Doxorubicin plus lurbinectedin in patients with advanced endometrial cancer: Results from an expanded phase i study

Objective: Second-line treatment of endometrial cancer is an unmet medical need. We conducted a phase I study evaluating lurbinectedin and doxorubicin intravenously every 3 weeks in patients with solid tumors. The aim of this study was to characterise the efficacy and safety of lurbinectedin and doxorubicin for patients with endometrial cancer. Methods: Thirty-four patients were treated: 15 patients in the escalation phase (doxorubicin 50 mg/m2 and lurbinectedin 3.0-5.0 mg) and 19 patients in the expansion cohort (doxorubicin 40 mg/m2 and lurbinectedin 2.0 mg/m2). All histological subtypes were eligible and patients had received one to two prior lines of chemotherapy for advanced disease. Antitumor activity was evaluated every two cycles according to the Response Evaluation Criteria in Solid Tumors version 1.1. Adverse events were graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4. Results: Median age (range) was 65 (51-78) years. Eastern Cooperative Oncology Group performance status was up to 1 in 97% of patients. In the escalation phase, 4 (26.7%) of 15 patients had confirmed response: two complete and two partial responses (95% CI 7.8% to 55.1%). Median duration of response was 19.5 months. Median progression-free survival was 7.3 (2.5 to 10.1) months. In the expansion cohort, confirmed partial response was reported in 8 (42.1%) of 19 patients (95% CI 20.3% to 66.5%). Median duration of response was 7.5 (6.4 to not reached) months, median progression-free survival was 7.7 (2.0 to 16.7) months and median overall survival was 14.2 (4.5 to not reached) months. Fatigue (26.3% of patients), and transient and reversible myelosuppression (neutropenia, 78.9%; febrile neutropenia, 21.1%; thrombocytopenia, 15.8%) were the main grade 3 and higher toxicities in the expanded cohort. Conclusions: In patients with recurrent advanced endometrial cancer treated with doxorubicin and lurbinectedin, response rates (42%) and duration of response (7.5 months) were favorable. Further evaluation of doxorubicin and lurbinectedin is warranted in this patient population

Probing empirical contact networks by simulation of spreading dynamics

Disease, opinions, ideas, gossip, etc. all spread on social networks. How these networks are connected (the network structure) influences the dynamics of the spreading processes. By investigating these relationships one gains understanding both of the spreading itself and the structure and function of the contact network. In this chapter, we will summarize the recent literature using simulation of spreading processes on top of empirical contact data. We will mostly focus on disease simulations on temporal proximity networks -- networks recording who is close to whom, at what time -- but also cover other types of networks and spreading processes. We analyze 29 empirical networks to illustrate the methods

The effect of seasoning with herbs on the nutritional, safety and sensory properties of reduced-sodium fermented Cobrançosa cv. table olives

This study aimed at evaluating the effectiveness of seasoning Cobrancosa table olives in a brine with aromatic ingredients, in order to mask the bitter taste given by KCl when added to reduced-sodium fermentation brines. Olives were fermented in two different salt combinations: Brine A, containing 8% NaCl and, Brine B, a reduced-sodium brine, containing 4% NaCl + 4% KCl. After the fermentation the olives were immersed in seasoning brines with NaCl (2%) and the aromatic herbs (thyme, oregano and calamintha), garlic and lemon. At the end of the fermentation and two weeks after seasoning, the physicochemical, nutritional, organoleptic, and microbiological parameters, were determined. The olives fermented in the reduced-sodium brines had half the sodium concentration, higher potassium and calcium content, a lower caloric level, but were considered, by a sensorial panel, more bitter than olives fermented in NaCl brine. Seasoned table olives, previously fermented in Brine A and Brine B, had no significant differences in the amounts of protein (1.23% or 1.11%), carbohydrates (1.0% or 0.66%), fat (20.0% or 20.5%) and dietary fiber (3.4% or 3.6%). Regarding mineral contents, the sodium-reduced fermented olives, presented one third of sodium, seven times more potassium and three times more calcium than the traditional olives fermented in 8% NaCl. Additionally, according to the panelists' evaluation, seasoning the olives fermented in 4% NaCl + 4% KCl, resulted in a decrease in bitterness and an improvement in the overall evaluation and flavor. Escherichia coli and Salmonella were not found in the olives produced.info:eu-repo/semantics/publishedVersio

Genome-wide polyadenylation site mapping datasets in the rice blast fungus Magnaporthe oryzae

Polyadenylation plays an important role in gene regulation, thus affecting a wide variety of biological processes. In the rice blast fungus Magnaporthe oryzae the cleavage factor I protein Rpb35 is required for pre-mRNA polyadenylation and fungal virulence. Here we present the bioinformatic approach and output data related to a global survey of polyadenylation site usage in M. oryzae wild-type and Delta rbp35 strains under a variety of nutrient conditions, some of which simulate the conditions experienced by the fungus during part of its infection cycle

Literature-based discovery of diabetes- and ROS-related targets

Abstract Background Reactive oxygen species (ROS) are known mediators of cellular damage in multiple diseases including diabetic complications. Despite its importance, no comprehensive database is currently available for the genes associated with ROS. Methods We present ROS- and diabetes-related targets (genes/proteins) collected from the biomedical literature through a text mining technology. A web-based literature mining tool, SciMiner, was applied to 1,154 biomedical papers indexed with diabetes and ROS by PubMed to identify relevant targets. Over-represented targets in the ROS-diabetes literature were obtained through comparisons against randomly selected literature. The expression levels of nine genes, selected from the top ranked ROS-diabetes set, were measured in the dorsal root ganglia (DRG) of diabetic and non-diabetic DBA/2J mice in order to evaluate the biological relevance of literature-derived targets in the pathogenesis of diabetic neuropathy. Results SciMiner identified 1,026 ROS- and diabetes-related targets from the 1,154 biomedical papers (http://jdrf.neurology.med.umich.edu/ROSDiabetes/). Fifty-three targets were significantly over-represented in the ROS-diabetes literature compared to randomly selected literature. These over-represented targets included well-known members of the oxidative stress response including catalase, the NADPH oxidase family, and the superoxide dismutase family of proteins. Eight of the nine selected genes exhibited significant differential expression between diabetic and non-diabetic mice. For six genes, the direction of expression change in diabetes paralleled enhanced oxidative stress in the DRG. Conclusions Literature mining compiled ROS-diabetes related targets from the biomedical literature and led us to evaluate the biological relevance of selected targets in the pathogenesis of diabetic neuropathy.http://deepblue.lib.umich.edu/bitstream/2027.42/78315/1/1755-8794-3-49.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/2/1755-8794-3-49-S7.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/3/1755-8794-3-49-S10.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/4/1755-8794-3-49-S8.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/5/1755-8794-3-49-S3.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/6/1755-8794-3-49-S1.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/7/1755-8794-3-49-S4.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/8/1755-8794-3-49-S2.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/9/1755-8794-3-49-S12.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/10/1755-8794-3-49-S11.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/11/1755-8794-3-49-S9.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/12/1755-8794-3-49-S5.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/13/1755-8794-3-49-S6.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/14/1755-8794-3-49.pdfPeer Reviewe

Evaluation of rK39 rapid diagnostic tests for canine visceral leishmaniasis : longitudinal study and meta-analysis

Canine visceral leishmaniasis is a vector-borne disease caused by the intracellular parasite Leishmania infantum. It is an important veterinary disease, and dogs are also the main animal reservoir for human infection. The disease is widespread in the Mediterranean area, and parts of Asia and South and Central America, and is potentially fatal in both dogs and humans unless treated. Diagnosis of canine infections requires serological or molecular tests. Detection of infection in dogs is important prior to treatment, and in epidemiological studies and control programmes, and a sensitive and specific rapid diagnostic test would be very useful. Rapid diagnostic tests (RDTs) have been developed, but their diagnostic performance has been reported to be variable. We evaluated the sensitivity of a RDT based on serological detection of the rK39 antigen in a cohort of naturally infected Brazilian dogs. The sensitivity of the test to detect infection was relatively low, but increased with time since infection and the severity of infection. We then carried out a meta-analysis of published studies of rK39 RDTs, evaluating the sensitivity to detect disease and infection. The results suggest that rK39 RDTs may be useful in a veterinary clinical setting, but the sensitivity to detect infection is too low for operational control programmes

MultiMetEval: comparative and multi-objective analysis of genome-scale metabolic models

Comparative metabolic modelling is emerging as a novel field, supported by the development of reliable and standardized approaches for constructing genome-scale metabolic models in high throughput. New software solutions are needed to allow efficient comparative analysis of multiple models in the context of multiple cellular objectives. Here, we present the user-friendly software framework Multi-Metabolic Evaluator (MultiMetEval), built upon SurreyFBA, which allows the user to compose collections of metabolic models that together can be subjected to flux balance analysis. Additionally, MultiMetEval implements functionalities for multi-objective analysis by calculating the Pareto front between two cellular objectives. Using a previously generated dataset of 38 actinobacterial genome-scale metabolic models, we show how these approaches can lead to exciting novel insights. Firstly, after incorporating several pathways for the biosynthesis of natural products into each of these models, comparative flux balance analysis predicted that species like Streptomyces that harbour the highest diversity of secondary metabolite biosynthetic gene clusters in their genomes do not necessarily have the metabolic network topology most suitable for compound overproduction. Secondly, multi-objective analysis of biomass production and natural product biosynthesis in these actinobacteria shows that the well-studied occurrence of discrete metabolic switches during the change of cellular objectives is inherent to their metabolic network architecture. Comparative and multi-objective modelling can lead to insights that could not be obtained by normal flux balance analyses. MultiMetEval provides a powerful platform that makes these analyses straightforward for biologists. Sources and binaries of MultiMetEval are freely available from https://github.com/PiotrZakrzewski/MetEv​al/downloads

Gene silencing in tick cell lines using small interfering or long double-stranded RNA

Gene silencing by RNA interference (RNAi) is an important research tool in many areas of biology. To effectively harness the power of this technique in order to explore tick functional genomics and tick-microorganism interactions, optimised parameters for RNAi-mediated gene silencing in tick cells need to be established. Ten cell lines from four economically important ixodid tick genera (Amblyomma, Hyalomma, Ixodes and Rhipicephalus including the sub-species Boophilus) were used to examine key parameters including small interfering RNA (siRNA), double stranded RNA (dsRNA), transfection reagent and incubation time for silencing virus reporter and endogenous tick genes. Transfection reagents were essential for the uptake of siRNA whereas long dsRNA alone was taken up by most tick cell lines. Significant virus reporter protein knockdown was achieved using either siRNA or dsRNA in all the cell lines tested. Optimum conditions varied according to the cell line. Consistency between replicates and duration of incubation with dsRNA were addressed for two Ixodes scapularis cell lines; IDE8 supported more consistent and effective silencing of the endogenous gene subolesin than ISE6, and highly significant knockdown of the endogenous gene 2I1F6 in IDE8 cells was achieved within 48 h incubation with dsRNA. In summary, this study shows that gene silencing by RNAi in tick cell lines is generally more efficient with dsRNA than with siRNA but results vary between cell lines and optimal parameters need to be determined for each experimental system

Transplantation of canine olfactory ensheathing cells producing chondroitinase ABC promotes chondroitin sulphate proteoglycan digestion and axonal sprouting following spinal cord injury

Olfactory ensheathing cell (OEC) transplantation is a promising strategy for treating spinal cord injury (SCI), as has been demonstrated in experimental SCI models and naturally occurring SCI in dogs. However, the presence of chondroitin sulphate proteoglycans within the extracellular matrix of the glial scar can inhibit efficient axonal repair and limit the therapeutic potential of OECs. Here we have used lentiviral vectors to genetically modify canine OECs to continuously deliver mammalian chondroitinase ABC at the lesion site in order to degrade the inhibitory chondroitin sulphate proteoglycans in a rodent model of spinal cord injury. We demonstrate that these chondroitinase producing canine OECs survived at 4 weeks following transplantation into the spinal cord lesion and effectively digested chondroitin sulphate proteoglycans at the site of injury. There was evidence of sprouting within the corticospinal tract rostral to the lesion and an increase in the number of corticospinal axons caudal to the lesion, suggestive of axonal regeneration. Our results indicate that delivery of the chondroitinase enzyme can be achieved with the genetically modified OECs to increase axon growth following SCI. The combination of these two promising approaches is a potential strategy for promoting neural regeneration following SCI in veterinary practice and human patients

No association between the common calcium-sensing receptor polymorphism rs1801725 and irritable bowel syndrome

Background The calcium-sensing receptor (CaSR) is a calcium (Ca2+) sensitive G protein-coupled receptor implicated in various biological processes. In particular, it regulates Ca2+/Mg2+- homeostasis and senses interstitial Ca2+ levels and thereby controls downstream signalling cascades. Due to its expression in the gut epithelium, the enteric nervous system and smooth muscles and its key function in regulation and coordination of muscular contraction and secretion, it represents an excellent candidate gene to be investigated in the pathophysiology of irritable bowel syndrome (IBS). Disturbed CaSR structure and function may impact gastrointestinal regulation of muscular contraction, neuronal excitation and secretion and consequently contribute to symptoms seen in IBS, such as disordered defecation as well as disturbed gut motility and visceral sensitivity. Methods We have therefore genotyped the functional CASR SNP rs1801725 in three case control samples from the UK, Belgium and the USA. Results Genotype frequencies showed no association in the three genotyped case–control samples, neither with IBS nor with IBS subtypes. Conclusions Although we could not associate the SNP to any of the established bowel symptom based IBS subtypes we cannot rule out association to altered Ca2+ levels and disturbed secretion and gut motility which were unfortunately not assessed in the patients genotyped. This underlines the necessity of a more detailed phenotyping of IBS patients and control individuals in future studies