A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301)

\ua9 The Author(s) 2024.Purpose: 5-fluorouracil (5-FU) is inefficiently converted to the active anti-cancer metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), is associated with dose-limiting toxicities and challenging administration schedules. NUC-3373 is a phosphoramidate nucleotide analog of fluorodeoxyuridine (FUDR) designed to overcome these limitations and replace fluoropyrimidines such as 5-FU. Patients and methods: NUC-3373 was administered as monotherapy to patients with advanced solid tumors refractory to standard therapy via intravenous infusion either on Days 1, 8, 15 and 22 (Part 1) or on Days 1 and 15 (Part 2) of 28-day cycles until disease progression or unacceptable toxicity. Primary objectives were maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) and schedule of NUC-3373. Secondary objectives included pharmacokinetics (PK), and anti-tumor activity. Results: Fifty-nine patients received weekly NUC-3373 in 9 cohorts in Part 1 (n = 43) and 3 alternate-weekly dosing cohorts in Part 2 (n = 16). They had received a median of 3 prior lines of treatment (range: 0–11) and 74% were exposed to prior fluoropyrimidines. Four experienced dose-limiting toxicities: two Grade (G) 3 transaminitis; one G2 headache; and one G3 transient hypotension. Commonest treatment-related G3 adverse event of raised transaminases occurred in < 10% of patients. NUC-3373 showed a favorable PK profile, with dose-proportionality and a prolonged half-life compared to 5-FU. A best overall response of stable disease was observed, with prolonged progression-free survival. Conclusion: NUC-3373 was well-tolerated in a heavily pre-treated solid tumor patient population, including those who had relapsed on prior 5-FU. The MTD and RP2D was defined as 2500 mg/m2 NUC-3373 weekly. NUC-3373 is currently in combination treatment studies. Trial registration: Clinicaltrials.gov registry number NCT02723240. Trial registered on 8th December 2015. https://clinicaltrials.gov/study/NCT02723240

Symptomatic snapping knee from biceps femoris tendon subluxation: an unusual case of lateral pain in a marathon runner

Snapping biceps femoris syndrome is an uncommon cause of lateral knee pain and may be difficult to diagnose, resulting in unsuccessful surgical intervention. In this report, we present an unusual case of a 37-year-old male marathon runner with unilateral snapping knee secondary to dislocation of the long head of the biceps femoris over the fibular head during knee flexion. The pain was great enough to interfere with his ability to practice sport. Possible causes of symptomatic snapping knee include multiple intra-articular or extra-articular pathology. Biceps femoris snapping over the fibular head is a rare condition. Reported causes include an anomalous insertion of the tendon into the tibia, trauma, and fibular-head abnormality. However, none of those conditions accounted for his symptoms. Failing conservative treatment, the patient underwent surgery for partial resection of the fibular head, with subsequent sudden resolution of symptoms and return to sport. Accurate knowledge and management of this rare condition is mandatory to avoid inappropriate therapy and unnecessary surgical procedures

Effective Dark Matter Model: Relic density, CDMS II, Fermi LAT and LHC

The Cryogenic Dark Matter Search recently announced the observation of two signal events with a 77% confidence level. Although statistically inconclusive, it is nevertheless suggestive. In this work we present a model-independent analysis on the implication of a positive signal in dark matter scattering off nuclei. Assuming the interaction between (scalar, fermion or vector) dark matter and the standard model induced by unknown new physics at the scale $\Lambda$, we examine various dimension-6 tree-level induced operators and constrain them using the current experimental data, e.g. the WMAP data of the relic abundance, CDMS II direct detection of the spin-independent scattering, and indirect detection data (Fermi LAT cosmic gamma-ray), etc. Finally, the LHC reach is also explored

Public Opinion on Migration and the Role of the Media in the Context of the “European Refugee Crisis”

This book presents an overview of European migration policy and the various institutional arrangements within and between various actors, such as local councils, local media, local economies, and local civil society initiatives. Both the role of local authorities in this policy field and their cooperation with civil society initiatives or networks are under-explored topics for research. In response, this book provides a range of detailed case studies focusing on the six main groups of national and administrative traditions in Europe: Germanic, Scandinavian, Napoleonic, Southeastern European, Central-Eastern European and Anglo-Saxon.Peer reviewe

Nut production in Bertholletia excelsa across a logged forest mosaic: implications for multiple forest use

Although many examples of multiple-use forest management may be found in tropical smallholder systems, few studies provide empirical support for the integration of selective timber harvesting with non-timber forest product (NTFP) extraction. Brazil nut (Bertholletia excelsa, Lecythidaceae) is one of the world’s most economically-important NTFP species extracted almost entirely from natural forests across the Amazon Basin. An obligate out-crosser, Brazil nut flowers are pollinated by large-bodied bees, a process resulting in a hard round fruit that takes up to 14 months to mature. As many smallholders turn to the financial security provided by timber, Brazil nut fruits are increasingly being harvested in logged forests. We tested the influence of tree and stand-level covariates (distance to nearest cut stump and local logging intensity) on total nut production at the individual tree level in five recently logged Brazil nut concessions covering about 4000 ha of forest in Madre de Dios, Peru. Our field team accompanied Brazil nut harvesters during the traditional harvest period (January-April 2012 and January-April 2013) in order to collect data on fruit production. Three hundred and ninety-nine (approximately 80%) of the 499 trees included in this study were at least 100 m from the nearest cut stump, suggesting that concessionaires avoid logging near adult Brazil nut trees. Yet even for those trees on the edge of logging gaps, distance to nearest cut stump and local logging intensity did not have a statistically significant influence on Brazil nut production at the applied logging intensities (typically 1–2 timber trees removed per ha). In one concession where at least 4 trees ha-1 were removed, however, the logging intensity covariate resulted in a marginally significant (0.09) P value, highlighting a potential risk for a drop in nut production at higher intensities. While we do not suggest that logging activities should be completely avoided in Brazil nut rich forests, when a buffer zone cannot be observed, low logging intensities should be implemented. The sustainability of this integrated management system will ultimately depend on a complex series of socioeconomic and ecological interactions. Yet we submit that our study provides an important initial step in understanding the compatibility of timber harvesting with a high value NTFP, potentially allowing for diversification of forest use strategies in Amazonian Perù

Phylodynamic assessment of intervention strategies for the West African Ebola virus outbreak

Genetic analyses have provided important insights into Ebola virus spread during the recent West African outbreak, but their implications for specific intervention scenarios remain unclear. Here, we address this issue using a collection of phylodynamic approaches. We show that long-distance dispersal events were not crucial for epidemic expansion and that preventing viral lineage movement to any given administrative area would, in most cases, have had little impact. However, major urban areas were critical in attracting and disseminating the virus: preventing viral lineage movement to all three capitals simultaneously would have contained epidemic size to one-third. We also show that announcements of border closures were followed by a significant but transient effect on international virus dispersal. By quantifying the hypothetical impact of different intervention strategies, as well as the impact of barriers on dispersal frequency, our study illustrates how phylodynamic analyses can help to address specific epidemiological and outbreak control questions.info:eu-repo/semantics/publishe

Interferon lambda 4 impacts the genetic diversity of hepatitis C virus

Hepatitis C virus (HCV) is a highly variable pathogen that frequently establishes chronic infection. This genetic variability is affected by the adaptive immune response but the contribution of other host factors is unclear. Here, we examined the role played by interferon lambda-4 (IFN-λ4) on HCV diversity; IFN-λ4 plays a crucial role in spontaneous clearance or establishment of chronicity following acute infection. We performed viral genome-wide association studies using human and viral data from 485 patients of white ancestry infected with HCV genotype 3a. We demonstrate that combinations of host genetic variants, which determine IFN-λ4 protein production and activity, influence amino acid variation across the viral polyprotein - not restricted to specific viral proteins or HLA restricted epitopes - and modulate viral load. We also observed an association with viral di-nucleotide proportions. These results support a direct role for IFN-λ4 in exerting selective pressure across the viral genome, possibly by a novel mechanism

Neuromuscular training to enhance sensorimotor and functional deficits in subjects with chronic ankle instability: A systematic review and best evidence synthesis

<p>Abstract</p> <p>Objective</p> <p>To summarise the available evidence for the efficacy of neuromuscular training in enhancing sensorimotor and functional deficits in subjects with chronic ankle instability (CAI).</p> <p>Design</p> <p>Systematic review with best evidence synthesis.</p> <p>Data Sources</p> <p>An electronic search was conducted through December 2009, limited to studies published in the English language, using the Pubmed, CINAHL, Embase, and SPORTDiscus databases. Reference screening of all included articles was also undertaken.</p> <p>Methods</p> <p>Studies were selected if the design was a RCT, quasi RCT, or a CCT; the patients were adolescents or adults with confirmed CAI; and one of the treatment options consisted of a neuromuscular training programme. The primary investigator independently assessed the risk of study bias and extracted relevant data. Due to clinical heterogeneity, data was analysed using a best-evidence synthesis.</p> <p>Results</p> <p>Fourteen studies were included in the review. Meta-analysis with statistical pooling of data was not possible, as the studies were considered too heterogeneous. Instead a best evidence synthesis was undertaken. There is limited to moderate evidence to support improvements in dynamic postural stability, and patient perceived functional stability through neuromuscular training in subjects with CAI. There is limited evidence of effectiveness for neuromuscular training for improving static postural stability, active and passive joint position sense (JPS), isometric strength, muscle onset latencies, shank/rearfoot coupling, and a reduction in injury recurrence rates. There is limited evidence of no effectiveness for improvements in muscle fatigue following neuromuscular intervention.</p> <p>Conclusion</p> <p>There is limited to moderate evidence of effectiveness in favour of neuromuscular training for various measures of static and dynamic postural stability, active and passive JPS, isometric strength, muscle onset latencies, shank/rearfoot coupling and injury recurrence rates. Strong evidence of effectiveness was lacking for all outcome measures. All but one of the studies included in the review were deemed to have a high risk of bias, and most studies were lacking sufficient power. Therefore, in future we recommend conducting higher quality RCTs using appropriate outcomes to assess for the effectiveness of neuromuscular training in overcoming sensorimotor deficits in subjects with CAI.</p