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Combined approach to counteract experimental cancer cachexia: eicosapentaenoic acid and training exercise
Fabio Penna1,2,
Silvia Busquets2,
Fabrizio Pin1,
Miriam Toledo2,
Francesco M. Baccino1,
Francisco J. López-Soriano2,
Paola Costelli1 &
Josep M. Argilés2
Journal of Cachexia, Sarcopenia and Muscle volume 2, pages 95–104 (2011)Cite this article
Cancer cachexia is a syndrome characterized by loss of skeletal muscle protein, depletion of lipid stores, anorexia, weakness, and perturbations of the hormonal homeostasis. Despite several therapeutic approaches described in the past, effective interventions countering cancer cachexia are still lacking.
The present work was aimed to verify the ability of eicosapentaenoic acid (EPA) to prevent the muscle depletion in Lewis lung carcinoma-bearing mice and to test the ability of endurance exercise training to increase the EPA effect.
EPA alone did not prevent the muscle loss induced by tumor growth while the combination with exercise induced a partial rescue of muscle strength and mass. Moreover, the association of EPA and exercise reduced the dramatic PAX-7 accumulation and stimulated the increase of PCG-1 protein.
Overall, the present data suggest that exercise is an effective tool that should be added for combined therapeutic approaches against cancer cachexia.
Cancer patients frequently develop a condition of general wasting known as cachexia. This is a multifactorial syndrome that complicates patients' management, increases morbidity and mortality rates, reduces the tolerance to antineoplastic therapies, and results in poor quality of life [1]. Cachexia is characterized by muscle and fat wasting, anemia, anorexia, and perturbations of the hormonal homeostasis. The pathogenetic mechanisms underlying cachexia are complex and only partially identified, thereby effective therapeutic strategies are lacking.
Several therapeutic approaches have been proposed to counteract cachexia. Among these are nutritional interventions, frequently including omega-3 polyunsaturated fatty acids (PUFA) [2], antioxidants [3], branched-chain amino acids [4], agonists of the melanocortin receptor [5], ghrelin [6], and anti-myostatin agents [7]. The omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid have been shown to suppress the production of proinflammatory cytokines of several molecules deriving from the arachidonic acid cascade and of acute-phase reactants such as C-reactive protein (reviewed in [8, 9]). EPA administration to animals bearing the MAC16 tumor improves body weight loss and attenuates the catabolic effects of both lipid mobilizing factor and proteolysis-inducing factor (see [10]). In particular, in the MAC16 model system, EPA has been shown to inhibit the activity of the ubiquitin–proteasome-dependent proteolysis, thus reducing skeletal muscle wasting [11]. Finally, experimental studies suggest that omega-3 PUFAs may impair both tumor growth and metastatic spread, mainly by inducing apoptotic cell death, reducing pro-angiogenic factors, and inhibiting oncogene expression (reviewed in [10]). By contrast, EPA proved ineffective in preventing cachexia in rats bearing the AH-130 hepatoma [12].
Clinical trials performed in malnourished cancer patients have shown that EPA administration improves body weight and lean body mass, likely in force of its anti-inflammatory properties [9, 13]. These observations, however, have not been completely confirmed by a large multicenter study performed on pancreatic cancer patients [14]. Finally, EPA administration per se has been demonstrated to exert no statistically significant benefit in the treatment of cancer cachexia [15].
In addition to nutritional interventions, other therapeutic strategies could effectively contribute to attenuate cancer-related muscle wasting. In particular, exercise training has been proposed as a suitable tool, in view of recent observations, suggesting that decreased physical activity plays a role in the onset of muscle atrophy in cancer patients [16]. Indeed, exercise training stimulates the increase of muscle mass and strength and might improve cancer-associated skeletal muscle wasting by stimulating anabolic pathways as well as by down-regulating the activity of proinflammatory cytokines [17]. The molecular events that follow an acute bout of resistance exercise have been described by several studies (reviewed in [18]); by contrast, little is known about the effect induced by repeated exercise bouts.
The aim of the present study has been to investigate if EPA effectiveness in the prevention of cancer-related cachexia might be enhanced by the association with endurance exercise training. The study has been performed on a well-established model of cancer cachexia, namely mice bearing the Lewis lung carcinoma (LLC). The results obtained show that EPA administration to tumor hosts does not modify the wasting process, while the association with the exercise results in partial restoration of both muscle mass and strength.
All materials were supplied by Sigma (St. Louis, MO, USA), unless differently specified.
Animals and experimental design
C57BL/6 mice weighing about 20 g (Interfauna, Barcelona, Spain) were maintained on a regular dark–light cycle (light from 08:00 to 20:00) with free access to food and water during the whole experimental period. They were cared for in compliance with the Policy on Humane Care and Use of Laboratory Animals elaborated by the National Institues of Health. The experimental protocol has been approved by the Bioethical Committee of the University of Barcelona. All animal manipulations were made in accordance with the European Community guidelines for the use of laboratory animals.
Animals were randomized and divided into two groups, namely controls (C, n = 15) and tumor bearers (LLC, n = 24). Tumor-bearing mice were inoculated intramuscularly with 5 × 105 LLC cells. Both controls and LLC where divided into three sub-groups (n = 5 for C, n = 8 for LLC): untreated, treated with EPA, and treated with EPA and submitted to endurance exercise. EPA-treated groups received daily intragastric administration of 0.5 g/kg EPA in corn oil starting from the fourth day of tumor growth (the same dose used by [19]) while untreated groups received vehicle alone. As for the exercise protocol, mice were exercised on a Panlab/Harvard-Apparatus treadmill (Barcelona, Spain). Briefly, mice were made to get used to the treadmill for 5 days before tumor injection (starting from 6 m/min for 15 min, increasing speed and time daily until reaching 60–70% of maximum oxygen consumption, corresponding to 14 m/min for 45 min). VO2 max (using a Panlab/Harvard-Apparatus Oxylet System, Barcelona, Spain) was measured after the 5 days adaptation period, and the exercise conditions were maintained constant for all the experimental period. Mice were exercised 5 days/week starting the day after tumor implantation. A schematic drawing of the experimental design including the time points of the different measures in the animals is presented in Fig. 1.
Schematic drawing of the experimental design including the time points of the different measurements performed in the mice. Group size is presented in parentheses
Animal weight and food intake were recorded daily. Tumor-bearing mice were sacrificed under anesthesia 14 days after tumor injection. Several muscle ant tissues were rapidly excised, weighed, frozen in isopentane cooled with liquid nitrogen, and stored at −80°C for further analysis.
Total physical activity
Total physical activity (IR ACTIMETER System and ACTITRAK software from PANLAB, Barcelona) was determined during the last 24 h before the sacrifice of the animals in control and tumor-bearing animals using activity sensors that translate individual changes in the infrared pattern caused by movements of the animals into arbitrary activity counts [20]. For the measurements, animals remained in their home cage. A frame containing an infrared beam system was placed on the outside of the cage; this minimized stress to the animals.
Grip force assessment
Skeletal muscular strength in mice was quantified by the grip-strength test [21, 22]. The grip-strength device (Panlab/Harvard Apparatus, Spain) comprised a triangular pull bar connected to an isometric force transducer (dynamometer). Basically, the grip-strength meter was positioned horizontally, and the mice are held by the tail and lowered towards the device. The animals are allowed to grasp the triangular pull bar and were then pulled backwards in the horizontal plane. The force applied to the bar just before it lost grip was recorded as the peak tension. At least three measurements were taken per mouse on both baseline and test days, and the results were averaged for analysis.
γ-Interferon (IFN) serum levels were detected by a commercially available mouse ELISA kit, used according to the manufacturer instructions (Bender MedSystems, Vienna, Austria). Serum from each animal (50 μl) was assayed in duplicate. Quantitative calibration was obtained performing a standard curve with recombinant mouse γ-IFN.
Samples from gastrocnemius muscle (about 50 mg) were homogenized in 10 mM 4-(2-hydroxyethyl)-1 piperazineethanesulfonic acid (HEPES), pH 7.5, containing 10 mM MgCl2, 5 mM KCl, 0.1 mM ethylenediaminetetraacetic acid (EDTA), and 0.1% Triton X-100, with freshly added protease and phosphatase inhibitor cocktails, centrifuged at 3,000×g for 5 min at 4°C and the supernatant collected as cytosolic extract. The pellet was resuspended in 20 mM HEPES, pH 7.9, containing 1.5 mM MgCl2, 500 mM NaCl, 0.2 mM EDTA, and 25% glycerol, with freshly added protease and phosphatase inhibitor cocktails, incubated on ice for 30 min, centrifuged at 3,000×g for 5 min at 4°C, and the supernatant collected as nuclear extract. Protein concentration was assayed by the method of Lowry [23] using bovine serum albumine as working standard. Equal amounts of protein (30 μg) were heat-denaturated in sample-loading buffer (50 mM Tris–HCl, pH 6.8, 100 mM dithiothreitol, 2% Sodium Dodecyl Sulphate (SDS), 0.1% bromophenol blue, 10% glycerol), resolved by SDS-PolyAcrylamide Gel Electrophoresis and transferred to nitrocellulose membranes (Bio-Rad, Hercules, CA, USA). The filters were blocked with Tris-buffered saline containing 0.05% Tween and 5% non-fat dry milk and then incubated overnight with antibodies directed against: PGC-1 (Millipore, Billerica, MA, USA), atrogin-1 (ECM Biosciences, Versailles, KY, USA), and Pax7 (developed by Atsushi Kawakami, obtained from the Developmental Studies Hybridoma Bank, University of Iowa). Peroxidase-conjugated IgG (Bio-Rad, Hercules, CA, USA) were used as secondary antibodies. Membrane-bound immune complexes were detected by an enhanced chemiluminescence system (Santa Cruz Biotechnology, USA) on a photon-sensitive film (Hyperfilm ECL, GE Healthcare, Milano, Italy). Protein loading was normalized according to tubulin (Sigma, St. Louis, MO, USA) expression. Quantification of the bands was performed by densitometric analysis using specific software (TotalLab, NonLinear Dynamics, Newcastle upon Tyne, UK).
Proteasome enzymatic activity
Proteasome activity in the gastrocnemius was determined by cleavage of specific fluorogenic substrates. The tissue was homogenized in 20 mM Tris–HCl, pH 7.2, containing 0.1 mM EDTA, 1 mM 2-mercaptoethanol, 5 mM ATP, 20% glycerol, and 0.04% (v/v) Nonidet P-40. Muscle homogenates were then centrifuged at 13,000×g for 15 min at 4°C. The supernatant was collected and protein concentration determined as described above. Aliquots of 50 μg protein were then incubated for 60 min at 37°C in the presence of succinyl-Leu-Leu-Val-Tyr-7-AMC (LLVY). The incubation buffer for the evaluation of the enzymatic activity was 50 mM HEPES, pH 8.0, containing 5 mM ethylene glycol tetraacetic acid. Fluorescence was read with a spectrofluorometer (380 nm excitation, 460 nm emission; Perkin–Elmer, Norwalk, CT, USA). The activity was calculated by using free AMC as working standard.
Data analysis and presentation
All results were expressed as mean±SD. Significance of the differences was evaluated by analysis of variance followed by Tukey's test.
In comparison with control animals, mice bearing the LLC tumor markedly reduce their cumulative food intake; daily administration of EPA (0.5 g/kg; this dose effectively prevents cachexia in MAC16-bearing mice; see [19]) does not modify the decrease in food intake that is partially corrected by treatment with EPA and exercise (C = 64.8 g, LLC = 50.0 g, LLC EPA EX = 54.6 g; Fig. 2a).
Cumulative food intake (a) and voluntary grasping strength (b) in control (C) and LLC-bearing mice (LLC). Both groups were subdivided in untreated, EPA-treated (EPA), and EPA-treated plus exercised (EPA EX, see Section 2). Data (means±SD) expressed as grams (g) for food intake and Newtons (N) for strength. Significance of the differences: *p < 0.05 vs C; $ p < 0.05 vs LLC
In a voluntary grip-strength test, LLC-bearing mice develop a force 30% lower than control animals (\( C = {1}.{19}\pm 0.0{5}\;{\text{N}} \), \( {\text{LLC}} = 0.{84}\pm 0.{16}\,{\text{N}} \); Fig. 2b). EPA administration does not prevent force reduction in LLC hosts, whereas its combination with exercise results in a limited but significant recovery (\( {\text{LLC}}\;{\text{EPA}}\;{\text{EX}} = 0.{96}\pm 0.{21}\;{\text{N}} \), p = 0.04 vs LLC). Muscle strength in control groups is not affected by EPA or EPA + exercise (Fig. 2b).
Analysis of the animal behavior, evaluated for 24 h in a continuous recording activity cage, shows a dramatic fall in the total activity of LLC-bearing mice (Fig. 3a); both fast and slow movements are reduced, the former more markedly than the latter (Fig. 3b). Despite the protection exerted against muscle weight loss, the combination of EPA and exercise reveals unable to prevent the decrease of both total and specific activity induced by LLC growth (Fig. 3a, b). Activity (total or specific) in control groups is qualitatively comparable to the corresponding LLC hosts (Fig. 3a, b).
a Spontaneous locomotor activity in control (C) and LLC-bearing mice (LLC) either untreated or EPA-treated and exercised (EPA EX). Data (means±SD) expressed as percentages of controls. Significance of the differences: **p < 0.01 vs C. b The total activity was subdivided in percentage of resting time, slow movements (between 2 and 5 cm/s) and fast movements (faster than 5 cm/s)
Tumor growth in LLC-bearing mice is associated with loss of skeletal muscle mass (Fig. 4). Consistently with the loss of muscle strength, 14 days after tumor injection, the weight of both gastrocnemius and tibialis muscles is about 70% of controls (gastrocnemius, \( C = {57}0\pm {32} \), \( {\text{LLC}} = {417}\pm {3}0 \); tibialis: \( C = {163}\pm {13} \), \( {\text{LLC}} = {118}\pm {14}\;{\text{mg}}/{1}00\,{\text{g}} \) initial body weight). By contrast, the heart is only slightly affected and loses about 7% of control weight (\( C = {466}\pm {25} \), \( {\text{LLC}} = {434}\pm {31}\,{\text{mg}}/{1}00{\text{g}}\;{\text{i}}.{\text{b}}.{\text{w}}. \)). EPA treatment does not counteract muscle atrophy in LLC-bearing mice (Fig. 4). When EPA treatment is associated with training exercise, LLC-induced gastrocnemius depletion is partially prevented (\( {\text{LLC EPA EX}} = {455}\pm {24}\,{\text{mg}}/{1}00\,{\text{g}}\;{\text{i}}.{\text{b}}.{\text{w}}. \), p = 0.02 vs LLC; Fig. 4).
Gastrocnemius (GSN), tibialis and heart weight in control (C), and LLC-bearing mice (LLC). Both groups were subdivided in untreated, EPA-treated (EPA), and EPA-treated plus exercised (EPA EX, see Section 2). Data (means±SD) expressed as percentages of controls. Significance of the differences: ***p < 0.001 vs C; $ p < 0.05 vs LLC
Among the other tissues analyzed, liver weight is unchanged in all experimental groups, while spleen mass increases about fourfold in all LLC-bearing animals, independently from the treatment (Fig. 5). The systemic inflammation, suggested by the spleen hypetrophy, is confirmed by the increased circulating levels of γ-IFN (\( C = {46}\pm {3}0 \), \( {\text{LLC}} = {188}\pm {127}\,{\text{pg}}/{\text{ml}} \)). Similar to the spleen weight, EPA administration, alone or in combination with the exercise, does not prevent the γ-IFN raise (\( {\text{LLC EPA}} = {194}\pm {141} \), \( {\text{LLC EPA EX}} = {196}\pm {118}\,{\text{pg}}/{\text{ml}} \)). Finally, white perirenal adipose tissue virtually disappears in both untreated and treated LLC hosts (Fig. 5).
Liver, spleen, perirenal white adipose tissue (WAT) and tumor weight in control (C) and LLC-bearing mice (LLC). Both groups were subdivided in untreated, EPA-treated (EPA) and EPA-treated plus exercised (EPA EX, see Section 2). Data (means±SD) expressed as percentages of controls. Significance of the differences: ***p < 0.001 vs C; $ p < 0.05 vs LLC
Tumor mass remains comparable between untreated and EPA-treated mice (Fig. 5). However, when EPA is coupled to exercise, a small but statistically significant tumor reduction in size can be observed (\( {\text{LLC}} = {5}.{42}\pm 0.{46} \), \( {\text{LLC EPA EX}} = {4}.{42}\pm 0.{92}\,{\text{g}} \), p = 0.013; Fig. 5).
Muscle wasting in cancer cachexia mainly relies on a hypercatabolic response in which the ubiquitin–proteasome system seems to play a major role [24]. Atrogin-1 is a muscle-specific Ub-protein ligase (E3) critically involved in the enhancement of proteolysis [25], overexpressed in several conditions associated with muscle atrophy [26]. In apparent contrast with these reports, however, the present study shows that atrogin-1 protein expression in the gastrocnemius is comparable between untreated and treated LLC-bearing mice (Fig. 6a). This observation suggests that atrogin-1 expression might not the best marker of muscle proteolysis, as recently proposed [27], and/or that other catabolic systems likely contribute to muscle wasting in LLC hosts. The latter hypothesis is supported by the observation that proteasome chymotrypsin-like activity does not increase in the skeletal muscle of TB mice, at least at the time point considered in the present study (Fig. 6b).
a Atrogin-1 protein expression in the cytosolic fraction in the GSN of controls, LLC-bearing mice (LLC), and LLC-treated with EPA plus exercised (EPA EX, see Section 2). Densitometric quantifications were normalized according to tubulin levels. b Proteasome enzymatic activity in the above-mentioned experimental groups. Data (means±SD) expressed as percentages of controls
Protein hypercatabolism apart, muscle wasting could also be associated with alterations in the myogenic process. Impaired myogenesis has been recently suggested to contribute to the onset of muscle wasting in experimental cancer cachexia [28]. Pax7 protein levels, measured in the nuclear extracts, markedly increase in LLC-bearing mice (Fig. 7); such increase is prevented in part by the combination EPA + exercise.
PAX-7 and PGC-1 protein expression in the nuclear fraction in the GSN of controls, LLC-bearing mice (LLC) and LLC-treated with EPA plus exercised (EPA EX, see Section 2). Densitometric quantifications were normalized according to GAPDH levels. Data (means±SD) expressed as percentages of controls. Significance of the differences: *p < 0.05 vs C; **p < 0.01 vs C; $ p < 0.05 vs LLC
Previous observations have shown that the levels of the peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1 (PGC-1), a factor that stimulates the switch from glycolytic to oxidative fibers, is reduced in different models of skeletal muscle atrophy, including cancer cachexia [29, 30]. In the present experimental setting, however, PGC-1 protein levels do not decrease in tumor-bearing mice with respect to controls, while they are increased by EPA administration coupled to exercise (Fig. 7).
In the present study, EPA, a widely studied PUFA, was combined with exercise training in order to enhance its hypothetical effectiveness in the prevention of experimental cancer cachexia.
Several studies proposed PUFA supplementation as an effective tool against different pathologies, including sepsis, coronary artery disease, asthma, inflammatory bowel disease, and cancer (reviewed in [31]). The results obtained in the present study showed that EPA administration to LLC-bearing mice was completely ineffective in preventing tumor-induced muscle wasting. This is in contrast with a number of reports demonstrating a protective action of EPA in mice bearing the MAC16 tumor [19, 32–34]. The discrepancy between the present results on LLC-bearing mice and those reported in the MAC16 hosts could reside in the intrinsic differences that characterize these experimental models. In this regard, studies performed on rats bearing the AH-130 hepatoma [12] and clinical trials involving cachectic patients affected by gastrointestinal or lung cancer [15] reported the ineffectiveness of EPA supplementation. Finally, another fatty acid with antinflammatory properties, the c9t11 conjugated linoleic acid, did not improve muscle depletion in Colon26-bearing mice [35]. These considerations apart, however, the possibility that the dose of EPA adopted in the present study might be insufficient to elicit changes should be taken into account. Actually, there is no general consensus about the optimal EPA dosage needed to obtain pharmacological effects. As an example, 110 mg/day was required to revert insulin resistance in obese mice [36] while 0.49 mg/day were used in another study [37]; in both reports, EPA supplementation was effective, despite the very different range (200-folds). The doses above are 11-fold higher and 20-fold lower, respectively, than the one used in the present study (0.5 g/kg body weight, corresponding to 10 mg/day). Choosing EPA dosage, particular attention has been given to look for a therapeutic dose unable to interfere with tumor growth. In this regard, 0.5 g/kg was shown to prevent muscle wasting in MAC16-bearing mice [19] while 2.5 g/kg also resulted in tumor growth inhibition [32], rendering quite impossible to enucleate muscle-specific effects of the treatment.
In the clinical practice, exploitation of the potential benefits of PUFA administration is still largely limited by the poor knowledge of their mechanisms of action. In this regard, PUFA therapeutic effects are commonly accepted to rely on their antinflammatory actions, exerted by reducing the production of inflammatory cytokines, such as tumor necrosis factor alpha, interleukin-1, and interleukin-6 [31]. In the present study, spleen weight, an indirect indicator of the systemic inflammatory state, was increased by fourfold in LLC-bearing mice and not modified by EPA administration, suggesting that tumor-induced systemic inflammation was only marginally affected by the treatment. This hypothesis is further supported by the observation that circulating levels of γ-IFN, the mediator mainly involved in the pathogenesis of cachexia in LLC-bearing mice [38], increased in tumor hosts and were not modified by EPA. In this regard, a recent study proposed that suppression of immune response and proinflammatory cytokine production by PUFA may not be a general finding [39].
Summarizing, treatment with EPA alone does not appear suitable to prevent cancer cachexia, despite being a good candidate for the treatment of other experimental wasting conditions such as diabetes [40] and arthritis [41]. The different effectiveness of EPA in counteracting the various types of muscle atrophies may depend on the underlying pathogenetic mechanisms. As an example, the redox imbalance differently contributes to muscle depletion in diabetes and in cancer cachexia, as shown by the observation that antioxidant treatment markedly prevented muscle atrophy in the former while only partially in the latter [42].
Several reports suggested training exercise as a strategy to mitigate muscle wasting in chronic pathological conditions (reviewed in [17]). The underlying mechanisms accounting for these protective effects are still not entirely clear. Exercise training was proposed to stimulate mitochondrial biogenesis to increase muscle protein synthesis rate and to attenuate protein hypercatabolism [17]. Moreover, resistance training proved effective in restoring lean body mass and function in patients with rheumatoid arthritis-related cachexia, stimulating the enhancement of muscle IGF-1 levels [43].
Unfortunately, the usefulness of exercise in cancer patients received little attention in the past. The currently available data provide preliminary evidence that exercise training is a well-tolerated and safe complementary therapy that can mitigate several common treatment-related side effects, including breath shortness and pain [44]. A common feature of cancer patient is fatigue. In this regard, a large body of evidence supports the beneficial effect of exercise training in counteracting fatigue [45]. In the present work, we provide the first evidence that endurance training coupled to EPA administration partially prevented the loss of muscle mass and strength in tumor-bearing mice. The improvement of muscle depletion was associated with a small but significant decline in tumor burden in exercised, EPA-treated mice, while no differences were seen in mice treated with EPA alone. This observation is consistent with previous data showing that anaerobic resistance training in Waker-256-bearing rats strongly reduced tumor growth [46] while swimming exercise attenuated colon carcinogenesis in the rat [47]. On the contrary, however, another study reported that tumorigenesis increased in p53-deficient mice exercised with a treadmill protocol similar to the one used in the present study [48]. Exercise-induced suppression of tumor growth was hypothesized to depend on modulations of inflammation [49, 50]. However, both spleen hypertrophy and γ-IFN circulating levels in LLC-bearing mice were not affected by the combination of exercise and EPA, suggesting that, at least in the present experimental conditions, the systemic inflammatory response is not involved in the inhibition of LLC growth. On the whole, the effect of exercise training on tumor growth is still debated, and on the other side, the modulation of molecular pathways induced by the exercise plus EPA in the muscle suggests that the small reduction of tumor growth has a limited relevance in the anti-cachectic effects here reported.
EPA did not prevent muscle wasting when administered alone but was able to modulate both muscle mass and strength when coupled to exercise. From this point of view, the effectiveness of EPA + exercise could primarily result from exercise alone. Although this is a relevant point, such possibility was discarded in the present study, since previous results obtained on Colon26-bearing mice showed that the same exercise protocol adopted for the LLC hosts not only did not prevent, but even worsened tumor-induced muscle wasting (Electronic Supplementary Fig. S1). Similar results were obtained when Colon26-bearing mice were exposed to an 8-week exercise protocol, thus excluding that the lack of protection could depend on exercise duration and suggesting the adoption of a combined approach.
The association of EPA with exercise in LLC-bearing mice resulted in attenuation of tumor-induced anorexia, associated with unchanged voluntary (extra-exercise) activity that was close to untreated LLC bearers. In this regard, physical conditions in LLC hosts might be improved by exercise and EPA, leading tumor bearers to cope with the increased energy requirements by enhancing food intake rather than by further increasing the resting period, already significantly higher than that observed in treated, exercised controls. On the other side, food intake remained comparable between control groups (EPA-treated, exercised, and EPA untreated, sedentary). Such a discrepancy between trained, EPA-treated controls, and LLC hosts might reflect a different response to exercise. Indeed, voluntary activity was lower in trained than in sedentary controls, suggesting that healthy animals managed the enhanced energy requirement by simply recovering after exercise, without modifying food intake. On the contrary, in LLC hosts, resting time, already markedly higher than in controls, did not further increase after training. Also taking into consideration that cachexia can be associated with increased resting energy expenditure [10], modulation of food intake might be the mechanism by which trained animals manage the enhanced energy requirement.
Apart from reduced food intake that was shown to play a limited role in cancer-associated muscle depletion [26, 35], other tumor-induced metabolic alterations could be targeted by the exercise. Indeed, endurance exercise was shown to induce the restoration of lipid metabolism in tumor-bearing rats [51] while resistance exercise modulates both protein synthesis and degradation rates in normal or wasting conditions (reviewed by [52]). Finally, resistance training increased muscle mitochondrial biogenesis in patients affected by chronic kidney disease [53]. In the present work, endurance training in association with EPA induced the increase of PGC-1 protein levels in LLC-bearing mice, possibly stimulating mitochondrial biogenesis and a shift from fast- to slow-twitch oxidative fibers, less susceptible to atrophy.
Recent data showed that muscle wasting in Colon26-bearing mice was associated with reduced myogenin levels and increased expression of Pax7, an inhibitor of the myogenic program [54], suggesting the occurrence of impaired myogenesis [28]. The results obtained in the present work confirmed the enhancement of Pax7 expression also in the skeletal muscle of LLC-bearing mice; this might suggest an increased satellite cell proliferation or their impaired differentiation. Loss of myonuclei, previously reported in Colon26-bearing mice [55], could lead to enhancement of satellite cell proliferation; such increase, however, could be vanished by the inability to complete the myogenic program, contributing to the atrophic phenotype. The present work provides the first evidence that endurance exercise, even for the short period adopted for this study, in association with EPA, partially prevented muscle Pax7 increase in LLC hosts; this observation suggests that satellite cells might proceed into the myogenic program, thus partially explaining the protection exerted by such experimental protocol against LLC-induced muscle wasting.
In conclusion, the results shown in the present study demonstrate that the association between EPA and endurance exercise improved muscle wasting in LLC hosts, mainly by modulating some of the molecular pathways involved in the pathogenesis of muscle depletion, encouraging the inclusion of training exercise in the multi-disciplinary therapeutic approach that should be adopted to prevent cancer cachexia.
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Sinis N, Guntinas-Lichius O, Irintchev A, Skouras E, Kuerten S, Pavlov SP, et al. Manual stimulation of forearm muscles does not improve recovery of motor function after injury to a mixed peripheral nerve. Exp Brain Res. 2008;185:469–83. doi:10.1007/s00221-007-1174-y.
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193:265–75.
Acharyya S, Guttridge DC. Cancer cachexia signaling pathways continue to emerge yet much still points to the proteasome. Clin Cancer Res. 2007;13:1356–61. doi:10.1158/1078-0432.CCR-06-2307.
Gomes MD, Lecker SH, Jagoe RT, Navon A, Goldberg AL. Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy. Proc Natl Acad Sci USA. 2001;98:14440–5. doi:10.1073/pnas.251541198.
Lecker SH, Jagoe RT, Gilbert A, Gomes M, Baracos V, Bailey J, et al. Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. FASEB J. 2004;18:39–51. doi:10.1096/fj.03-0610com.
Attaix D, Baracos VE. MAFbx/Atrogin-1 expression is a poor index of muscle proteolysis. Curr Opin Clin Nutr Metab Care. 13:223–4. doi:10.1097/MCO.0b013e328338b9a6
Penna F, Costamagna D, Fanzani A, Bonelli G, Baccino FM, Costelli P. Muscle wasting and impaired myogenesis in tumor bearing mice are prevented by ERK inhibition. PLoS One. 5:e13604. doi:10.1371/journal.pone.0013604.
Sandri M, Lin J, Handschin C, Yang W, Arany ZP, Lecker SH, et al. PGC-1alpha protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proc Natl Acad Sci USA. 2006;103:16260–5. doi:10.1073/pnas.0607795103.
Penna F, Bonetto A, Muscaritoli M, Costamagna D, Minero VG, Bonelli G et al. Muscle atrophy in experimental cancer cachexia: Is the IGF-1 signaling pathway involved? Int J Cancer. 127:1706–17. doi:10.1002/ijc.25146.
Fetterman Jr JW, Zdanowicz MM. Therapeutic potential of n-3 polyunsaturated fatty acids in disease. Am J Health-Syst Pharm. 2009;66:1169–79. doi:10.2146/ajhp080411.
Beck SA, Smith KL, Tisdale MJ. Anticachectic and antitumor effect of eicosapentaenoic acid and its effect on protein turnover. Cancer Res. 1991;51:6089–93.
Smith HJ, Greenberg NA, Tisdale MJ. Effect of eicosapentaenoic acid, protein and amino acids on protein synthesis and degradation in skeletal muscle of cachectic mice. Br J Cancer. 2004;91:408–12. doi:10.1038/sj.bjc.6601981.
Whitehouse AS, Smith HJ, Drake JL, Tisdale MJ. Mechanism of attenuation of skeletal muscle protein catabolism in cancer cachexia by eicosapentaenoic acid. Cancer Res. 2001;61:3604–9.
Tian M, Kliewer KL, Asp ML, Stout MB, Belury MA. c9t11-Conjugated linoleic acid-rich oil fails to attenuate wasting in colon-26 tumor-induced late-stage cancer cachexia in male CD2F1 mice. Mol Nutr Food Res. doi:10.1002/mnfr.201000176.
Kalupahana NS, Claycombe K, Newman SJ, Stewart T, Siriwardhana N, Matthan N et al. Eicosapentaenoic acid prevents and reverses insulin resistance in high-fat diet-induced obese mice via modulation of adipose tissue inflammation. J Nutr. 140:1915–22. doi:10.3945/jn.110.125732.
Bonnet N, Ferrari SL. Effects of long-term supplementation with omega-3 fatty acids on longitudinal changes in bone mass and microstructure in mice. J Nutr Biochem. doi:10.1016/j.jnutbio.2010.05.006.
Matthys P, Heremans H, Opdenakker G, Billiau A. Anti-interferon-gamma antibody treatment, growth of Lewis lung tumours in mice and tumour-associated cachexia. Eur J Cancer. 1991;27:182–7.
Rockett BD, Salameh M, Carraway K, Morrison K, Shaikh SR. n-3 PUFA improves fatty acid composition, prevents palmitate-induced apoptosis, and differentially modifies B cell cytokine secretion in vitro and ex vivo. J Lipid Res. 51:1284–97. doi:10.1194/jlr.M000851.
Figueras M, Olivan M, Busquets S, Lopez-Soriano FJ, Argiles JM. Effects of eicosapentaenoic acid (EPA) treatment on insulin sensitivity in an animal model of diabetes: improvement of the inflammatory status. Obesity (Silver Spring). doi:10.1038/oby.2010.194.
Castillero E, Martin AI, Lopez-Menduina M, Villanua MA, Lopez-Calderon A. Eicosapentaenoic acid attenuates arthritis-induced muscle wasting acting on atrogin-1 and on myogenic regulatory factors. Am J Physiol Regul Integr Comp Physiol. 2009;297:R1322–31. doi:10.1152/ajpregu.00388.2009.
Mastrocola R, Reffo P, Penna F, Tomasinelli CE, Boccuzzi G, Baccino FM, et al. Muscle wasting in diabetic and in tumor-bearing rats: role of oxidative stress. Free Radic Biol Med. 2008;44:584–93. doi:10.1016/j.freeradbiomed.2007.10.047.
Lemmey AB, Marcora SM, Chester K, Wilson S, Casanova F, Maddison PJ. Effects of high-intensity resistance training in patients with rheumatoid arthritis: a randomized controlled trial. Arthritis Rheum. 2009;61:1726–34. doi:10.1002/art.24891.
Jones LW, Peppercom J, Scott JM, Battaglini C. Exercise therapy in the management of solid tumors. Curr Treat Options Oncol. 11:45–58. doi:10.1007/s11864-010-0121-5.
Barsevick AM, Newhall T, Brown S. Management of cancer-related fatigue. Clin J Oncol Nurs. 2008;12:21–5. doi:10.1188/08.CJON.S2.21-25.
de Lima C, Alves LE, Iagher F, Machado AF, Bonatto SJ, Kuczera D, et al. Anaerobic exercise reduces tumor growth, cancer cachexia and increases macrophage and lymphocyte response in Walker 256 tumor-bearing rats. Eur J Appl Physiol. 2008;104:957–64. doi:10.1007/s00421-008-0849-9.
Demarzo MM, Martins LV, Fernandes CR, Herrero FA, Perez SE, Turatti A, et al. Exercise reduces inflammation and cell proliferation in rat colon carcinogenesis. Med Sci Sports Exerc. 2008;40:618–21. doi:10.1249/MSS.0b013e318163274d.
Colbert LH, Westerlind KC, Perkins SN, Haines DC, Berrigan D, Donehower LA, et al. Exercise effects on tumorigenesis in a p53-deficient mouse model of breast cancer. Med Sci Sports Exerc. 2009;41:1597–605. doi:10.1249/MSS.0b013e31819f1f05.
Lira FS, Rosa JC, Zanchi NE, Yamashita AS, Lopes RD, Lopes AC, et al. Regulation of inflammation in the adipose tissue in cancer cachexia: effect of exercise. Cell Biochem Funct. 2009;27:71–5. doi:10.1002/cbf.1540.
Batista ML, Jr., Rosa JC, Lopes RD, Lira FS, Martins E, Jr., Yamashita AS et al. Exercise training changes IL-10/TNF-alpha ratio in the skeletal muscle of post-MI rats. Cytokine. 49:102–8. doi:10.1016/j.cyto.2009.10.007.
Lira FS, Tavares FL, Yamashita AS, Koyama CH, Alves MJ, Caperuto EC, et al. Effect of endurance training upon lipid metabolism in the liver of cachectic tumour-bearing rats. Cell Biochem Funct. 2008;26:701–8. doi:10.1002/cbf.1495.
Little JP, Phillips SM. Resistance exercise and nutrition to counteract muscle wasting. Appl Physiol Nutr Metab. 2009;34:817–28. doi:10.1139/h09-093.
Balakrishnan VS, Rao M, Menon V, Gordon PL, Pilichowska M, Castaneda F et al. Resistance training increases muscle mitochondrial biogenesis in patients with chronic kidney disease. Clin J Am Soc Nephrol. 5:996–1002. doi:10.2215/CJN.09141209.
Olguin HC, Olwin BB. Pax-7 up-regulation inhibits myogenesis and cell cycle progression in satellite cells: a potential mechanism for self-renewal. Dev Biol. 2004;275:375–88. doi:10.1016/j.ydbio.2004.08.015.
Berardi E, Aulino P, Murfuni I, Toschi A, Padula F, Scicchitano BM, et al. Skeletal muscle is enriched in hematopoietic stem cells and not inflammatory cells in cachectic mice. Neurol Res. 2008;30:160–9. doi:10.1179/174313208X281046.
von Haehling S, Morley JE, Coats AJS, Anker SD. Ethical guidelines for authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle. J Cachexia Sarcopenia Muscle. 2010;1:7–8.
All authors of this manuscript certify that they comply with the ethical guidelines for authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle [56].
Fabio Penna received grant support from MFAG6211-Associazione Italiana per la Ricerca sul Cancro (AIRC), Milano. Paola Costelli received supprt from IG9153 AIRC, Milano; Fondazione San Paolo, Torino; Ministero per l'Università e la Ricerca, Roma (PRIN projects); University of Torino (ex-60% funds); and Regione Piemonte. Josep M. Argilés received support from Ministerio de Ciencia y Tecnología of Spain (SAF-02284-2008).
The authors state they have no conflict of interest.
Department of Experimental Medicine and Oncology, University of Torino, Torino, Italy
Fabio Penna, Fabrizio Pin, Francesco M. Baccino & Paola Costelli
Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
Fabio Penna, Silvia Busquets, Miriam Toledo, Francisco J. López-Soriano & Josep M. Argilés
Fabio Penna
Silvia Busquets
Fabrizio Pin
Miriam Toledo
Francesco M. Baccino
Francisco J. López-Soriano
Paola Costelli
Josep M. Argilés
Correspondence to Fabio Penna.
Below is the link to the electronic supplementary material.
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Penna, F., Busquets, S., Pin, F. et al. Combined approach to counteract experimental cancer cachexia: eicosapentaenoic acid and training exercise. J Cachexia Sarcopenia Muscle 2, 95–104 (2011). https://doi.org/10.1007/s13539-011-0028-4
Issue Date: June 2011
Experimental cancer cachexia
Muscle wasting


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Actors perform in "The Braille Legacy." (LA Times Today)
Visually impaired cast brings 'The Braille Legacy' to life onstage
By LA Times Today Staff Inglewood
PUBLISHED 3:16 PM PT Jun. 30, 2022 PUBLISHED 3:16 PM PDT Jun. 30, 2022
"The Braille Legacy" is a musical about the boy who invented a system of reading and writing for the blind.
It debuted to sell out crowds in Los Angeles in June, marking the first time the show had been performed in the U.S. — and the first time it was performed by a cast fully comprised of blind actors.
The cast spoke with "LA Times Today." Coco Atama plays Louis Braille in "The Braille Legacy" and discussed why it's important for this musical to be staged.
"We felt like this was a story that needed to be told. This was an experience that needed to be brought to people so that they could not only understand what life was like in a world where literacy, simple literacy, was elusive to you, but also to understand we are not done yet. There's a lot that we need to do before blind people can feel fully adequate in this world."
Theater by the Blind is the only entirely blind theater company in the country. Some actors are completely blind, and others have varying levels of partial blindness.
"We do need a little extra help, but who doesn't?" said Malaika Mitchell, who plays Rose. "The way we need help is not to the point to where we're convalescent. We didn't get the help with the acting or the singing that was already a talent. It's just someone actually giving us an opportunity to show our talents."
"We work to navigate a stage together and learn through sound cues, how to get around, and texture and surfaces that are on the floor that allow you to orientation of space," said director Greg Shane. "The road to get to tonight was so long and filled with so many challenges. But I think it's just so impressive to have a cast that stuck together two and a half years. But 99% of them were all together standing on stage. ... That's pretty impressive."
Opening night was emotional for Mitchell and her castmates.
"When we got a standing ovation. I just broke down crying just because we worked so hard. We did it," she said.
Click the arrow above to watch the full video.
Watch "LA Times Today" at 7 and 10 p.m. Monday through Friday on Spectrum News 1 and the Spectrum News app.

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Amazon buy newest twist in MGM saga
Georgina Giles 7 October, 2021 7 October, 2021
From "Gone With the Wind" to "Ben-Hur" to James Bond, the enduring MGM film studio, symbolized by its roaring lion, has a storied historical past worthy of a Hollywood blockbuster.
Within the newest chapter within the up-and-down saga of the practically century-old firm, MGM is being purchased by on-line purchasing large Amazon for $8.45 billion.
Metro Goldwyn Mayer was created in 1924 with the merger of Metro Photos Corp., Goldwyn Photos and Louis B. Mayer Productions.
Mayer and producer Irving Thalberg, referred to as "The Boy Surprise," seized the reins of the studio and helped usher in what got here to be referred to as the Golden Age of Hollywood.
MGM's wealthy historical past spans from the early days of black-and-white silent motion pictures to the primary movies in Technicolor to the digital period of immediately.
Its heyday was within the Nineteen Thirties, '40s and '50s when it dominated the Hollywood scene with a galaxy of stars that included Greta Garbo, Joan Crawford, Clark Gable, Katherine Hepburn, Mickey Rooney, Spencer Tracy and Elizabeth Taylor.
The corporate's unofficial motto: "Extra stars than there are in heaven."
Its official motto — in lettering above Leo the Lion — "Ars Gratia Artis," or "Artwork for artwork's sake."
In 1939, MGM motion pictures "Gone With the Wind" and "The Wizard of Oz" had been each nominated for Finest Image on the Academy Awards.
"Gone With the Wind" gained.
Lavish musicals equivalent to "Singin' within the Rain" additionally turned a trademark of the studio that includes such stars as Judy Garland, Fred Astaire and Gene Kelly.
In 1959, MGM produced considered one of its greatest field workplace hits, "Ben-Hur" starring Charlton Heston, which went on to win 11 Academy Awards.
– Inventive stoop –
MGM went right into a inventive stoop starting within the Nineteen Sixties although it nonetheless produced such classics through the decade equivalent to "Physician Zhivago" in 1965 and "2001: A House Odyssey" in 1968.
After years of decline, the fading studio was purchased by billionaire investor Kirk Kerkorian in 1969.
Kerkorian would go on to purchase and promote MGM twice extra over the following few years, together with as soon as to Ted Turner, who would take management of a lot of the corporate's pre-1986 catalog of movies.
One other main studio, United Artists, as soon as residence to Charlie Chaplin, Mary Pickford and different early silent film stars, merged with MGM in 1981.
In 2010, MGM filed for chapter and resurfaced beneath new possession.
MGM's present archive contains greater than 4,000 motion pictures together with Finest Image winners equivalent to "The Condo," "West Aspect Story," "Midnight Cowboy," "Rocky," "Annie Corridor," "Platoon," "Rain Man," "Dances With Wolves" and "The Silence of the Lambs."
Among the many movie franchises nonetheless owned by MGM are James Bond, Rocky and The Pink Panther.
Based on MGM, 007 alone has earned the corporate practically $7 billion in worldwide field workplace receipts whereas the Rocky and Creed sequence has pulled in one other $1 billion.
MGM's present tv archive of greater than 17,000 episodes contains such standard sequence as "The Handmaid's Story" and "Fargo" in addition to actuality TV exhibits equivalent to "Survivor."
Like different film studios, MGM was exhausting hit over the previous 12 months by the Covid-19 pandemic and was pressured to delay the discharge of its newest money-spinning Bond flick, "No Time to Die."
The motion movie starring Daniel Craig was initially scheduled to hit theaters in March 2020. It'll now be launched in September.
cl/bgs
Tagged Amazon, latest, MGM, purchase, saga, twist
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COLUMBIA- The annual blood drive for fallen officer Molly Bowden came at a time when collecting blood is vital.
The American Red Cross has paired with this specific drive since 2012 and a representative said the organization has cancelled 500 blood drives in 2018 due to weather.
"We're under urgent appeal. That's where hospitals are using blood as fast as we can collect it. This drive today, along with all the other drives, is so very important so we can have blood product for our patients," Red Cross Account Manager Jennifer Books said.
Just one unit of blood can save up to three lives.
Molly Bowden, 26, was a officer with the Columbia Police Department for over three years. She was killed in 2005 during a routine traffic stop. Bowden was the first Columbia Police Officer to be killed in the line of duty.
Bowden's family and friends believe the blood drive is something she would be proud to have her name attached to.
"I think she would be so excited to see the impact that her life has been able to have on the community," family friend Beth Cowgill said.
Bowden inspired Cowgill to pursue a career in law enforcement but family life interfered with the opportunity. In order to still show support for first responders in the Columbia community, Cowgill founded a holiday campaign called Operation Holly Jolly Heroes.
"We raise money to create these little care packages that we hand deliver to law enforcement, first responders and EMT's in the area," Cowgill said.
Volunteers and the Columbia Police Department say that even though Bowden is no longer here, her spirit is shining down over the blood drive.
"We've got spectacular weather. This is the warmest day we've had in quite a while. So we like to say that Molly's looking down on us, smiling and very happy that we're all coming together as a community," Columbia Police Department Sergeant Chad Craig said.


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text:
Carl Osburn (USA)
Shooting spotlight
What we learned: Shooting wrap from the Tokyo 2020 Olympics
Vincent HANCOCK
Skeet Finals - Shooting | Tokyo 2020 Replays
Women's 25 Pistol Finals - Shooting | Tokyo 2020 Replays
Men's 25 Rapid Fire Pistol - Shooting | Tokyo 2020 Replays
Men's 50 Rifle 3 Positions Finals - Shooting | Tokyo 2020 Replays
Abhinav BINDRA
When Abhinav Bindra dug deep and found gold
Beijing 2008 | Olympic Games
Daily wrap-up: The top moments from Day 12 of the 2020 Paralympic Games in Tokyo
Paralympic Games | Tokyo 2020
Daily wrap-up: The top moments from Day 6 of the 2020 Paralympic Games in Tokyo
Discover & relive past events, watch Original Films & Series related to Shooting in Olympic Channel
From just five shooting events at the inaugural 1896 Olympic Games to the 15 today, the sport has grown steadily alongside the advance in firearms technology.
Shooting as a sport has been practised for hundreds of years in European countries, with some German shooting clubs dating back more than 500 years. The popularity of the sport grew in English-speaking countries with the formation of the National Rifle Association in 1859, which originally met in Wimbledon, London, and the National Rifle Association (USA) in 1871.
There are 15 events in the Olympic programme, divided into three different groups: rifle, pistol and shotgun. The rifle and pistol competitions are held on shooting ranges, where marksmen aim at targets at distances of 10, 25 and 50 metres. In the shotgun event, competitors shoot at clay targets propelled at a series of different directions and angles.
Heartbeats and Bullseyes
Marksmen need to be as steady as possible to be accurate. In order to achieve this, they use relaxation techniques to drop their heartbeat to half its normal rate, fire between heartbeats and use blinkers to hit a bullseye, which appears as no more than a tiny dot in the distance.
Comeback King
As an example of overcoming adversity, Karoly Takacs has few peers. He was part of Hungary's world champion pistol-shooting team in 1938, when an army grenade exploded, crippling his right hand. Ten years later, having taught himself to shoot with his left, he won two gold medals in the rapid-fire class.


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"A Thought" to change the perception of Heritage in India!
By Debarati Roy
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"Mujhe ek khayaal aya!" (An idea just crossed my mind!)- That's how most of our innovations begin. Just having a vision doesn't really work every time. The portrayal of that vision is equally important to get the idea delivered well. I have been working up my mind since quite a few days now, wondering what to cover for my first blog. And finally, I got this 'thought'. Yes, a thought about writing the most inspiring story I came across lately. It is about four such youngsters who come from varied socio-cultural backgrounds. They come collectively to work on 'one thought' that binds the entire nation together.
The one who acted as my source for this wonderful idea is my best friend who is a part of this initiative. Her name is Shaoni and she is from West Bengal. Shaoni was in town for her visits in rural Bengal when I thought of meeting my busy friend for a cup of coffee. Surprisingly so, her other teammates were also accompanying her for the visit. I could not afford to miss the chance of meeting these creative souls. Her other friends include Aayushi (Delhi), Shailja (Ahmedabad) and Gourav (Nimar).
These four fresh post-graduates dreamt separately, until the zeal to have a social impact played the card. I would like to call them "The Fantastic Four", for their ideas might play a huge role in managing the heritage and the culture that resides in our nation. They are basically a group who has been traveling across the country collecting details about various art forms that are on the verge of extinction. They plan to work on them in a way that the artisans are able to earn out of it. Their idea is to promote the already existing cultural treasure to the modern world and create a social awareness through the endeavor. They like to call their venture "Khayaal- A thought".
'Khayaal' was born in the month of May 2018, on the occasion of World Museum Day. It is a social enterprise that works under four distinct territories namely 'Tohfa', the product wing, 'Biradari', the education wing, 'Iraadein', the event wing and 'Pehchaan', a virtual awareness wing. As Aayushi says, "We want to provide a platform for dialogue between people from different sections of the society".
One thing that struck a chord was the fact that they are doing it partly by their own money and then started a little fundraising and went through a lot of hurdles on a personal level. However, nothing could stop them from establishing their idea. Today, they have covered 17 cities, reached 12 craft practices with 10 handmade products and 10 institutional collaborations. All of this and more in just two months!
Our short conversation seemed too less for me to incorporate such wide ideas that these people have. I realized that our country is so rich in culture but a large part of it still lies unexplored. Being from a creative background myself, I could not help but fall in love with the concept of revisiting my roots through their vision. On one hand during my visits to the rural areas I came across issues regarding low demand of their local handmade products. It makes me sad to see how people work so hard just to get the recognition they deserve. But on the other hand, I also feel proud to be associated with the team Khayaal and relate to their dreams. Through my writing, I just hope to reach out to the greater mass of people and acknowledge their efforts.
With a huge scarcity of opportunities in this sector, this initiative opens the door for all the creative groups and their recognition. It gives me immense pleasure to have a conversation with such talented people. I look forward to their success and hope that they achieve a lot more with their noble cause in mind.


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Reading: Book review of Yoad Winter's Elements of formal semantics (2016)
Book review of Yoad Winter's Elements of formal semantics (2016)
Jessica Rett
UCLAUS
Yoad Winter's (2016) new textbook, Elements of formal semantics, is a formally sophisticated introduction to semantic theory. It treats standard beginner topics (e.g. transitivity, quantifiers, relative clauses) carefully and efficiently, using a directly compositional lambda calculus.
Keywords: textbook, semantics, lambda calculus, direct compositionality
How to Cite: Rett, J. (2016). Book review of Yoad Winter's Elements of formal semantics (2016). Glossa: A Journal of General Linguistics, 1(1), 42. DOI: http://doi.org/10.5334/gjgl.231
Published on 20 Oct 2016
Introductory semantics textbooks generally fall into three categories: empirically-driven; philosophically-driven; and formally-driven. Yoad Winter's very careful and thorough new book, Elements of Formal Semantics, falls into the latter category, making it a welcome and accessible successor to Allwood, Andersson, and Dahl's (1977) Logic in linguistics and L.T.F. Gamut's (1991) Logic, language, and meaning.
Elements of formal semantics (henceforth EFS) is published in a series geared towards "the later years of undergraduate study" but it is additionally quite suitable for two other populations: undergraduates with strong formal backgrounds interested in learning about basic linguistic semantics (students "of relevant undergraduate courses in artificial intelligence, computer science, cognitive science and philosophy," Winter 2016: 7); and beginner graduate students (perhaps alongside supplemental, empirically-driven texts).
EFS divides naturally into two parts. The first part addresses, quite efficiently, the standard underpinnings of Montague Grammar: set theory and model theory (Chapter 2), type logic and lambda calculus (Chapter 3), and Generalized Quantifier Theory (Chapter 4). The second part consists of useful extensions of this formal foundation, in particular a directly compositional treatment of relative clauses and other long-distance dependencies (Chapter 5), and a possible-worlds semantics for intensional expressions (Chapter 6).
EFS has several notable assets: it is formally careful and deliberate, as thorough as any logic textbook; it has a lot of varied and well-thought-out exercises (including practice exercises with solutions); a Conclusions chapter containing references on a number of phenomena (adjectives, definiteness, plurality, tense and aspect) students can extend the formal foundation to; and, at the end of each chapter, a Further Reading section that cites innovative, contemporary research articles as well as historical sources and other textbooks. As a result, it is a very versatile book, useful as a primary textbook, as a secondary textbook for more advanced or formally inclined students, or as a source of supplementary formal definitions and exercises.
The first four chapters of EFS cover roughly the same content as the first seven chapters of the familiar Semantics in generative grammar (henceforth SGG) by Heim and Kratzer (1993), and a direct comparison is useful for illustrating the unique contribution of the former. Both cover, in the same order: set theory; characteristic functions of sets; type logic; lambda calculus; and the semantics of quantifiers. SGG concentrates on the empirical motivation for each formal innovation, as well as creating a semantic theory that conforms to movement-based theories of syntax (introducing, famously, a semantics of traces and moved operators). But it does so at the cost of a thorough formal introduction: many teachers, including myself, have supplemented the text with their own inventory of metalanguage definitions and rules (e.g. a rule for beta-reduction in the lambda calculus) to allow students to perform the requested proofs in a principled way.
In contrast, EFS introduces its formalism (as well as its terms and notational conventions) impeccably carefully, in the tradition of logic textbooks, in a way that allows for more clear, thorough, and easy-to-follow exercises, and for students to more easily extend the formalism on their own to related phenomena if they choose to. Relations of type are, for instance, motivated formally (as a natural byproduct of the logic) instead of empirically (i.e. as needed for the treatment of transitive verbs). It accomplishes this, however, at the cost of some of the empirical motivation many linguistics students may be accustomed to, and it takes for granted that its readers know how to use a metalanguage and construct a proof.
Another notable difference is that EFS doesn't rely on any particular syntactic assumptions to treat these issues (although it does presuppose that its readers are familiar with constituency and tree diagrams). Instead of a treatment of moved operators (e.g. the Predicate Abstraction Rule in SGG), then, EFS introduces 'currying' (Winter 2016: 57) and type lifting (Winter 2016: 129), instruments that are refined in Chapter 5. And instead of assimilating the treatment of reflexives with traces and pronouns, as in SGG, EFS gives them a directly compositional variable-free treatment (Winter 2016: 70), inspired by Pauline Jacobson's work. These chapters additionally include a nice discussion of the difference between attributive and predicative adjectives on the one hand and intersective and subsective adjectives on the other; and of the properties of monotonicity and conservativity that are familiar from Generalized Quantifier Theory.
The second part of EFS turns to extensions of the formal foundation in this similarly precise, efficient, and directly compositional way. Chapter 5 introduces the Lambek-Van Bentham Calculus and treats relative clauses using a careful and intuitive explication of abstract types and function introduction. The contents of this chapter are the least standard of the book, but its discussion is so careful that it will be a useful exercise for even the most pro-movement of students, especially when viewed in contrast to the treatment of relative clauses in SGG. It can, at the very least, be read independently from the other chapters.
Chapter 6 is the most empirically rich chapter in the book, and is a nice combination of the motivating discussion of possible-world semantics in Allwood, Andersson and Dahl's Logic in linguistics and the modern, lambda-calculus introduction to intensional semantics in von Fintel and Heim's (2011) Intensional semantics lecture notes. Most notably, it contains an explicit model-theoretic discussion of intensions, and a very clear and theory-neutral explication of "The Quine-Montague Hypothesis," alleging that de dicto/de re ambiguities can be treated by the same mechanisms as scope ambiguity.
Students who are new to semantics tend to come in two varieties: those who have formal backgrounds, but little knowledge of syntax or linguistic methodology generally; and those who know linguistics, but have little experience with logics or formal systems. EFS is a great gift to the former, in the way that Heim and Kratzer's Semantics in generative grammar has been helpful to the latter. I believe that many teachers and students will benefit from a careful balance of both approaches, at both the undergraduate and graduate levels.
EFS = Elements of formal semantics, by Yoad Winter; SGG = Semantics in generative grammar, by Irene Heim and Angelika Kratzer
The author declares that she has no competing interests.
Allwood, Jens, Lars-Gunnar Andersson & Osten Dahl. 1977. Logic in linguistics. Cambridge: Cambridge University Press. DOI: https://doi.org/10.1017/CBO9780511621017.
Gamut, L.T.F. 1991. Logic, language, and meaning. University of Chicago Press.
Heim, Irene & Angelika Kratzer. 1998. Semantics in generative grammar. Malden, MA: Blackwell.
von Fintel, Kai & Irene Heim. 2011. Intensional semantics. Ms., Massachusetts Institute of Technology.
Winter, Yoad. 2016. Elements of formal semantics: An introduction to the mathematical theory of meaning in natural language. Edinburgh University Press.
Rett, J., 2016. Book review of Yoad Winter's Elements of formal semantics (2016). Glossa: a journal of general linguistics, 1(1), p.42. DOI: http://doi.org/10.5334/gjgl.231
Rett J. Book review of Yoad Winter's Elements of formal semantics (2016). Glossa: a journal of general linguistics. 2016;1(1):42. DOI: http://doi.org/10.5334/gjgl.231
Rett, J. (2016). Book review of Yoad Winter's Elements of formal semantics (2016). Glossa: A Journal of General Linguistics, 1(1), 42. DOI: http://doi.org/10.5334/gjgl.231
Rett J, 'Book Review of Yoad Winter's elements of Formal Semantics (2016)' (2016) 1 Glossa: a journal of general linguistics 42 DOI: http://doi.org/10.5334/gjgl.231
Rett, Jessica. 2016. "Book Review of Yoad Winter's elements of Formal Semantics (2016)". Glossa: A Journal of General Linguistics 1 (1): 42. DOI: http://doi.org/10.5334/gjgl.231
Rett, Jessica. "Book Review of Yoad Winter's elements of Formal Semantics (2016)". Glossa: A Journal of General Linguistics 1, no. 1 (2016): 42. DOI: http://doi.org/10.5334/gjgl.231
Rett, J.. "Book Review of Yoad Winter's elements of Formal Semantics (2016)". Glossa: A Journal of General Linguistics, vol. 1, no. 1, 2016, p. 42. DOI: http://doi.org/10.5334/gjgl.231