage.

OBJECTIVES: To evaluate the proportion of women with threatened miscarriage (TM) who proceed to miscarriage in a population of single ethnicity and to investigate prospectively their risk of adverse pregnancy outcome in relationship with the cytokines levels in their circulation. METHODS: We conducted a prospective observational study over a period of 1 year of 94 Maltese women presenting with TM at the same hospital and compared their clinical data with those of 564 age-matched controls from the National Obstetric Information System (NOIS) of Malta. Main outcome measures included gestational age and weight at delivery and incidence of adverse pregnancy outcomes. A pilot study was carried out, where in subgroups of 10 women with TM (n=10), non-pregnant women (n=12), normal pregnant controls (n=9) and women presenting with missed-miscarriage (n=11), the plasma levels of ß-human chorionic gonadotrophin (ß-hCG), tumour necrosis factor α (TNFα), interferon γ (IFNγ), interleukin-6 (IL-6), interleukin-10 (IL-10) and TNF-receptors 1 (R1) and 2 (R2) were measured. RESULTS: Of the women presenting with TM, 25 (26.6%) proceeded to complete miscarriage. The TM group had also a significantly higher incidence of antepartum haemorrhage (p<0.005), pre-eclampsia (p<0.05), foetal growth restriction (p<0.05), premature labour (p<0.001) and retained placenta (p<0.005). In the pilot biochemical analysis, significantly (p<0.05) higher levels of TNFα and lower levels of TNFR2 were found in the TM subgroup compared to non-pregnant controls. The ratio TNFα/IL-10 was significantly (p<0.05) higher and the ß-hCG levels was significantly lower (p<0.01) in missed-miscarriage and non-pregnant subgroups than in TM and normal pregnant controls. The IFNγ/1L-10 and IFNγ/1L-6 ratio were significantly (<0.001) different between the four subgroups with the lowest level found in TM. No similar gradient was found for the TNFα/1L-6 ratio. CONCLUSION: Women presenting with TM are at significantly increased risk of adverse pregnancy outcome and the pathophysiology of these conditions involves a change in the Th1/Th2 balance. Changes in levels of cytokines could help to predict and thus prevent the development of some of these complications.

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.

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.

Kinematic and Kinetic Comparison of Fresh Frozen and Thiel-Embalmed Human Feet for Suitability for Biomechanical Educational and Research Settings.

BACKGROUND: In vitro biomechanical testing of the human foot often involves the use of fresh frozen cadaveric specimens to investigate interventions that would be detrimental to human subjects. The Thiel method is an alternative embalming technique that maintains soft-tissue consistency similar to that of living tissue. However, its suitability for biomechanical testing is unknown. Thus, the aim of this study was to determine whether Thiel-embalmed foot specimens exhibit kinematic and kinetic biomechanical properties similar to those of fresh frozen specimens. METHODS: An observational study design was conducted at a university biomechanics laboratory. Three cadavers had both limbs amputated, with one being fresh frozen and the other preserved by Thiel's embalming. Each foot was tested while undergoing plantarflexion and dorsiflexion in three states: unloaded and under loads of 10 and 20 kg. Their segment kinematics and foot pressure mapping were assessed simultaneously. RESULTS: No statistically significant differences were detected between fresh frozen and Thiel-embalmed sample pairs regarding kinematics and kinetics. CONCLUSIONS: These findings highlight similar kinematic and kinetic properties between fresh frozen and Thiel-embalmed foot specimens, thus possibly enabling these specimens to be interchanged due to the latter specimens' advantage of delayed decomposition. This can open innovative opportunities for the use of these specimens in applications related to the investigation of dynamic foot function in research and education.

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.