Trifluridine/tipiracil in combination with oxaliplatin and either bevacizumab or nivolumab in metastatic colorectal cancer: a dose-expansion, phase I study

Càncer colorectal metastàtic; Oxaliplatina; Trifluridina/TipiracilCáncer colorrectal metastásico; Oxaliplatino; Trifluridina/TipiracilMetastatic colorectal cancer; Oxaliplatin; Trifluridine/tipiracilBackground In preclinical studies trifluridine/tipiracil (FTD/TPI) plus oxaliplatin (Industriestrasse, Holzkirchen, Germany) sensitised microsatellite stable (MSS) metastatic colorectal cancer (mCRC) to anti-programmed cell death protein-1; the addition of oxaliplatin or bevacizumab (F Hoffmann- la ROCHE AG, Kaiseraugst, Switzerland) enhanced the antitumour effects of FTD/TPI. This study aimed to investigate the safety and efficacy of FTD/TPI plus oxaliplatin and either bevacizumab or nivolumab (Uxbridge business Park, Uxbridge, United Kingdom) in patients with mCRC who had progressed after at least one prior line of treatment. Patients and methods In 14-day cycles, patients received FTD/TPI 35 mg/m2 (twice daily, days 1-5) plus oxaliplatin 85 mg/m2 (day 1), and, on day 1, either bevacizumab 5 mg/kg (cohort A) or nivolumab 3 mg/kg (cohort B). Patients in Cohort B had confirmed MSS status. Results In total, 54 patients were enrolled: 37 in cohort A and 17 in cohort B. Recruitment in cohort B was stopped early due to the low response rate (RR) observed at interim analyses of efficacy. The most common adverse events (AEs) in cohort A were neutropenia/decreased neutrophils (75.7%), nausea (59.5%), vomiting (40.5%), diarrhoea (37.8%), peripheral sensory neuropathy (37.8%), fatigue (35.1%) and decreased appetite (35.1%). In cohort B, the most common AEs were neutropenia/decreased neutrophils (70.6%), diarrhoea (58.8%), nausea (47.1%), vomiting (47.1%), fatigue (47.1%), asthenia (41.2%), paraesthesia (41.2%), thrombocytopenia/decreased platelets (35.3%) and decreased appetite (35.3%). Confirmed objective RR was 17.1% in cohort A and 7.1% in cohort B; the corresponding values for median progression-free survival in the two cohorts were 6.3 and 6.0 months. Conclusion FTD/TPI plus oxaliplatin and bevacizumab or nivolumab had an acceptable safety profile and demonstrated antitumour activity in previously treated patients with mCRC.The study was funded jointly by Servier, France and Taiho Pharmaceutical, Japan

Regulation of human renal adenocarcinoma cell growth by retinoic acid and its interactions with epidermal growth factor

Regulation of human renal adenocarcinoma cell growth by retinoic acid and its interactions with epidermal growth factor. Retinoic acid (RA) is a natural derivative of vitamin A which regulates the growth and differentiation of epithelia. We have previously proposed that RA participates in compensatory kidney growth and reported that RA inhibits rat mesangial cell growth. This paper describes the effects of RA on a human renal adenocarcinoma cell line (PAD) under different growth conditions, and its interactions with epidermal growth factor (EGF). PAD cells were shown to express RA receptors α and β by Northern blot analysis. In serum free cultures, addition of RA (10-7 M) markedly increased thymidine incorporation by PAD cells (155 ± 7% mean ± se vs. control in 6 separate experiments; P < 0.0001). RA also caused a significant increase in thymidine incorporation by PAD cells under conditions of rapid growth in serum supplemented medium (115 ± 2% vs. control; P < 0.001). RA by itself was unable to reverse contact inhibition of PAD cell growth (NS vs. control), but it synergistically enhanced the mitogenic effect of EGF on confluent monolayers (110 ± 0.6% vs. EGF alone; P < 0.05). Northern blot analysis demonstrated that PAD cells express EGF receptor mRNA, and this was not significantly modified by the addition of RA. Growth arrested (serum starved) PAD cells expressed RAR-α mRNA which was up-regulated eightfold at three hours following the addition of 10% FCS. Thus, our data show that RA is directly mitogenic for serum starved human renal adenocarcinoma cells and that it exerts complex modulation of cell growth in the presence of EGF and serum components

Tourism Firms’ Vulnerability to Risk: The Role of Organizational Slack in Performance and Failure

This study explores the influence of political risk on firms in the tourism industry. It addresses a research gap regarding the impact of political risk on firm-level performance and failure and uncovers the role of organizational slack in this relationship. Firm-level political risk is estimated from 2002 to 2019 financial data for firms across six tourism sectors in a developed economy, the United States. Such risk is found to be significantly associated with firm performance and business failure. From the perspectives of the resource-based view and the threat-rigidity hypothesis, the results support the moderating effects of absorbed and unabsorbed slack on links between risk, performance, and business failure. Given that the COVID-19 pandemic has highlighted the tourism industry’s vulnerability, this study will be of interest to tourism firms seeking to improve business sustainability and resilience

Nuclear magnetic resonance in conjunction with functional genomics suggests mitochondrial dysfunction in a murine model of cancer cachexia

Cancer patients commonly suffer from cachexia, a syndrome in which tumors induce metabolic changes in the host that lead to massive loss in skeletal muscle mass. Using a preclinical mouse model of cancer cachexia, we tested the hypothesis that tumor inoculation causes a reduction in ATP synthesis and genome-wide aberrant expression in skeletal muscle. Mice implanted with Lewis lung carcinomas were examined by in vivo 31P nuclear magnetic resonance (NMR). We examined ATP synthesis rate and the expression of genes that play key-regulatory roles in skeletal muscle metabolism. Our in vivo NMR results showed reduced ATP synthesis rate in tumor-bearing (TB) mice relative to control (C) mice, and were cross-validated with whole genome transcriptome data showing atypical expression levels of skeletal muscle regulatory genes such as peroxisomal proliferator activator receptor γ coactivator 1 ß (PGC-1ß), a major regulator of mitochondrial biogenesis and, mitochondrial uncoupling protein 3 (UCP3). Aberrant pattern of gene expression was also associated with genes involved in inflammation and immune response, protein and lipid catabolism, mitochondrial biogenesis and uncoupling, and inadequate oxidative stress defenses, and these effects led to cachexia. Our findings suggest that reduced ATP synthesis is linked to mitochondrial dysfunction, ultimately leading to skeletal muscle wasting and thus advance our understanding of skeletal muscle dysfunction suffered by cancer patients. This study represents a new line of research that can support the development of novel therapeutics in the molecular medicine of skeletal muscle wasting. Such therapeutics would have wide-spread applications not only for cancer patients, but also for many individuals suffering from other chronic or endstage diseases that exhibit muscle wasting, a condition for which only marginally effective treatments are currently available

Brexit, trade and UK advanced manufacturing sectors: a Midlands’ perspective

The paper examines how Brexit has impacted on Original Equipment Manufacturers (OEMs) and suppliers in the UK Midlands, and to what extent such firms are reconfiguring their supply chains with the increase in trade barriers with Brexit. To do this, the paper aims to add to macro studies in the area by using a mixed-methods approach that combines descriptive quantitative analysis of secondary data with a complementary qualitative research analysis based on a novel interview dataset. The latter is generated from 14 semi-structured interviews conducted in late 2021 with senior managers and directors in advanced manufacturing firms across the East and West Midlands regions of the UK. A key finding of this paper is that the imposition of new non-tariff barriers through Brexit has proved particularly challenging to smaller firms in manufacturing supply chains. The findings of our research highlight the need for policy support for smaller firms engaging in EU-wide supply chains, particularly around skillsets and access to talent, cost reduction for exports and facilitating trade

Nuclear magnetic resonance in conjunction with functional genomics suggests mitochondrial dysfunction in a murine model of cancer cachexia

Cancer patients commonly suffer from cachexia, a syndrome in which tumors induce metabolic changes in the host that lead to massive loss in skeletal muscle mass. Using a preclinical mouse model of cancer cachexia, we tested the hypothesis that tumor inoculation causes a reduction in ATP synthesis and genome-wide aberrant expression in skeletal muscle. Mice implanted with Lewis lung carcinomas were examined by in vivo 31P nuclear magnetic resonance (NMR). We examined ATP synthesis rate and the expression of genes that play key-regulatory roles in skeletal muscle metabolism. Our in vivo NMR results showed reduced ATP synthesis rate in tumor-bearing (TB) mice relative to control (C) mice, and were cross-validated with whole genome transcriptome data showing atypical expression levels of skeletal muscle regulatory genes such as peroxisomal proliferator activator receptor γ coactivator 1 ß (PGC-1ß), a major regulator of mitochondrial biogenesis and, mitochondrial uncoupling protein 3 (UCP3). Aberrant pattern of gene expression was also associated with genes involved in inflammation and immune response, protein and lipid catabolism, mitochondrial biogenesis and uncoupling, and inadequate oxidative stress defenses, and these effects led to cachexia. Our findings suggest that reduced ATP synthesis is linked to mitochondrial dysfunction, ultimately leading to skeletal muscle wasting and thus advance our understanding of skeletal muscle dysfunction suffered by cancer patients. This study represents a new line of research that can support the development of novel therapeutics in the molecular medicine of skeletal muscle wasting. Such therapeutics would have wide-spread applications not only for cancer patients, but also for many individuals suffering from other chronic or endstage diseases that exhibit muscle wasting, a condition for which only marginally effective treatments are currently available

The early experience of smart specialization implementation in EU cohesion policy

This paper discusses the early-stage experience of the smart specialization agenda within EU Cohesion Policy. The analysis examines the types of policy prioritization choices made by different member states and regions and seeks evidence on the extent to which weaker regions, in particular, might be constrained in their choices. The paper then reviews the evidence arising out of various surveys of policy-makers’ own experience and perceptions of the agenda, and concludes with a discussion of the major features of the policy progress so far and the main challenges ahead

Bricks in the eclectic modernist architecture of the City of Zamora (Spain): an analysis of the types, building tools used and the construction of the walls

El presente trabajo lleva a cabo una investigación sobre los tipos de ladrillos empleados en las fachadas de los inmuebles de la época decimonónica de la capital zamorana. Este estudio engloba no sólo los ladrillos sino la relación de los mismos con los usos de los inmuebles. El análisis desarrollado es fundamentalmente técnico, centrándose tanto en los aspectos materiales y morfológicos de las piezas como en la relación existente entre los mismos y los diferentes sistemas constructivos empleados en la ejecución de sus muros. La existencia de múltiple y variada documentación original, combinada con la información recabada in situ sobre los inmuebles que se conservan en la ciudad, ha permitido realizar un estudio exhaustivo y detallado, que se destaca como el objetivo primordial, pues permitirá desarrollar de cara a las futuras actuaciones de conservación, intervenciones para preservar y actuar sobre los elementos de interés.The present work studies the types of bricks used on the façades of the 19th century buildings of the City of Zamora. The study covers not only the bricks themselves but also their relationship with the use the buildings were put to. The analysis is essentially technical, focusing on both the material and morphological aspects of the bricks and the relationship between them and the different construction systems used to build the walls. The existence of abundant and varied original literature, together with information collected “in situ” about the buildings preserved in the City, has allowed an exhaustive study that stands out as an initial aim since it will offer a way to guide future actions of conservation and interventions aimed at preserving the elements of interest

A False Start in the Race Against Doping in Sport: Concerns With Cycling’s Biological Passport

Professional cycling has suffered from a number of doping scandals. The sport’s governing bodies have responded by implementing an aggressive new antidoping program known as the biological passport. Cycling’s biological passport marks a departure from traditional antidoping efforts, which have focused on directly detecting prohibited substances in a cyclist’s system. Instead, the biological passport tracks biological variables in a cyclist’s blood and urine over time, monitoring for fluctuations that are thought to indirectly reveal the effects of doping. Although this method of indirect detection is promising, it also raises serious legal and scientific concerns. Since its introduction, the cycling community has debated the reliability of indirect biological-passport evidence and the clarity, consistency, and transparency of its use in proving doping violations. Such uncertainty undermines the legitimacy of finding cyclists guilty of doping based on this indirect evidence alone. Antidoping authorities should address these important concerns before continuing to pursue doping sanctions against cyclists solely on the basis of their biological passports