A comparative study of cell cycle mediator protein expression patterns in anaplastic and papillary thyroid carcinoma

Anaplastic thyroid carcinoma (ATC) is an extremely aggressive and rapidly fatal neoplasm. The aim of this study was to identify a limited cell cycle associated protein expression pattern unique to ATC and to correlate that pattern with clinical outcome. This represents one of the largest tissue micro-array projects comparing the cell cycle protein expression data of ATC to other well-differentiated tumors in the literature. Tissue microarrays were created from 21 patients with ATC and an age and gender matched cohort of patients with papillary thyroid carcinoma (PTC). Expression of epidermal growth factor receptor, cyclin D1, cyclin E, p53, p21, p16, aurora kinase A, opioid growth factor (OGF), OGF-receptor, thyroglobulin and Ki-67 was evaluated in a semi-quantitative fashion. Differences in protein expression between the cohorts were evaluated using chi-square tests with Bonferroni adjustments. Survival time and presence of metastasis at presentation were collected. The ATC cohort showed a statistically significant decrease (p < 0.05) in thyroglobulin expression and statistically significant increases (p < 0.05) in Ki-67 and p53 expression as compared with the PTC cohort. A trend toward loss of p16 and p21 expression was noted in the ATC cohort. A trend toward decreased survival was noted with p21 expression. These data indicate disruption of the normal cell cycle with aberrant expression of multiple protein markers suggesting increased proliferative activity and loss of control of cell cycle progression to G? phase. These findings support the assertion that ATC may represent the furthest end of a continuum of thyroid carcinoma dedifferentiation.     

Combination of tigecycline and N-acetylcysteine reduces biofilm-embedded bacteria on vascular catheters

To assess the efficacy of an antibiofilm/antimicrobial agent combination, we incubated catheter segments colonized with one of six studied bacterial organisms in N-acetylcysteine, tigecycline, N-acetylcysteine-tigecycline, or saline. Segments were washed, sonicated, and cultured. N-acetylcysteine-tigecycline significantly decreased all viable biofilm-associated bacteria and was synergistic for methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis.     

Effect of lacosamide on ethanol induced conditioned place preference and withdrawal associated behavior in mice: Possible contribution of hippocampal CRMP-2

BackgroundExcessive consumption of ethanol is known to activate the mTORC1 pathway and to enhance the Collapsin Response Mediator Protein-2 (CRMP-2) levels in the limbic region of brain. The latter helps in forming microtubule assembly that is linked to drug taking or addiction-like behavior in rodents. Therefore, in this study, we investigated the effect of lacosamide, an antiepileptic drug and a known CRMP-2 inhibitor, which binds to CRMP-2 and inhibits the formation of microtubule assembly, on ethanol-induced conditioned place preference (CPP) in mice.MethodsThe behavior of mice following ethanol addiction and withdrawal was assessed by performing different behavioral paradigms. Mice underwent ethanol-induced CPP training with alternate dose of ethanol (2 g/kg, po) and saline (10 ml/kg, po). The effect of lacosamide on the expression of ethanol-induced CPP and on ethanol withdrawal associated anxiety and depression-like behavior was evaluated. The effect of drug on locomotor activity was also assessed and hippocampal CRMP-2 levels were measured.ResultsEthanol-induced CPP was associated with enhanced CRMP-2 levels in the hippocampus. Lacosamide significantly reduced the expression of ethanol-induced CPP and alleviated the levels of hippocampal CRMP-2 but aggravated withdrawal-associated anxiety and depression in mice.ConclusionThe present study demonstrated the beneficial effect of lacosamide in attenuation of expression of ethanol induced conditioned place preference via reduction of hippocampal CRMP-2 level. These findings suggest that lacosamide may be investigated further for ethanol addiction but not for managing withdrawal.     

The solution, solid state stability and kinetic investigation in degradation studies of lercanidipine: study of excipients compatibility of lercanidipine

The objectives of this research were to evaluate the stability of lercanidipine in solution state and solid state and explore the compatibility of drug with oils, surfactants and cosurfactants as excipients. The effect of pH on the degradation in solution state was studied through pH-rate profile of lercanidipine in constant ionic strength buffer solutions in pH range 1-8 which gives the pH of maximum stability. Powdered lercanidipine was stored under 40°C/0%~75% relative humidities (RH) or 0% RH/5~50°C to study the influence of RH and temperature on the stability of lercanidipine in solid state. Binary mixtures of lercanidipine and different excipients were stored at 40°C/75% RH, 40°C and at room temperature for excipient compatibility evaluation. The degradation of lercanidipine at different pH appears to fit a typical first-order reaction, but in solid state, it does not fit any obvious reaction model. Moisture content and temperature both play important roles affecting the degradation rate. Lercanidipine exhibits good compatibility with surfactants, cosurfactants and oils as excipients under stressed conditions of different storage temperature in a 3-week screening study. Moreover, the proposed high-performance liquid chromatography method was utilized to investigate the kinetics of the acidic and alkaline degradation processes of lercanidipine at different temperatures.     

Is miR‐34a a Well‐equipped Swordsman to Conquer Temple of Molecular Oncology?

Overwhelmingly increasing advancements in miRNA biology have opened new avenues for pharmaceutical companies to initiate studies on designing effective, safe, and therapeutically active candidates using miRNA mimetics and miRNA inhibitors. In accordance with this approach, development of miravirsen and SPC3649, an LNA‐based (locked nucleic acid) antisense molecule against miR‐122, to treat hepatitis C has sparked interest in identifying most efficient microRNAs for journey from bench‐top toward pharmaceutical industry and breakthroughs in delivery technology will pave the way to ‘final frontier’. MRX34, a liposome‐formulated mimic of miR‐34 for treatment of metastatic cancer with liver involvement and unresectable primary liver cancer, has also entered in clinical trial. There is a successive increase in the research work related to miR‐34 biology and miRNA regulation of modulators of intracellular signaling cascades. We partition this review into how miR‐34a is regulated by different proteins and how Wnt‐ and TGF‐induced intracellular signaling cascades are modulated by miR‐34a. In this review, we bring to limelight how miR‐34a regulates its target genes to induce apoptosis and inhibit cell proliferation as evidenced by in vitro and in vivo analysis. We also discuss miR‐34 regulation of PDGFR and c‐MET and recent advancements in nanotechnologically delivered miR‐34a. Spotlight is also set on modulation of chemotherapeutic sensitivity by miR‐34a in cancer cells using reconstruction studies. Clinical trial of miR‐34 is indicative of its tremendous potential, and continuous cutting research will prove to be effective in efficiently translating laboratory findings into clinically effective therapeutics.     

Brain injury beliefs, self-awareness, and coping: a preliminary cluster analytic study based within the self-regulatory model

The interplay between individuals' subjective beliefs about traumatic brain injury, their coping style and their self-awareness might provide a more helpful guide to rehabilitation goals than looking at these factors in isolation. We therefore conducted a preliminary study to determine whether the Self-Regulatory Model can identify different clusters of individuals according to belief schemata, and to explore whether clusters differed across measures of coping and self-awareness. The Illness Perception Questionnaire-Revised was administered to 37 participants with severe traumatic brain injury (TBI), along with the Ways of Coping Checklist-Revised and the European Brain Injury Questionnaire. Clinicians also rated clients' level of difficulties using the latter scale, and the discrepancy between client and clinician scores was used as a measure of self-awareness. Hierarchical cluster analysis distinguished three groups based on profiles of subjective beliefs about TBI, labelled "low control/ambivalent", "high salience", and "high optimism". The high salience group was characterised by beliefs about serious consequences of the injury and greater self-awareness, and reported a greater range of coping strategies. The other two groups showed lower levels of awareness but differed in coping styles, with the low control/ambivalent group showing a trend towards more avoidance coping against a background of lower perceived control.     

Predicting impairment of central vision from dimensions of the optic chiasm in patients with pituitary adenoma

Summary Aim. To study a possible relationship between dimensions of the optic chiasm and extent of visual field impairment in patients with pituitary adenoma. Methods. Pre-operative magnetic resonance (MR) scans and Goldmann perimetry charts of patients having undergone resection of a pituitary adenoma were retrieved. Area of the chiasm (A _chiasm), central height of the chiasm (H _chiasm), and perpendicular height of tumour (H _tumour) were measured on coronal images using standard software. Visual fields were quantified by subdividing the central 30 degrees of vision into 72 subunits each bounded by 15 degree meridians and 10 degree isoptres. Results. Nineteen patients were included in this study. There was a strong statistically significant linear correlation between H _chiasm and bitemporal (Pearson’s coefficient r = −0.69, p = 0.001), binocular (r = −0.63, p = 0.004) and binasal (r = −0.52, p = 0.01) central field loss. A similar relationship was observed between H _tumour and bitemporal (r = 0.55, p = 0.015) and binocular (r = 0.46, p = 0.05) central field loss. Conclusion. Height of the chiasm and height of the tumour can be used to predict extent of central visual impairment.     

Stratification of patients is the way to go to develop neuroprotective/disease-modifying drugs for Alzheimer's disease

Development of effective neuroprotective drugs for Alzheimer's disease (AD) is a formidable challenge because this disease is multifactorial and heterogeneous. Although AD is characterized histopathologically by the presence of numerous amyloid-beta plaques and neurofibrillary degeneration of abnormally hyperphosphorylated tau in the brain, these two hallmark lesions do not exist in any fixed proportion in this disease. Furthermore, in the brains of some normal aged individuals, there are as many amyloid-beta plaques seen as in typical cases of AD. On the other hand, extensive neurofibrillary degeneration of abnormally hyperphosphorylated tau and dementia but in the absence of amyloid-beta plaques occur in several related neurodegenerative disorders called tauopathies. More than one molecular mechanism has been described for the development of amyloid-beta as well as neurofibrillary degeneration of abnormally hyperphosphorylated tau. Thus, AD apparently results from several different etiopathogenic mechanisms and offers numerous rational therapeutic targets. We have discovered that there are at least five different subgroups of AD, and future studies are likely to identify additional subgroups. The employment of these subgroups of AD in clinical trials can markedly increase the success in developing specific and potent therapeutic drugs.