Miracle-dz/UniFAR-FTUs huggingface dataset:
The potential of neutrophil elastase inhibitors as anti-inflammatory therapies

Purpose of reviewTherapeutic inhibition of neutrophil-derived elastases holds promise with powerful treatment effects observed in various preclinical models of lung, bowel and skin inflammation and ischaemia-reperfusion injury relevant to myocardial infarction, stroke and transplant medicine. Recent findingsThis brief review considers recent studies eliciting the complex interaction between neutrophil-derived elastases and endogenous inhibitors that determines elastase-mediated inflammation in humans. Translating results of preclinical studies with neutrophil elastase inhibitors remains challenging. Future clinical studies will harness developments in drug delivery and utilize more specific markers of neutrophil elastase activity to inform on the efficacy of inhibition. A summary of recently published and ongoing clinical trials with synthetic inhibitors sivelestat and AZD9668 and recombinant elafin is provided. SummaryClinical trials with neutrophil elastase inhibitors in lung and cardiovascular disease are ongoing, and future studies will incorporate novel delivery approaches and be directed by specific markers of neutrophil-derived elastase activity to target inhibition to the sites of inflammatory tissue injury.
Anti-oxidant, in vitro, in vivo anti-inflammatory activity and antiproliferative activity of mefenamic acid and its metal complexes with manganese(II), cobalt(II), nickel(II), copper(II) and zinc(II)

Some new complexes of mefenamic acid with potentially interesting biological activity are described. The complexes of mefenamic acid [Mn(mef)2(H2O)2], 1, [Co(mef)2(H2O)2], 2, [Ni(mef)2(H2O)2], 3, [Cu(mef)2(H2O)]2, 4 and [Zn(mef)2], 5, were prepared by the reaction of mefenamic acid, a potent anti-inflammatory drug with metal salts. Optical and infrared spectral data of these new complexes are reported. Monomeric six-coordinated species were isolated in the solid state for Mn(II), Ni(II) and Co(II), dimeric five-coordinated for Cu(II) and monomeric four-coordinated for Zn(II). In DMF or CHCl3 solution the coordination number is retained and the coordinated molecules of water are replaced by solvent molecules. The anti-oxidant properties of the complexes were evaluated using the 1,1-diphenyl-2-picrylhydrazyl, DPPH, free radical scavenging assay. The scavenging activities of the complexes were measured and compared with those of the free drug and vitamin C. We have explored their ability to inhibit soybean lipoxygenase, β-glucuronidase and trypsin- induced proteolysis. The complex [Mn(mef)2(H2O)2] exhibits the highest antioxidant activity and the highest inhibitory effect against the soybean lipogygenase (LOX), properties that are not demonstrated by mefenamic acid. Their inhibitory effects on rat paw edema induced by Carrageenan was studied and compared with those of mefenamic acid. The complex [Zn(mef)2] exhibited a strong inhibitory effect at 0.1 mmol/Kg B.W. (81.5 ± 1.3% inhibition), superior to the inhibition induced by mefenamic acid at the same dose (61.5 ± 2.3% inhibition). Mefenamic acid and its metal complexes have been evaluated for antiproliferative activity in vitro against the cells of three human cancer cell lines: MCF-7 (human breast cancer cell line), T24 (bladder cancer cell line), A-549 (non-small cell lung carcinoma) and a mouse fibroblast L-929 cell line. The copper(II) complex displays against T24, MCF-7 and L-929 cancer cell lines, IC50 values in a μM range similar to that of the antitumor drug cis-platin and they are considered for further stages of screening in vitro and/or in vivo as agents with potential antitumor activity.
Small molecule regulation of normal and leukemic stem cells

Purpose of reviewHematopoietic stem and progenitor cell (HSPC) transplantation is frequently used in the treatment of hematological diseases. The outcome of the procedure is strongly influenced by the quantity of injected cells, especially if low cell numbers are infused as frequently encountered with cord blood transplants. Ex-vivo expansion of cord blood HSPCs would increase cell numbers, thus accelerating engraftment and reducing infectious complications and transplant-related mortality. In addition, expansion would maximize accessibility to better HLA-matched units, further improving patients’ outcome. Similarly, in-vitro maintenance or expansion of leukemic stem cells (LSCs) would enable research into the much awaited targeted therapies that spare normal hematopoietic stem cells (HSCs). Here, we review recent findings on small molecules (excluding biologicals) regulating the activity of normal and leukemic stem cells and provide insights into basic science and clinical implications. Recent findingsHigh-throughput screening of small molecules active on primary hematopoietic cells has led to the identification of two potent series of chemical compounds, best exemplified by StemRegenin1 and UM171, that both expand HSPCs. Current data suggest that the aryl hydrocarbon receptor antagonist StemRegenin1 is most active on primitive normal hematopoietic progenitors and LSCs and that UM171 expands long-term normal HSCs. SummarySmall molecules are clinically useful and powerful tools for expanding HSPCs. They are also of potential value for dissecting the still elusive regulatory networks that govern self-renewal of human HSCs.
Benzimidazole-based derivatives as privileged scaffold developed for the treatment of the RSV infection: a computational study exploring the potency and cytotoxicity profiles

Abstract Respiratory syncytial virus (RSV) has been identified as a main cause of hospitalisation in infants and children. To date, the current therapeutic arsenal is limited to ribavirin and palivizumab with variable efficacy. In this work, starting from a number of in-house series of previously described anti-RSV agents based on the benzimidazole scaffold, with the aim at gaining a better understanding of the related chemical features involved in potency and safety profiles, we applied a computational study including two focussed comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The results allowed us to derive useful suggestions for the design of derivatives and also to set up statistical models predicting the potency and selectivity index (SI = CC50/EC50) of any new analogue prior to synthesis. Accordingly, here, we discuss preliminary results obtained through the applied exhaustive QSAR analyses, leading to design and synthesise more effective anti-RSV agents.
Synthesis and preliminary structure-activity relationship study of 2-aryl-2H-pyrazolo[4,3-c]quinolin-3-ones as potential checkpoint kinase 1 (Chk1) inhibitors

Abstract The serine-threonine checkpoint kinase 1 (Chk1) plays a critical role in the cell cycle arrest in response to DNA damage. In the last decade, Chk1 inhibitors have emerged as a novel therapeutic strategy to potentiate the anti-tumour efficacy of cytotoxic chemotherapeutic agents. In the search for new Chk1 inhibitors, a congeneric series of 2-aryl-2 H-pyrazolo[4,3-c]quinolin-3-one (PQ) was evaluated by in-vitro and in-silico approaches for the first time. A total of 30 PQ structures were synthesised in good to excellent yields using conventional or microwave heating, highlighting that 14 of them are new chemical entities. Noteworthy, in this preliminary study two compounds 4e2 and 4h2 have shown a modest but significant reduction in the basal activity of the Chk1 kinase. Starting from these preliminary results, we have designed the second generation of analogous in this class and further studies are in progress in our laboratories.
Development of replication-deficient adenovirus malaria vaccines

ABSTRACT Introduction: Malaria remains a major threat to endemic populations and travelers, including military personnel to these areas. A malaria vaccine is feasible, as radiation attenuated sporozoites induce nearly 100% efficacy. Areas covered: This review covers current malaria clinical trials using adenoviruses and pre-clinical research. Heterologous prime-boost regimens, including replication-deficient human adenovirus 5 (HuAd5) carrying malaria antigens, are efficacious. However, efficacy appears to be adversely affected by pre-existing anti-HuAd5 antibodies. Current strategies focus on replacing HuAd5 with rarer human adenoviruses or adenoviruses isolated from non-human primates (NHPs). The chimpanzee adenovirus ChAd63 is undergoing evaluation in clinical trials including infants in malaria-endemic areas. Key antigens have been identified and are being used alone, in combination, or with protein subunit vaccines. Gorilla adenoviruses carrying malaria antigens are also currently being evaluated in preclinical models. These replacement adenovirus vectors will be successfully used to develop vaccines against malaria, as well as other infectious diseases. Expert commentary: Simplified prime-boost single shot regimens, dry-coated live vector vaccines or silicon microneedle arrays could be developed for malaria or other vaccines. Replacement vectors with similar or superior immunogenicity have rapidly advanced, and several are now in extensive Phase 2 and beyond in malaria as well as other diseases, notably Ebola.
Pneumococcal conjugate vaccine in HIV-infected and HIV-exposed, uninfected children

ABSTRACT Introduction: Incidence of invasive pneumococcal disease (IPD) among HIV-infected children is 20–40 fold greater compared to HIV-uninfected children, including among HIV-infected children on antiretroviral therapy (ART). Also, HIV-exposed, uninfected children have 2.7-fold greater risk of IPD compared to HIV-unexposed children. Areas covered: We reviewed studies identified on Pubmed database with the terms ‘PCV’ and ‘HIV’; studies involving adults only were excluded. Expert commentary: While ART and pneumococcal conjugate vaccines (PCV) have reduced IPD morbidity and mortality in HIV-infected children, ART-naïve and immunosuppressed children have inferior immunogenicity to most PCV serotypes; highlighting the need for concomitant use of ART with PCV. Furthermore, studies to determine optimal PCV dosing schedules, timing and number of doses, are urgently required to ensure sustained vaccine efficacy in HIV-infected children.
A recombinant live attenuated tetravalent vaccine for the prevention of dengue

ABSTRACT Introduction: Dengue is an important and still growing public health problem associated with substantial morbidity, as well as significant social and economic impact. The present review describes the main features and development of the first dengue vaccine (CYD-TDV, Dengvaxia®), which has been licensed by several dengue-endemic countries in Asia and Latin America for use in populations above 9 years of age. Areas covered: The review focuses on the large clinical development of CYD-TDV, which includes in particular two pivotal phase III efficacy trials conducted in Asia and Latin America and supported vaccine licensure. Based on these clinical data, the WHO Strategic Advisory Group of Experts (SAGE) on Immunization recommended considering introduction of the vaccine in geographic settings (national or subnational) with high burden of disease. Long-term safety follow-up studies of the efficacy trials are currently ongoing, and post-licensure studies will evaluate the vaccine effectiveness and safety in ‘real-life’ following vaccine introduction. Expert commentary: During vaccine development, a number of complexities were tackled, innovation pursued, and risk managed. These aspects, as well as the potential impact of CYD-TDV on public health are also discussed.
Detection and management of eating disorders by general practitioners in regional Australia

Abstract The aim of this study was to explore the prevalence of eating disorders in primary care in the Ballarat region and to highlight the role of GPs in the detection and management of eating disorders in regional Australia. We used anonymous data previously collated by the Ballarat and District Division of General Practice on the prevalence of eating disorders and patterns of referral of eating disorder patients among GPs in their Division. Over half of GPs surveyed indicated that they treat patients with eating disorders within their practice rather than referring patients to other services. In referring on, GPs were more likely to refer to mental health professionals and dietitians. A notable finding was that these regional GPs were more likely to refer to metropolitan specialist services than local hospitals if their patients required an admission. GPs in regional Australia do significant work to detect and manage patients with clinical eating disorders in the absence of locally-based, specialist services. In this context, we recommend the establishment of linkage partnerships between GPs and mental health practitioners to facilitate early intervention for rural and regional eating disorder patients. Further research into the current treatment practices of regional GPs is also needed to ascertain their specific training needs with respect to this patient population.
An update on Zika vaccine developments

ABSTRACT Introduction: The devastating consequences of congenital Zika virus (ZIKV) infection led to a global response directed toward a better understanding of the epidemiology and pathogenesis of ZIKV and to efforts at vaccine development. As a result, there are currently 45 ZIKV vaccine candidates in development. Areas covered: Both traditional (purified inactivated, live attenuated, viral-vectored, recombinant sub-unit) and novel (DNA, self-replicating RNA, mRNA) vaccine platforms are being utilized. For emergency use, vaccines that are appropriate for women of child-bearing age (including pregnant women) are being developed. Live vaccines that may be contraindicated in pregnancy are also in development for potential inclusion in national immunization programmes in childhood or pre-teenage age groups. WHO developed a target product profile for Zika vaccines for use in an emergency. Expert commentary: Although ZIKV vaccine development had a quick head start, further development may be hampered because of the inability to conduct large efficacy trials with the decline in cases globally and unpredictability of new outbreaks. Furthermore, there are complex ethical issues involved in conducting efficacy trials in pregnant women.
Defining genetic risk for graft-versus-host disease and mortality following allogeneic hematopoietic stem cell transplantation

Purpose of reviewThis review explores what is known about the genetics of hematopoietic stem cell transplantation (HCT) and how genetic polymorphism affects risk of graft-versus-host disease (GVHD) and mortality. Recent findingsGenetic variation found across the human genome can impact HCT outcome by causing genetic disparity between patient and donor and modifying gene function. Single nucleotide polymorphism (SNP) and structural variation can result in mismatching for cellular peptides known as histocompatibility antigens. At least 25–30 polymorphic genes are known to encode functional histocompatibility antigens in mismatched individuals, but their individual contribution to clinical GVHD is unclear. HCT outcome may also be affected by polymorphism in donor or recipient. Association studies have implicated several genes associated with GVHD and mortality, however results have been inconsistent most likely due to limited sample size, and differences in racial diversity and clinical covariates. New technologies using DNA arrays genotyping for a million or more SNPs promise genome-wide discovery of HCT-associated genes, however adequate statistical power requires study populations of several thousand patient–donor pairs. SummaryAvailable data offers strong preliminary support for the impact that genetic variation has on risk of GVHD and mortality following HCT. Definitive results however await future genome-wide studies of large multicenter HCT cohorts.
Gender differences in lower limb frontal plane kinematics during landing

The aim of this study was to investigate gender differences in knee valgus angle and inter-knee and inter-ankle distances in university volleyball players when performing opposed block jump landings. Six female and six male university volleyball players performed three dynamic trials each for which they were instructed to jump up and block a volleyball suspended above a net set at the height of a standard volleyball net as it was spiked against them by an opposing player. Knee valgus/varus, inter-knee distance, and inter-ankle distance (absolute and relative to height) were determined during landing using three-dimensional motion analysis. Females displayed significantly greater maximum valgus angle and range of motion than males. This may increase the risk of ligament strain in females compared with males. Minimum absolute inter-knee distance was significantly smaller, and absolute and relative inter-knee displacement during landing significantly greater, in females than males. Both absolute and relative inter-ankle displacement during landing was significantly greater in males than females. These findings suggest that the gender difference in the valgus angle of the knee during two-footed landing is influenced by gender differences in the linear movement of the ankles as well as the knees. Coaches should therefore develop training programmes to focus on movement of both the knee and ankle joints in the frontal plane in order to reduce the knee valgus angle during landing, which in turn may reduce the risk of non-contact anterior cruciate ligament injury.
Array‐based comparative genomic hybridization in early‐stage mycosis fungoides: Recurrent deletion of tumor suppressor genes BCL7A, SMAC/DIABLO, and RHOF

The etiology of mycosis fungoides (MF), the most frequent form of cutaneous T cell lymphoma (CTCL), is poorly understood. No specific genetic aberration has been detected, especially in early‐stage disease, possibly due to the clinical and histological heterogeneity of patient series and to the different sources of malignant cells (skin, blood, or lymph node) included in most studies. Frozen skin biopsies from 16 patients with early‐stage MF were studied using array‐based comparative genomic hybridization. A DNA pool from healthy donors was used as the reference. Results demonstrated recurrent loss of 19, 7p22.1‐p22.3, 7q11.1‐q11.23, 9q34.12, 12q24.31, and 16q22.3‐q23.1, and gain of 8q22.3‐q23.1 and 21q22.12. The 12q24.31 region was recurrently deleted in 7/16 patients. Real‐time PCR investigation for deletion of genes BCL7A, SMAC/DIABLO, and RHOF—three tumor suppressor genes with a putative role in hematological malignancies—demonstrated that they were deleted in 9, 10, and 13 cases, respectively. The identified genomic alterations and individual genes could yield important insights into the early steps of MF pathogenesis. © 2008 Wiley‐Liss, Inc.
Application of functional principal component analysis in race walking: An emerging methodology

This study considered the problem of identifying and evaluating the factors of individual performance during race walking. In particular, the study explored the use of functional principal component analysis (f-PCA), a multivariate data analysis, for assessing and classifying the kinematics and kinetics of the knee joint in competitive race walkers. Seven race walkers of international and national level participated to the study. An optoelectronic system and a force platform were used to capture three-dimensional kinematics and kinetics of lower limbs during the race walking cycle. Functional principal component analysis was applied bilaterally to the sagittal knee angle and net moment data, because knee joint motion is fundamental to race walking technique. Scatterplots of principal component scores provided evidence of athletes' technical differences and asymmetries even when traditional analysis (mean ± s curves) was not effective. Principal components provided indications for race walkers' classification and identified potentially important technical differences between higher and lower skilled athletes. Therefore, f-PCA might represent a future aid for the fine analysis of sports movements, if consistently applied to performance monitoring.
Characterization of B‐ and T‐lineage acute lymphoblastic leukemia by integrated analysis of MicroRNA and mRNA expression profiles

Acute lymphoblastic leukemia (ALL) is an heterogeneous disease comprising several subentities that differ for both immunophenotypic and molecular characteristics. Over the years, the biological understanding of this neoplasm has largely increased. Gene expression profiling has allowed to identify specific signatures for the different ALL subsets and permitted the identification of pathways deregulated by a given lesion. MicroRNAs (miRNAs) are small noncoding RNAs, which play a pivotal role in several cellular functions. In this study, we investigated miRNAs expression profiles in a series of adult ALL cases by microarray analysis. Unsupervised hierarchical clustering largely recapitulated ALL subgroups. Furthermore, we identified miR‐148, miR‐151, and miR‐424 as discriminative of T‐lineage versus B‐lineage ALL; ANOVA highlighted a set of six miRNAs—namely miR‐425‐5p, miR‐191, miR‐146b, miR‐128, miR‐629, and miR‐126—that can discriminate B‐lineage ALL subgroups harboring specific molecular lesions. These results were confirmed and extended by quantitative‐PCR on a further cohort of cases. Finally, we used Pearson correlation analysis to combine miRNA and gene expression profiles. The distribution of correlation coefficients generated by comparing the expression of every miRNA/gene pair in our data set shows enrichment of both positively and negatively correlated pairs over background distributions obtained using randomized data. Moreover, a clear enrichment for predicted miRNA:target pairs is observed at negative correlation coefficient intervals. Signal‐to‐noise ratio highlighted several miRNA/gene pairs with a possible role in the disease. In fact, gene set enrichment analysis of genes composing the selected miRNA/gene pairs displays over‐representation of functional categories related to cancer and cell‐cycle regulation. © 2009 Wiley‐Liss, Inc.
Reliability of accelerometry to assess impact loads of jumping and landing tasks

Abstract Overuse injuries, resulting from repetitive subacute impact loading, are a problem in high-performance sports. Monitoring of impact loading may aid in the prevention of these injuries. The current study aimed to establish the intra-day and inter-day reliability of a tri-axial accelerometer to assess impact loading during jumping and landing tasks. Twelve participants wore an accelerometer on their upper and lower back. They performed a continuous hopping task as well as drop landings and rebound jumps from three drop heights (37.5, 57.5 and 77.5 cm), peak resultant acceleration (PRA) was calculated for all tasks. The tasks were performed twice, one week apart at the same time of day. The difference in the mean, intra-class correlation coefficient, coefficient of variation and Cohen’s effect size were calculated as measures of reliability. PRA showed good intra-day reliability for the hopping task. Inter-day reliability of the PRA was moderate to good across all tasks. Reliability of PRA was slightly higher when accelerations were recorded on the lower back compared to the upper back. To assess impact loading, during continuous hopping, drop landings and rebound jumps, PRA recorded at both the upper and lower back appears to be a reliable measure.