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Background: Accelerated muscle and adipose tissue loss are two of the main aspects of cancer cachexia. β2-agonists seem to be successful in the treatment of cachexia in experimental animals. The aim if the present investigation was to study the effects on body weight loss in tumor-bearing animals of a combination of formoterol and AR-42, an inhibitor of histone deacetylase (HDAC). Methods: Rats were divided into two groups, namely controls (C) and tumor-bearing (T). TB group was further divided into four subgroups: untreated (saline as a vehicle), treated with Formoterol (F) (0,3 mg/kg body weight in saline, subcutaneous (s.c.), daily), treated with AR-42 (A) (20 mg/kg body weight in olive oil, intragastric (i.g.), only the last 4 days). and double-treated treated (TFA) with Formoterol (0,3 mg/kg body weight, subcutaneous (s.c.), daily) and AR-42 (20 mg/kg body weight in olive oil, intragastric (i.g.), only the last 4 days). 7 days after tumor transplantation, muscle weights, grip force and total physical activity were determined in all experimental groups. Results: The presence of the Yoshida AH-130 ascites hepatoma induced severe muscle wasting in rats. Treatment of the tumor-bearing animals with the beta2-agonist formoterol (0,3 mg/kg), resulted in a significant improvement in the cachectic state of the animals. Treatment of the tumor-bearing animals with AR42 did not result in any effects on muscle wasting in the cachectic rats. Furthermore, the combination of formoterol and AR42 showed no additional effects to those observed with just formoterol. Conclusion: The results presented question the previously described effects of AR42 on cancer cachexia, probably due to its effect on tumor growth.

This article performs empirical research and finds a negative relationship between accidents in the workplace and financial performance. The relationship is stronger and more persistent for performance 1 year ahead than for the current year. We find no significant evidence of curvilinear U-shaped or inverted U-shaped relationships. Results are strong across different industries and samples, variable definitions and model specifications. The study contributes to the scarce extant research with reliable data and samples of a wide span of industries. The study also contributes methodologically with refined analyses of the curvilinear relationship and providing robust widespread inference for a large number of industries.

After the approval of a code of ethics, the creation of a permanent board‐level ethics committee is the next step in the institutionalization of business ethics. This study explores how the board's structure and demographic characteristics explain the decision to form an ethics committee. The analysis is based on the constituents of the Standard and Poor's Europe 350 index. Consistent with our hypotheses, we find that ethics committees are more likely to be found in firms with a lower presence of executive directors and of directors holding MBA degrees. However, we also observe that boards chaired by executive directors seem to favor the creation of an ethics committee. Additionally, as we had anticipated, firms with stronger agency conflicts seem to be more willing to create committees. The analysis conducted with segmented samples reveals that the model has greater explanatory power when applied to firms from common‐law and French civil‐law countries than when applied to firms from the German–Scandinavian civil‐law area. Finally, our results indicate that a firm's country of origin is a more influential factor in explaining the decision to create an ethics committee than the industry to which it belongs or even the magnitude of its agency conflicts.

We conduct empirical research on the flexibility of operating costs of e-commerce firms. With an international sample of firms from different European countries, we find that e-commerce firms have a different cost structure than traditional retail firms, with a lower share of labor costs and cost of goods sold, but a higher share of other operating costs. While we find no significant different behavior in cost of goods sold and labor costs between the two types of firms, e-commerce firms are more flexible in adjusting other operating costs than traditional retail firms when activity decreases. Results are robust to different models, estimations methods and samples. The higher flexibility of e-commerce firms relies on other operating costs, but e-commerce creates qualified jobs with higher wages than traditional retail, with no additional exposure to labor uncertainty for employees.

We investigate the effects of an exogenous demand shock arising from the award of public service contracts by Italian public administrations in 2015 on a sample of 1782 winning small and medium firms that were not awarded any contract during the previous 3 years. Using a difference-in-differences model with continuous treatments estimated on a propensity score matched sample, our results reveal that higher awarded values enhance various performance dimensions of the winning firms as well as their average payroll per employee. Nonetheless, higher winning rebates moderate the positive effects of the award on payroll by inducing the winning firms to downward manage both salaries and social security contributions per employee to maintain their desired level of performance. The effects are mostly significant for smaller microenterprises. In addition, winning rebates negatively affect the performance of firms in the construction industry by leading these firms to downward manage the payroll of their employees more aggressively than firms in other industries. Our findings provide novel insights for the implementation of industrial policies aimed at achieving sustainable macroeconomic and social goals, within the business fabric, through the effective management of public service procurement.

Purpose: The CASC-IN score has been designed with two very clear objectives: first, as a means to quantitatively assess pre-cachexia in cancer patients, and second, as a tool to discriminate the patients where cachexia staging is relevant. From this point of view, the CASC-IN tool is tightly linked with the so-called CAchexia SCOre (CASCO) previously described1 and validated2 by our research team. The results presented here classify a population of cancer patients into non-cachectic, precachectic or cachectic. Patients and Methods: An observational prospective case-control study has been performed and a total of 179 carcinoma patients and 117 age-matched control subjects were included. All the participants in the study were recruited at the Department of Medical Oncology (University of Cagliari, Cagliari, Italy) from June 2011 to September 2014. 179. Results: Using the mentioned patient's groups in the cancer group, --patients affected by a different tumour types-- the frequencies observed have been non-cachectic: 58 (32.4%), pre-cachectic: 7 (3.9%) and cachectic: 114 (63.7%). Conclusion: It is concluded that CASC-IN can be satisfactorily used for both assessing cachectic and precachectic cancer patients. It constitutes the only available tool for the classification of pre-cachectic patients.

We investigate whether the geographic concentration of non-EU immigrants in the various Italian provinces affects labour tax avoidance (LTAV) practices adopted by firms located in the same provinces, as well as in the neighbouring provinces, and operating in construction and agriculture industries that mostly employ immigrants in Italy. For this purpose, we develop a LTAV proxy based on the financial accounting information of a sample of 993,606 firm-years, disseminated throughout the 108 Italian provinces, over the period 2008-2016. Our results, based on a Spatial Durbin Model panel regression, reveal a statistically significant positive association between the concentration of non-EU immigrants and LTAV at province level, as well as the presence of spillover effects among neighbouring provinces. Our findings are robust to several additional analyses, including instrumental variable estimations. Our study provides empirical support to previous structuralist or marginalization theories holding that socioeconomically marginalized groups, such as non-EU immigrants, are more likely to be involved in labour exploitation practices, which could underlie our LTAV outcomes. Furthermore, it supports the need for tax authorities to strengthen labour inspections, coordinated at national level, especially in those contexts where non-EU immigrants are mostly employed. On the other hand, a greater social integration, assistance, and recognition of rights of immigrants may help to alleviate their situation of weakness that makes them more vulnerable to LTAV practices. Finally, tackling LTAV, associated with the underemployment of immigrants, may prevent its negative effects for society arising from the reduction of public resources to sustain the social welfare and finance public goods and services.

Alterations in amino acid and protein metabolism particularly in skeletal muscle are a key feature of cancer that contributes to the cachexia syndrome. Thus, skeletal muscle protein turnover is characterized by an exacerbated rate of protein degradation, promoted by an activation of different proteolytic systems that include the ubiquitin-proteasome and the autophagic-lysosomal pathways. These changes are promoted by both hormonal alterations and inflammatory mediators released as a result of the systemic inflammatory response induced by the tumor. Other events, such as alterations in the rate of myogenesis/apoptosis and decreased regeneration potential also affect skeletal muscle in patients with cancer. Mitochondrial dysfunction also contributes to changes in skeletal muscle metabolism and further contributes to the exacerbation of the cancer-wasting syndrome. Different inflammatory mediators either released by the tumor or by the patient's healthy cells are responsible for the activation of these catabolic processes that take place in skeletal muscle and in other tissues/organs, such as liver or adipose tissues. Indeed, white adipose tissue is also subject to extensive wasting and 'browning' of some of the white adipocytes into beige cells; therefore increasing the energetic inefficiency of the patient with cancer. Recently, an interest in the role of micromRNAs either free or transported into exosomes has been related to the events that take place in white adipose tissue during cancer cachexia.

This article examines the relationship between CEO characteristics and firm performance with a sample formed by the best performing CEOs in the world according to Harvard Business Review. The empirical analysis is based on descriptive statistics techniques and studies the universe of CEOs included in the 2016 ranking “The Best-Performing CEOs in the World” released by Harvard Business Review. Moreover, it addresses performance at various levels: financial performance, environmental, social and governance performance (ESG) and overall performance. The findings of the study show: 1) a strongly negative association between financial and ESG performance; 2) outsider CEOs outperform insider CEOs in overall performance; 3) CEOs with engineering degrees show significantly higher ESG performance; 4) CEOs with longer tenures in the firm present stronger financial performance though weaker ESG performance; and 5) the CEO’s country of origin emerges as an important driver to explain the different types of performance. Results in this field contradict the conventional wisdom of Anglo-Saxon CEOs as the best performers CEOs.

The aim of this article is to review the metabolic background of the cachectic syndrome and to analyze the recent therapeutic approaches designed to counteract the wasting suffered by the cancer patient with cachexia.The main changes associated with the development of this multiorganic syndrome are glucose intolerance, fat depletion and muscle protein hypercatabolism. Among the most promising approaches for the treatment of cachexia include the use of ghrelin agonists, beta-blockers, beta-adrenergic agonists, androgen receptor agonists and antimyostatin peptides. The multitargeted approach seems essential in these treatments, which should include the combination of both nutritional support, drugs and a suitable program of physical exercise, in order to ameliorate both anorexia and the metabolic changes associated with cachexia. In addition, another very important aspect for the design of clinical trials for the treatment of cancer cachexia is to staging cancer patients in relation with the degree of cachexia, in order to start as early as possible, this triple approach in the course of the disease, even before weight loss can be detected.Cancer cachexia has two main components: anorexia and metabolic alterations and both have to be taken into consideration for the treatment of the syndrome.

Directive 2014/56/EU and Regulation (EU) No. 537/2014, which came into effect in June 2016, introduced the mandatory rotation of audit firms after a maximum period of 10 years with the same client. We conduct a cross‐European study with the aim of assessing whether long audit firm tenures are associated with lower levels of audit quality. The sample for the study is based on the constituents of the Standard & Poor's Europe 350 index for the years between 2009 and 2016, and we utilize three different sets of proxies for audit quality: discretionary accruals, differences between reported earnings and earnings benchmarks, and accounting restatements. The main result of the study finds that companies with more than 10 years of tenure with their auditors do not have a lower audit quality than other firms. In fact, this study provides some evidence of a higher audit quality for these firms. The results are robust to various checks. Therefore, if there does not seem to be a problem of a lack of audit quality associated with long audit firm tenures, the necessity of establishing a maximum tenure, as the new European regulation does, may be questioned.

This research analyses the convenience and consequences of the ANECA criteria for the assessment of the research performed by accounting academics in Spain. We focus on the level for the accreditation of catedrático de universidad, and the publication patterns and possibilities of the accounting scholars in Spain. We find that they have more difficulties for publication than their counterparts in adjacent fields of knowledge. Most of the accounting academics affiliated to Spanish institutions than have succeeded in publishing in the top international accounting journals co-authored their articles with foreign authors, mainly affiliated to USA or UK institutions, and/or focused their research on international setting and topics. The Spanish regulation for accreditation stresses this pattern. This situation may have serious consequences for the survival of the accounting discipline in Spain and for the research on topics focused on Spanish problems. Este trabajo analiza la conveniencia y consecuencias de los criterios de evaluación de la actividad investigadora en contabilidad establecidos por ANECA, concretándonos en los criterios para la acreditación de catedrático de universidad, así como el patrón y posibilidades de publicación de los académicos contables en España, Europa y a nivel mundial. Encontramos que los académicos del área contable tienen unas dificultades para publicar que son substancialmente superiores a las de los académicos de otras áreas de empresa. La mayor parte de los académicos afiliados a instituciones españolas que consiguen publicar en las principales revistas académicas contables recurren a co-autorías, principalmente estadounidenses y británicas, y a focalizar el contenido de sus trabajos en contextos y problemáticas no españolas. La normativa española de acreditación acentúa este comportamiento. Esta situación puede tener graves implicaciones para la supervivencia del área de conocimiento, el tratamiento de las temáticas y problemáticas específicamente ligadas al contexto español.

Silvia Busquets,1,2 Marta Castillejo,1 Queralt Jové,1 Baptiste Jude,3 Patricia Mejías,1 Francisco J López-Soriano,1,2 Josep M Argilés1,2 1Cancer Research Group, Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; 2Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Spain; 3Laboratoire de Physiologie - EA 4324 ORPHY, IBSAM, Université de Bretagne Occidentale, Brest, FranceCorrespondence: Silvia BusquetsCancer Research Group, Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Diagonal 643, Barcelona, 08028, SpainTel +34-934021002Fax +34-934021559Email silviabusquets@ub.eduBackground: During cancer cachexia, both skeletal muscle and adipose tissue losses take place. The use of β 2-agonists, formoterol in particular, has proven to be very successful in the treatment of the syndrome in pre-clinical models. The object of the present research was to study the effects of a combination of formoterol and dantrolene, an inhibitor of the ryanodine receptor 1 (RyR1), on body weight loss and cachexia in tumour-bearing animals.Methods: Rats were separated into two groups: controls (C) and tumour bearing (TB). TB group was further subdivided into four groups: untreated (saline as a vehicle), treated with Formoterol (TF) (0,3 mg/kg body weight in saline, subcutaneous (s.c.), daily), treated with Dantrolene (TD) (5 mg/kg body weight in saline, subcutaneous (s.c.), daily), and double-treated treated (TFD) with Formoterol (0,3 mg/kg body weight, subcutaneous (s.c.), daily) and Dantrolene (5 mg/kg body weight, subcutaneous (s.c.), daily). 7 days after tumour transplantation, muscle weight, grip force, and total physical activity were specified in all experimental groups.Results: While formoterol had, as in previous studies, a very positive effect in reducing muscle weight loss, dantrolene had no effects, neither on skeletal muscle nor on any of the parameters studied. Finally, the combined treatment (formoterol and dantrolene) did not result in any significant benefit on the action of the β 2-agonist.Conclusion: It is concluded that, in the preclinical cachectic model used, no synergy exists between β 2-agonist treatment and the blockade of sarcoplasmic-calcium flow.Keywords: cancer cachexia, skeletal muscle, dantrolene, formoterol, calcium, ryanodine receptor 1

Despite evidence suggesting that specialised knowledge should be more relevant than generic knowledge to explain different levels of audit quality across individual auditors, no study to date has addressed the respective impacts of the industry-specific and the generic audit experience of audit partners on the quality of audit services. Our study investigates this issue in the Spanish audit market. We proxy audit quality by discretionary accruals and by the opinion of the audit report, and differentiate among client-specific experience, industry-specific experience and generic audit experience of individual auditors. As expected, our results show significantly higher audit quality when the client is audited by a partner with stronger industry-specific audit experience. Furthermore, we observe that neither client-specific experience nor generic audit experience of audit partners are significant determinants of the quality of audit services provided by these auditors. These results may have some interesting implications for audit firms. Therefore, whereas some prior studies on the related issue of industry specialization point out that specialised knowledge is more relevant than generic knowledge to explain the quality of audit services, our findings suggest that specialised knowledge is, in fact, the only type of knowledge that seems to matter. A pesar de la evidencia que sugiere que el conocimiento especializado debería resultar más relevante que el genérico para explicar diferentes niveles de calidad de auditoría asociados a los auditores individuales, ningún estudio hasta la fecha ha abordado el posible impacto diferencial de la experiencia genérica y específica en la calidad de los servicios de auditoría. Nuestro estudio investiga esta cuestión en el mercado de auditoría español. Aproximamos la calidad de la auditoría a partir de los ajustes de devengo discrecionales y la opinión del informe de auditoría; diferenciando entre experiencia específica con el propio cliente, experiencia sectorial y experiencia de auditoría genérica. Como se esperaba, los resultados muestran una mayor calidad de auditoría cuando el cliente es auditado por un socio con mayor experiencia en el sector de actividad del cliente. También observamos que ni la experiencia específica con el propio cliente, ni la experiencia genérica de auditoría del socio auditor son determinantes significativos de la calidad de los servicios de auditoría. Por otro lado, mientras que algunos estudios previos señalan que el conocimiento especializado resulta más relevante que el genérico para explicar la calidad de los servicios de auditoría, este trabajo sugiere que el conocimiento especializado es, de hecho, el único tipo de conocimiento que resulta relevante. Estos resultados pueden tener implicaciones interesantes para las firmas de auditoría

On May 27, 2014, Regulation (EU) No 537/2014 was published in the Official Journal of the European Union. Aiming to enhance audit quality, the new regulation establishes important limitations to the selling of non-audit services by the audit firm to audit clients and a maximum tenure of ten years with the audit firm. However, it should be noted that the extant research has not consistently supported that non-audit services or long tenures impair the quality of audits. This research studies whether these provisions have been empirically associated with reduced audit quality for Spain. Because of its low litigation risk, the potentially negative impact of both non-audit services and tenure on audit quality should be clearly observed in the Spanish audit market. Nevertheless, we do not find significantly lower levels of audit quality associated with either non-audit services or long audit tenures. However, these results are conditional on the validity of using abnormal accruals to measure audit quality.

Alterations in amino acid protein metabolism are a key feature of the cancer cachexia syndrome. These changes -induced by both hormonal changes (that affect insulin sensitivity) and inflammatory mediators- are present in skeletal muscle influencing both, amino acid uptake and protein synthesis. In addition, skeletal muscle protein turnover is characterized by an exacerbated rate of protein degradation, promoted by an activation of different proteolytic systems that include the ubiquitin-proteasome and the autophagic-lysosomal pathways. Changes in the rate of myogenesis/apoptosis also determine skeletal muscle mass during cancer cachexia. Indeed, a decreased skeletal muscle regeneration capacity is observed together with an increased rate of cell death, resulting in muscle wasting. Mitochondrial dysfunction also results in changes in skeletal muscle metabolism and further contributes to the exacerbation of the cancer-wasting syndrome. Different inflammatory mediators -either released by the tumor or by healthy cells of the cancer patient- are responsible for the activation of these catabolic processes that take place in skeletal muscle.

Cancer cachexia is a multifactorial syndrome characterized by anorexia, weight loss and muscle wasting that impairs patients' quality of life and survival. Aim of this work was to evaluate the impact of either autophagy inhibition (knocking down beclin-1) or promotion (overexpressing TP53INP2/DOR) on cancer-induced muscle wasting. In C26 tumor-bearing mice, stress-induced autophagy inhibition was unable to rescue the loss of muscle mass and worsened muscle morphology. Treating C26-bearing mice with formoterol, a selective β2-agonist, muscle sparing was paralleled by reduced static autophagy markers, although the flux was maintained. Conversely, the stimulation of muscle autophagy exacerbated muscle atrophy in tumor-bearing mice. TP53INP2 further promoted atrogene expression and suppressed mitochondrial dynamics-related genes. Excessive autophagy might impair mitochondrial function through mitophagy. Consistently, tumor-induced mitochondrial dysfunction was detected by reduced ex vivo muscle fiber respiration. Overall, the results evoke a central role for muscle autophagy in cancer-induced muscle wasting.

We develop new transaction management (TRM) proxies, to find empirical evidence of the strategic management of accounting transactions, aiming to carry out money laundering activities, within a sample of 355 firms controlled by Italian Mafias. Our results reveal that, using a cluster analysis, Mafia-controlled firms can be classified into two different groups corresponding to real firms and shell firms, based on specific assumptions on their distinctive peculiarities. Importantly, our regression estimations provide evidence of different TRM practices of these firms, which may be linked to specific money laundering activities. Finally, the seizure of Mafia-controlled firms and their assignment to legal administrators only have a significant impact on TRM within Mafia-controlled shell firms, whereas the null impact on TRM, within Mafia-controlled real firms, casts doubt on the ability of legal administrators to completely deter money laundering. This study proposes new TRM proxies, based on the nature of the expenditure transaction, which could be used by authorities as accounting red flags of money laundering activities. Furthermore, this study may support critical arguments against the orthodox view of the anti-money laundering role of accounting and the suitability of traditional TRM proxies to depict practices within firms sharing common traits with Mafia-controlled firms. Indeed, these firms may engage in TRM for illicit and/or opportunistic purposes, when the external scrutiny is weak, their financial statements are irrelevant for trading with stakeholders, because of competitive advantages or dominant market positions, and they can count on colluded actors as counterparties of money laundering transactions.

Formoterol is a highly potent β2-adrenoceptor-selective agonist, which is a muscle growth promoter in many animal species. Myostatin/activin inhibition reverses skeletal muscle loss and prolongs survival of tumor-bearing animals. The aim of this investigation was to evaluate the effects of a combination of the soluble myostatin receptor ActRIIB (sActRIIB) and the β2-agonist formoterol in the cachectic Lewis lung carcinoma model. The combination of formoterol and sActRIIB was extremely effective in reversing muscle wasting associated with experimental cancer cachexia in mice. Muscle weights from tumor-bearing animals were completely recovered following treatment and this was also reflected in the measured grip strength. This combination increased food intake in both control and tumor-bearing animals. The double treatment also prolonged survival significantly without affecting the weight and growth of the primary tumor. In addition, it significantly reduced the number of metastasis. Concerning the mechanisms for the preservation of muscle mass during cachexia, the effects of formoterol and sActRIIB seemed to be additive, since formoterol reduced the rate of protein degradation (as measured in vitro as tyrosine release, using incubated isolated individual muscles) while sActRIIB only affected protein synthesis (as measured in vivo using tritiated phenylalanine). Formoterol also increased the rate of protein synthesis and this seemed to be favored by the presence of sActRIIB. Combining formoterol and sActRIIB seemed to be a very promising treatment for experimental cancer cachexia. Further studies in human patients are necessary and may lead to a highly effective treatment option for muscle wasting associated with cancer.

We examine the effects of Mafia infiltration on public procurement performance, based on a sample of 68,063 public work contracts (PWC) awarded by Italian municipalities over the period 2012–2017, of which 687 are identified as Mafia-infiltrated, either because of being awarded by municipal councils subsequently dissolved due to Mafia infiltration, or because of being won by Mafia-owned firms. Our results reveal that Mafia infiltration is positively associated with number of submitted bids, awarding rebates and execution cost overruns, whereas it is negatively associated with delivery delays for PWC. The effect of Mafia infiltration on execution cost overruns and the probability of their occurrence is weaker for larger PWC, and the elections of the new municipal councils, after the dissolution of the previous ones, do not significantly influence the performance of PWC. Our findings suggest the presence of collusive schemes among bidding firms within the Mafia network and provide new insights for the implementation of more sound policies to tackle practices associated with Mafia infiltration in public procurement.

Cachexia is a systemic condition that occurs during many neoplastic diseases, such as cancer. Cachexia in cancer is characterized by loss of body weight and muscle and by adipose tissue wasting and systemic inflammation. Cancer cachexia is often associated with anorexia and increased energy expenditure. Even though the cachectic condition severely affects skeletal muscle, a tissue that accounts for ~40% of total body weight, it represents a multi-organ syndrome that involves tissues and organs such as white adipose tissue, brown adipose tissue, bone, brain, liver, gut and heart. Indeed, evidence suggests that non-muscle tissues and organs, as well as tumour tissues, secrete soluble factors that act on skeletal muscle to promote wasting. In addition, muscle tissue also releases various factors that can interact with the metabolism of other tissues during cancer. In this Review, we examine the effect of non-muscle tissues and inter-tissue communication in cancer cachexia and discuss studies aimed at developing novel therapeutic strategies for the condition. Cachexia is a multi-organ syndrome associated with cancer. In this Review, Josep M. Argiles and colleagues discuss the role of different tissues and organs in cancer cachexia and examine studies that investigate the development of novel therapeutics for the condition.

Background L-Leu and its metabolite β-hydroxy-β-methylbutyrate (HMB) stimulate muscle protein synthesis enhancing the phosphorylation of proteins that regulate anabolic signalling pathways. Alterations in these pathways are observed in many catabolic diseases, and HMB and L-Leu have proven their anabolic effects in in vivo and in vitro models. The aim of this study was to compare the anabolic effects of L-Leu and HMB in myotubes grown in the absence of any catabolic stimuli. Methods Studies were conducted in vitro using rat L6 myotubes under normal growth conditions (non-involving L-Leu-deprived conditions). Protein synthesis and mechanistic target of rapamycin signalling pathway were determined. Results Only HMB was able to increase protein synthesis through a mechanism that involves the phosphorylation of the mechanistic target of rapamycin as well as its downstream elements, pS6 kinase, 4E binding protein-1, and eIF4E. HMB was significantly more effective than L-Leu in promoting these effects through an activation of protein kinase B/Akt. Because the conversion of L-Leu to HMB is limited in muscle, L6 cells were transfected with a plasmid that codes for α-keto isocaproate dioxygenase, the key enzyme involved in the catabolic conversion of α-keto isocaproate into HMB. In these transfected cells, L-Leu was able to promote protein synthesis and mechanistic target of rapamycin regulated pathway activation equally to HMB. Additionally, these effects of leucine were reverted to a normal state by mesotrione, a specific inhibitor of α-keto isocaproate dioxygenase. Conclusion Our results suggest that HMB is an active L-Leu metabolite able to maximize protein synthesis in skeletal muscle under conditions, in which no amino acid deprivation occurred. It may be proposed that supplementation with HMB may be very useful to stimulate protein synthesis in wasting conditions associated with chronic diseases, such as cancer or chronic heart failure.

Background The effectiveness of drugs aimed at counteracting cancer cachexia is generally tested in pre-clinical rodent models, where only the tumour-induced alterations are taken into account, excluding the co-presence of anti-tumour molecules that could worsen the scenario and/or interfere with the treatment. Methods The aim of the present investigation has been to assess the efficacy of a multifactorial treatment, including formoterol and megestrol acetate, in cachectic tumour-bearing rats (Yoshida AH-130, a highly cachectic tumour) undergoing chemotherapy (sorafenib). Results Treatment of cachectic tumour-bearing rats with sorafenib (90 mg/kg) causes an important decrease in tumour cell content due to both reduced cell proliferation and increased apoptosis. As a consequence, animal survival significantly improves, while cachexia occurrence persists. Multi-factorial treatment using both formoterol and megestrol acetate is highly effective in preventing muscle wasting and has more powerful effects than the single formoterol administration. In addition, both physical activity and grip strength are significantly improved as compared with the untreated tumour-bearing animals. The effects of the multi-factorial treatment include increased food intake (likely due to megestrol acetate) and decreased protein degradation, as shown by the reduced expression of genes associated with both proteasome and calpain proteolytic systems. Conclusions The combination of the two drugs proved to be a promising strategy for treating cancer cachexia in a pre-clinical setting that better resembles the human condition, thus providing a strong rationale for the use of such combination in clinical trials involving cachectic cancer patients.

PURPOSE OF REVIEW The aim of the present review is to examine the impact of mitochondrial dysfunction in cancer cachexia. RECENT FINDINGS Oxidative pathways are altered in this tissue during muscle wasting and this seems to be a consequence of mitochondrial abnormalities that include altered morphology and function, decreased ATP synthesis and uncoupling. SUMMARY An alteration of energy balance is the immediate cause of cachexia. Both alterations in energy intake and expenditure are responsible for the wasting syndrome associated with different types of pathological conditions, such as cancer. Different types of molecular mechanisms contribute to energy expenditure and, therefore, involuntary body weight loss, one of which is mitochondrial dysfunction.

This paper develops a model that can contribute to the detection of legally registered firms defined as Mafia firms (LMFs) due to having been confiscated by judicial authorities, in relation to alleged connections of their owners with Italian organized crime. The model correctly classifies 76.41% of firms within a matched sample of 852 firm-years including LMFs and lawful firms. Furthermore, we present an analysis of financial statement characteristics of singular private firms which are socially irresponsible by nature and whose incentives, modus operandi and legal financial statement formats differ from those of listed companies. In particular, we show that specific accruals and earnings management proxies may provide more insight into accounting manipulation patterns of LMFs. More importantly, our paper can help practitioners and regulators identify accounting signals that can be used in risk assessment models or in the detection of criminal infiltrations and related illicit practices.

Muscle mass loss and wasting are characteristic features of patients with chronic conditions including cancer. Beta-adrenoceptors attenuate muscle wasting. We hypothesized that specific muscle atrophy signaling pathways and altered metabolism may be attenuated in cancer cachectic animals receiving treatment with the beta

Anorexia and metabolic alterations are the main components of the cachectic syndrome. Glucose intolerance, fat depletion, muscle protein catabolism and other alterations are involved in the development of cancer cachexia, a multi-organ syndrome. Nutritional approach strategies are not satisfactory in reversing the cachectic syndrome. The aim of the present review is to deal with the recent therapeutic targeted approaches that have been designed to fight and counteract wasting in cancer patients. Indeed, some promising targeted therapeutic approaches include ghrelin agonists, selective androgen receptor agonists, β-blockers and antimyostatin peptides. However, a multi-targeted approach seems absolutely essential to treat patients affected by cancer cachexia. This approach should not only involve combinations of drugs but also nutrition and an adequate program of physical exercise, factors that may lead to a synergy, essential to overcome the syndrome. This may efficiently reverse the metabolic changes described above and, at the same time, ameliorate the anorexia. Defining this therapeutic combination of drugs/nutrients/exercise is an exciting project that will stimulate many scientific efforts. Other aspects that will, no doubt, be very important for successful treatment of cancer wasting will be an optimized design of future clinical trials, together with a protocol for staging cancer patients in relation to their degree of cachexia. This will permit that nutritional/metabolic/pharmacological support can be started early in the course of the disease, before severe weight loss occurs. Indeed, timing is crucial and has to be taken very seriously when applying the therapeutic approach.

We perform an empirical analysis on the benefits of, and the challenges faced by, sustainability accounting in measuring the effects of climate change for a sample of Spanish rice farms. We use farm yields, revenues and incomes as indicators of economic performance, and greenhouse gas emissions, and direct and indirect energy consumption as indicators of climate change effects. According to our data, farms with higher yields, revenues and income are responsible for a greater environmental impact, measured in total gigajoules of energy consumed and tons of carbon dioxide emitted, than farms with a lower economic performance. Results show that in our sample the achievement of higher yields is attributable to the greater use of chemical inputs and fossil fuels and not to innovative and sustainable farming practices. The results indicate that accounting for climate change effects is not only possible but also necessary to provide more accurate information on the overall costs and benefits of farming. Greater transparency in accounting information should serve to highlight which farming activities are better able to reduce climate change impacts.

According to a recent consensus, cachexia is a complex metabolic syndrome associated with underlying illness and characterised by loss of muscle with or without loss of fat mass. The prominent clinical feature of cachexia is weight loss. Cachexia occurs in the majority of terminal cancer patients and it is responsible for the deaths of 22% of cancer patients. Although body weight is, indeed, an important factor to be taken into consideration in any cachexia treatment, body composition, physical performance and quality of life should be monitored. From the results presented here, one can speculate that a single therapy may not be completely successful in the treatment of cachexia. From this point of view, treatments involving different combinations are more likely to be successful. The objectives of any therapeutical combination are two: an anticatabolic aim directed towards both fat and muscle catabolism and an anabolic objective leading to the synthesis of macromolecules such as contractile proteins.

Rome was not built in a day. Likewise, if one considers the evolution of systemic anti-cancer treatment, it took decades to go from acceptance of any therapy at all to single agents achieving isolated tumour responses (without prolongation of survival) to the current use of combination regimens as adjuvant therapy to surgery. Such incremental progress has led to improved quality of life and eventually survival for patients with some types of cancer. Cachexia and skeletal muscle wasting in cancer are significant clinical problems of high medical need for a large proportion of cancer patients and associated with very poor quality of life and very high mortality.1,2 An effective treatment of a complex multifactorial syndrome such as cachexia will likely evolve from a series of steps of discovery and new interventions before a comprehensive multimodal strategy can be identified that improves patient’s quality and quantity of life.3 There are reasons to be optimistic about the possibility that in the future, cachexia may be treated effectively. A number of drugs have already been developed that target key underlying mechanisms, namely, reduced food intake and altered metabolism and regulation of muscle mass, with the latter being split into pro-anabolic and anti-catabolic approaches. However, there is also some reason to be concerned because of the wide variability in current trial design, including different inclusion criteria, endpoints, analysis plans and the definition of best concomitant supportive care. Taken to the extreme, such differences in general approach have resulted in divergent opinions on what to consider a meaningful clinical endpoint by the European Medicines Agency (EMA) versus the US Food and Drug Administration (FDA). A result has been that in the clinical development programmes of some drugs, different endpoint assessments for American versus European regulatory authorities within the same trials using the same source data have been adopted. An example is the case of the POWER 1 and 2 trials testing the selective androgen receptor modulator enobosarm in patients with cancer suffering from muscle wasting.4–6 There has been a considerable influence from regulatory authorities on trial design. In the last 10 years, some regulatory authorities have consistently suggested that the design of randomized controlled trials testing treatments for cachexia should be aimed at demonstrating appropriate risk versus benefit, where benefit is defined as concomitant improvement in skeletal muscle mass (or lean mass) and relevant/meaningful physical function or improved survival. Whilst this is an admirable goal, from recent phase III trial results, this appears to be possibly unachievable with single modality interventions. Equally, it is not defined to whom the change is supposed to be ‘meaningful’: patient, caregiver, doctor, nurse or healthcare provider? The recent phase III trials of enobosarm used a co-primary end-point of lean body mass and stair climb power.4–6 Based on the FDA agreed co-primary responder analysis the trials failed to reach significance, principally because of lack of benefit in terms of the functional end point. In the responder analysis demanded by the FDA, an increase in performance of at least 10% for stair-climb power test was required for a patient to be considered to have benefited clinically [paper submitted]. Preventing a decline in performance was not considered in these analyses. In the analysis suggested by the EMA (which generally aims to assess clinically meaningful change regardless of direction), the same data were analysed using continuous data, and one of the two POWER trials may be considered successful, as both tests for change in lean mass and for stair-climb power showed significant changes over time. The two trials also had to be different, because of different background chemotherapy demanded in the inclusion criteria (i.e. taxane and non-taxane based). It is not clear, whether these are two trials in two orphan-type cancer indications (with different results), or are instead two trials in one indication with inconsistent results. It all depends on your approach to drug development (and maybe also on the regulatory body you talk to), but certainly it is a confusing situation by any standard. Similarly, the phase III (ROMANA) trials of the ghrelin receptor agonist anamorelin have shown significant benefit in terms of lean and fat body mass, but not for hand grip strength.7 These findings are not completely unexpected since whilst in healthy young individuals there is a strong positive correlation between muscle mass and muscle strength/power per se and between changes thereof,8,9 in older, sick individuals, the magnitude of strength generated by a certain unit of mass tends to be lower. These findings suggest that preservation/augmentation of muscle mass does not necessarily always translate into clinical benefits in non-muscular aspects of the cachexia syndrome as other factors may remain unchanged from a unimodal approach (e.g. targeting muscle anabolism). If other aspects of the cachexia syndrome remain unchanged (like systemic inflammation and catabolism or physical inactivity and undernutrition), can unimodal approaches lead to an increase in physical activity and/or preservation of independence? It appears that a more comprehensive approach to the cachexia syndrome is warranted if the reference outcomes of improved physical activity/preservation of independence are to be pursued. Still, preservation of function (and not its improvement) may also be a laudable aim of treatment development in cachexia, and regulatory guidance should permit for that. However, unlike areas such as hypertension where a given change in blood pressure is accepted as a surrogate for clinical events, it has to be recognized that in cachexia, the ‘relevance’ or ‘meaningfulness’ of a change in surrogates such as hand grip strength, stair-climb power, leg extension strength or timed sit-up-and-go is not known. Perhaps direct measures of patients’ daily physical activity would be better? In the related field of COPD-associated body wasting, exercise rehabilitation is well established with extensive guideline recommendations that are evidence-based.10 These guidelines have been developed over time and are multimodal in focus and are explicitly aimed at improving physical functioning and physical activity levels, nutritional status and quality of life. For patients with heart failure, chronic kidney disease, stroke or ageing-related frailty, such multimodal approaches are frequently considered,11–13 but evidence is so far weak compared with what has been achieved in COPD. Novel therapeutic agents under development for cachexia mostly focus on specific aspects of the syndrome (e.g. muscle anabolism, inflammation or appetite stimulation).14 Surely, phase III registration trials should assess safety in general, but efficacy specifically in relation to the target of the drug based on its mechanism of action. It may not be right to discard an intervention as ineffective because it does not yet affect a functional outcome, if, in fact – when inserted into a multimodal intervention that reflects the multifaceted aspect of the cachexia syndrome – the drug shows extended benefits that touch on issues such as health-related quality of life, patient-reported symptoms and tolerance of anti-cancer therapy. In the context of a complex disease process and a desire for multimodal therapies, regulatory advice on co-therapy with nutrition and exercise is also needed. Suggestions as to how best to include in this context supportive care in clinical trials 15 may also be helpful. We understand that this may include additional clinical trials for food products and supportive care approaches and surely this is acceptable, if the rules of the ‘game’ are clear for the good of our patients. Regulators need to be engaged in encouraging the testing of these modalities and their systematic inclusion in trial designs. In heart failure, such activities have already been initiated and aim to shift the development and authorization of medicines from the molecule paradigm to their evaluation in the context of the whole healthcare regimen.16 If a trial of a new agent incorporates these elements and is successful, it cannot lie with the pharmaceutical company to ensure that such adjuncts are available in precisely the same format everywhere in the world. Rather, the approved drug label may need to recommend such adjuncts for optimal effect. Clearly, this is not an easy field for new developments, but the medical need is great and the commercial returns for those who make it may be big. Once drugs are approved, the longer process of incorporating new agents into best clinical practice can begin. It should be clear to pharmaceutical companies, academic trialists and regulators that they may need to be more realistic about what can be achieved in a single step. Maybe also the adaptive licensing approach proposed by EMA 13 can help in this process of developing regulatory pathways. A willingness to consider current data with an open mind and a ‘Notice on Regulatory Guidance’ on cachexia trial design for cancer and beyond that cuts across continents would be a major step forwards to maintain drug development momentum, if there is to be genuine progress at this exciting juncture in the development of cachexia therapy. We want to help make that a reality whichever way we can.

INTRODUCTION: Cachexia is a wasting condition that manifests in several types of cancer. The main characteristic of this condition is a profound loss of muscle mass.METHODS: By using a microarray system, expression of several hundred genes was screened in skeletal muscle of rats bearing a cachexia-inducing tumor, the AH-130 Yoshida ascites hepatoma. This model induced a strong decrease in muscle mass in the tumor-bearing animals, as compared with their healthy counterparts.RESULTS: The results show important differences in gene expression in EDL skeletal muscle between tumor-bearing animals with cachexia and control animals.CONCLUSIONS: The differences observed pertain to genes related to intracellular calcium homeostasis and genes involved in the control of mitochondrial oxidative phosphorylation and protein turnover, both at the level of protein synthesis and proteolysis. Assessment of these differences may be a useful tool for the design of novel therapeutic strategies to fight this devastating syndrome.

Cachexia is a multiorganic syndrome associated with cancer, characterized by body weight loss, muscle and adipose tissue wasting and inflammation, being often associated with anorexia. The aim of the present review is to examine the impact of megestrol acetate in the treatment of cancer cachexia, both at the biochemical and physiological level taking into account new experimental data related to protein muscle metabolism. Based on experimental evidence, it is concluded that megestrol acetate is a good candidate for muscle wasting treatment and future studies addressed at the interaction between the drug and protein turnover in human skeletal muscle should be performed.

Summary Background & aims Tumour growth is associated with weight loss resulting from both adipose and muscle wasting. Methods Administration of l -carnitine (1 g/kg body weight) to rats bearing the AH-130 Yoshida ascites hepatoma, a highly cachectic rat tumour. Results The treatment results in a significant improvement of food intake and in muscle weight (gastrocnemius, EDL and soleus). These beneficial effects are directly related to improved physical performance (total physical activity, mean movement velocity and total travelled distance). Administration of l -carnitine decreases proteasome activity and the expression of genes related with this activity, such as ubiquitin, C8 proteasome subunit and MuRF-1. Interestingly, l -carnitine treatment also decreases caspase-3 mRNA content therefore suggesting a modulation of apoptosis. Moreover, addition of 50 μM of l -carnitine to isolated EDL muscles results in a significant decrease in the proteolytic rate suggesting a direct effect. Conclusions It can be concluded that l -carnitine supplementation may be a good approach for a multi-targeted therapy for the treatment of cancer-related cachexia.

This paper undertakes an empirical analysis of the impact of absorbed and unabsorbed slack, employing three different measures for each slack type, on firm profitability. We find that unabsorbed slack has a more favorable influence on future firm profitability than absorbed slack. While all the absorbed slack indicators have a significant negative influence on future profitability, the three unabsorbed slack indicators present positive, negative, and non-significant influences, respectively. The fewer constraints of unabsorbed slack on the redeployment to exploit new opportunities point to its comparative advantage over absorbed slack. We find evidence for the differential impact of absorbed versus unabsorbed slack on profitability in firms with lower levels of slack, which suggests firms prefer to withdraw resources from current business and redeploy them to develop new and more favorable business opportunities.

Skeletal muscle is recognized as vital to physical movement, posture, and breathing. In a less known but critically important role, muscle influences energy and protein metabolism throughout the body. Muscle is a primary site for glucose uptake and storage, and it is also a reservoir of amino acids stored as protein. Amino acids are released when supplies are needed elsewhere in the body. These conditions occur with acute and chronic diseases, which decrease dietary intake while increasing metabolic needs. Such metabolic shifts lead to the muscle loss associated with sarcopenia and cachexia, resulting in a variety of adverse health and economic consequences. With loss of skeletal muscle, protein and energy availability is lowered throughout the body. Muscle loss is associated with delayed recovery from illness, slowed wound healing, reduced resting metabolic rate, physical disability, poorer quality of life, and higher health care costs. These adverse effects can be combatted with exercise and nutrition. Studies suggest dietary protein and leucine or its metabolite β-hydroxy β-methylbutyrate (HMB) can improve muscle function, in turn improving functional performance. Considerable evidence shows that use of high-protein oral nutritional supplements (ONS) can help maintain and rebuild muscle mass and strength. We review muscle structure, function, and role in energy and protein balance. We discuss how disease- and age-related malnutrition hamper muscle accretion, ultimately causing whole-body deterioration. Finally, we describe how specialized nutrition and exercise can restore muscle mass, strength, and function, and ultimately reverse the negative health and economic outcomes associated with muscle loss. Sin financiación 5.775 JCR (2016) Q1, 4/49 Geriatrics & Gerontology UEM

Summary Background & aims Cachexia is a multi-organic syndrome associated with cancer, characterized by body weight loss, muscle and adipose tissue wasting and inflammation, being often associated with anorexia. The aim of the present investigation was to study the effects of megestrol acetate (MA) on the rate of leucine incorporation into muscle tissue and on the uptake of AIB (a non-metabolizable analogue of alanine) in both skeletal muscle and liver tissue. Methods The effects of MA (100 mg/kg) were tested in cachectic tumour-bearing rats (Yoshida AH-130 ascites hepatoma). Tissue amino acid uptake was assessed by means of the alanine analogue α-amino-3H-isobutyrate (AIB). 14C-leucine oxidation and tissue protein incorporation were also determined. Results Administration of MA to tumour-bearing rats resulted in an important reversal of the muscle wasting process, as reflected by individual muscle weights. Treatment with the progestogen resulted in an increased AIB uptake together with an increased leucine incorporation in skeletal muscle. MA treatment significantly decreased AIB uptake by the liver. Conclusions MA treatment results in both a significant increased uptake of neutral amino acids (AIB) by skeletal muscle and a significant incorporation of the branched-chain amino acid leucine into muscle protein, indicating a clear anabolic action of the drug on muscle tissue.

Cancer cachexia is a complex syndrome characterized by inflammation, body weight loss, muscle, and adipose tissue wasting that is responsible for the death of a considerable percentage of cancer patients. In addition, during cachexia muscle strength and endurance are dramatically reduced, limiting the ability to perform daily activities and severely affecting the patient’s quality of life. Different studies have emphasized that a single therapy may not be completely successful in the treatment of cachexia. Beyond pharmacological strategies, exercise training has been suggested as a promising countermeasure to prevent cachexia, in order to restore both strength and endurance, depending on the type of exercise. Unfortunately, a small number of studies, in both clinical and experimental settings, have been performed to date. Moreover, when considering exercise in cancer, several factors have to be taken into consideration, in particular those alterations that could limit the capacity to perform exercise and consequently the resulting beneficial or detrimental effects. This editorial is aimed at stimulating the debate on the suitability of including exercise training in a multi-functional approach against cachexia taking into consideration both limitations and advantages.

The main aim of the present review is to summarize and evaluate the different molecular mechanisms and catabolic mediators (mainly cytokines) involved in cancer cachexia since they may represent targets for future promising clinical investigations.

There is an intense debate on the convenience of moving from historical cost (HC) toward the fair value (FV) principle. The debate and academic research is usually concerned with financial instruments, but the IAS 41 requirement of fair valuation for biological assets brings it into the agricultural domain. This paper performs an empirical study with a sample of Spanish farms valuing biological assets at HC and a sample applying FV, finding no significant differences between both valuation methods to assess future cash flows. However, most tests reveal more predictive power of future earnings under fair valuation of biological assets, which is not explained by differences in volatility of earnings and profitability. The study also evidences the existence of flawed HC accounting practices for biological assets in agriculture, which suggests scarce information content of this valuation method in the predominant small business units existing in the agricultural sector in advanced Western countries. La evolución de la contabilidad desde el coste histórico (CH) hacia el valor razonable (VR) ha suscitado debates y controversias, tanto en el ámbito profesional, como en el académico. Si bien el debate y los estudios se han referido principalmente a los instrumentos financieros, el requerimiento de la NIC41 de valorar los activos biológicos al VR ha ampliado el debate a la contabilidad agrícola. Este trabajo realiza un estudio empírico mediante una muestra de explotaciones agrícolas españolas que valoran sus activos biológicos al CH y otra que valoran al VR, para comparar el poder predictivo de ambos criterios de valoración. No se encuentran diferencias significativas entre ambos criterios para la predicción de los futuros flujos de tesorería. No obstante, la mayor parte de los tests realizados revelan un mayor poder predictivo de los futuros resultados contables bajo el valor razonable, que no se explica en función de diferencias en la volatilidad. El estudio evidencia también la existencia de prácticas defectuosas de cálculo del CH por parte de las explotaciones agrícolas, lo cual sugiere un escaso contenido informativo de la contabilidad bajo este criterio dado el universo de pequeñas explotaciones familiares predominantes en los países occidentales avanzados. The authors are grateful to University of Barcelona and to the Spanish Ministerio de Educación y Ciencia (SEJ2005-04037/ECON) for funding this research, as well as to CABSA for providing data that made possible this study

In this study we critically review the internal procedures of the accounting community for generating and disseminating knowledge. We contend that academic journals on accounting research are scarce, publish few articles and apply high rejection rates, and the review process is lengthy and expensive. Additionally, an academic elite has unparalleled predominance in comparison to other business disciplines, reflected in an unusual share of published articles with authors affiliated to a small number of academic institutions, and the predominance of certain topics and methodologies. The discipline does not allow the collaborative, iterative and flexible features of innovative knowledge communities. The discipline’s internal procedures favour restriction, control, slowness, and expiration, rather than participation, speed and renewal. They are ill suited for advancing knowledge and bode badly for successful research. As a result, accounting academics present low research performance and the discipline is facing steady decline. More importantly, the discipline is handicapped in producing innovative knowledge able to contribute to critical research and long term social well-being. We also focus on the Spanish institutional situation, arguing that Spanish requirements for reaching tenured positions are difficult for accountants to meet. We highlight the need to raise awareness of the problem and change the procedures En este estudio hacemos una revisión crítica de los procedimientos vigentes en la comunidad académica contable para la generación de conocimiento y su publicación. Exponemos que hay pocas revistas académicas para publicar la investigación contable, que éstas publican pocos artículos, aplican elevadas tasas de rechazo y el proceso de revisión es lento y costoso. Además, hay un predominio de una elite académica sin precedentes en otras disciplinas de empresa, lo cual se refleja en un mayor porcentaje de artículos pertenecientes a autores afiliados a un pequeño número de instituciones académicas, y el predominio de ciertos temas y metodologías. La disciplina no presenta los rasgos de colaboración, interactividad y flexibilidad propios de las comunidades dinámicas e innovadoras en la producción de conocimiento. El funcionamiento de la disciplina está más orientado al control que al avance del conocimiento. Los procedimientos seguidos en la disciplina no son los más apropiados para favorecer el éxito en la investigación. En consecuencia, los académicos contables presentan poca producción investigadora y tienen dificultades para desarrollar con éxito una carrera investigadora. Lo que es aún más importante, la disciplina ofrece pocas posibilidades de generar investigación crítica en cuestiones sociales y medioambientales. Este trabajo analiza también la situación institucional en España, aduciendo que los requisitos exigidos para alcanzar posiciones de estabilidad académica son difíciles de conseguir para los académicos que se dedican a la contabilidad. Ponemos de relieve la necesidad de tomar conciencia del problema, como primer paso para cambiar el funcionamiento de la disciplina.

Proteolysis in skeletal muscle is mainly carried out by the activity of the ubiquitin-dependent proteolytic system. For the study of protein degradation through the ubiquitin-proteasome pathway, we used a model of hyperthermia in murine myotubes. In C2C12 cells, hyperthermia (41°C) induced a significant increase in both the rate of protein synthesis (18%) and degradation (51%). Interestingly, the addition of the β(2) -adrenoceptor agonist formoterol resulted in a significant decrease in protein degradation (21%) without affecting protein synthesis. The decrease in proteolytic rate was associated with decreases in gene expression of the different components of the ubiquitin-dependent proteolytic system. The effects of the β(2) -agonist on protein degradation were dependent exclusively on cAMP formation, because inhibition of adenylyl cyclase completely abolished the effects of formoterol on protein degradation. It can be concluded that hyperthermia is a suitable model for studying the anti-proteolytic potential of drugs used in the treatment of muscle wasting.

PURPOSE: The development of cancer cachexia is the most common manifestation of advanced malignant disease. METHOD: The effects on muscle regeneration of β2�adrenoceptor agonist formoterol (0.3 mg/kg) were tested in cachectic tumourbearing rats (Yoshida AH�130 ascit es hepatoma). RESULTS: Administration of formoterol results in a significant increase in the mass and protein content of tibialis muscle in tumourbearin grats. This increase is associated with a decreased myogenin mRNA content together with an increased Pax�7 gene expression. Bupivacaine treatment by local injection results in an important reduction in tibialis weight together with significant increases in Pax�7, myogenin and MyoD gene expression. Formoterol treatment in bupivacainetreated rats results in significant increases in Pax�7 together with significant decreases in myogenin mRNA content, suggesting that this β2�agonist is favouring muscle regeneration by stimulating the proliferation of satellite cells. Altogether, the data reinforce the potential role of formoterol in the treatment of muscle wasting diseases.