Cancer immunology and canine malignant melanoma: a comparative review

Oral canine malignant melanoma (CMM) is a spontaneously occurring aggressive tumour with relatively few medical treatment options, which provides a suitable model for the disease in humans. Historically, multiple immunotherapeutic strategies aimed at provoking both innate and adaptive anti-tumour immune responses have been published with varying levels of activity against CMM. Recently, a plasmid DNA vaccine expressing human tyrosinase has been licensed for the adjunct treatment of oral CMM. This article reviews the immunological similarities between CMM and the human counterpart; mechanisms by which tumours evade the immune system; reasons why melanoma is an attractive target for immunotherapy; the premise of whole cell, dendritic cell (DC), viral and DNA vaccination strategies alongside preliminary clinical results in dogs. Current “gold standard” treatments for advanced human malignant melanoma are evolving quickly with remarkable results being achieved following the introduction of immune checkpoint blockade and adoptively transferred cell therapies. The rapidly expanding field of cancer immunology and immunotherapeutics means that rational targeting of this disease in both species should enhance treatment outcomes in veterinary and human clinics

A metastatic secretory gastric plasmacytoma with aberrant CD3 expression in a dog

A 10-year-old crossbred dog was presented with a 6-week history of hematemesis, melena, anorexia, and lethargy. Clinical evaluation revealed a gastric mass with a regional lymphadenomegaly as well as a monoclonal gammopathy manifesting as hyperglobulinemia. Cytologic and histopathologic analyses were consistent with a round cell neoplasm; neoplastic cells showed nuclear immunoreactivity for MUM1 and diffuse cytoplasmic reactivity for CD3. Polymerase chain reactions performed on fixed and fresh tissue identified a clonal rearrangement with an IgH primer set. An extramedullary plasmacytoma (EMP) was confirmed by cellular morphology and molecular diagnostics. Following an objective response to chemotherapy, the dog was euthanized 8 months after diagnosis, and a postmortem examination confirmed the clinical findings. This is the first reported case of a monoclonal gammopathy secondary to a gastric EMP coupled with aberrant expression of CD3 in an aggressive plasmacytic tumor, and highlights the utility of molecular diagnostics for classifying atypical hemolymphoid neoplasms

Nutrient modulation in the management of disease-induced muscle wasting: evidence from human studies

Purpose of review: In addition to being essential for movement, skeletal muscles act as both a store and source of key macronutrients. As such, muscle is an important tissue for whole body homeostasis, undergoing muscle wasting in times of starvation, disease, and stress, for example, to provide energy substrates for other tissues. Yet, muscle wasting is also associated with disability, comorbidities, and mortality. As nutrition is so crucial to maintaining muscle homeostasis 'in health', it has been postulated that muscle wasting in cachexia syndromes may be alleviated by nutritional interventions. This review will highlight recent work in this area in relation to muscle kinetics, the acute metabolic (e.g. dietary protein), and longer-term effects of dietary interventions. Recent findings: Whole body and skeletal muscle protein synthesis invariably exhibit deranged kinetics (favouring catabolism) in wasting states; further, many of these conditions harbour blunted anabolic responses to protein nutrition compared with healthy controls. These derangements underlie muscle wasting. Recent trials of essential amino acid and protein-based nutrition have shown some potential for therapeutic benefit. Summary: Nutritional modulation, particularly of dietary amino acids, may have benefits to prevent or attenuate disease-induced muscle wasting. Nonetheless, there remains a lack of recent studies exploring these key concepts to make conclusive recommendations

Recent developments in deuterium oxide tracer approaches to measure rates of substrate turnover: implications for protein, lipid, and nucleic acid research

Purpose of review: Methods that inform on dynamic metabolism that can be applied to clinical populations to understand disease progression and responses to therapeutic interventions are of great importance. This review perspective will highlight recent advances, development, and applications of the multivalent stable isotope tracer deuterium oxide (D2O) to the study of substrate metabolism with particular reference to protein, lipids, and nucleic acids, and how these methods can be readily applied within clinical and pharmaceutical research. Recent findings: Advances in the application of D2O techniques now permit the simultaneous dynamic measurement of a range of substrates (i.e. protein, lipid, and nucleic acids, along with the potential for OMICs methodologies) with minimal invasiveness further creating opportunities for long-term ‘free living’ measures that can be used in clinical settings. These techniques have recently been applied to ageing populations and further in cancer patients revealing altered muscle protein metabolism. Additionally, the efficacy of numerous drugs in improving lipoprotein profiles and controlling cellular proliferation in leukaemia have been revealed. Summary: D2O provides opportunities to create a more holistic picture of in-vivo metabolic phenotypes, providing a unique platform for development in clinical applications, and the emerging field of personalized medicine

A 4-week, lifestyle-integrated, home-based exercise training programme elicits improvements in physical function and lean mass in older men and women: a pilot study

Background: Developing alternative exercise programmes that can alleviate certain barriers to exercise such as psychological, environmental or socio-economical barriers, but provide similar physiological benefits e.g. increases in muscle mass and strength, is of grave importance. This pilot study aimed to assess the efficacy of an unsupervised, 4-week, whole-body home-based exercise training (HBET) programme, incorporated into daily living activities, on skeletal muscle mass, power and strength. Methods: Twelve healthy older volunteers (63±3 years, 7 men: 5 women, BMI: 29±1 kg/m²) carried out the 4-week “lifestyle-integrated” HBET of 8 exercises, 3x12 repetitions each, every day. Before and after HBET, a number of physical function tests were carried out: unilateral leg extension 1-RM (one- repetition maximum), MVC (maximal voluntary contraction) leg extension, lower leg muscle power (via Nottingham Power Rig), handgrip strength and SPPBT (short physical performance battery test). A D3-Creatine method was used for assessment of whole-body skeletal muscle mass, and ultrasound was used to measure the quadriceps cross-sectional area (CSA) and vastus lateralis muscle thickness. Results: Four weeks HBET elicited significant (p<0.05) improvements in leg muscle power (276.7±38.5 vs. 323.4±43.4 W), maximal voluntary contraction (60°: 154.2±18.4 vs. 168.8±15.2 Nm, 90°: 152.1±10.5 vs. 159.1±11.4 Nm) and quadriceps CSA (57.5±5.4 vs. 59.0±5.3 cm2), with a trend for an increase in leg strength (1-RM: 45.7±5.9 vs. 49.6±6.0 kg, P=0.08). This was despite there being no significant differences in whole-body skeletal muscle mass, as assessed via D3-Creatine. Conclusions: This study demonstrates that increases in multiple aspects of muscle function can be achieved in older adults with just 4-weeks of “lifestyle-integrated” HBET, with a cost-effective means. This training mode may prove to be a beneficial alternative for maintaining and/or improving muscle mass and function in older adults

The effects of elective abdominal surgery on protein turnover: A meta-analysis of stable isotope techniques to investigate postoperative catabolism

Background & aimsElective surgery induces skeletal muscle wasting driven by an imbalance between muscle protein synthesis and breakdown. From examination of diverse stable isotope tracer techniques, the dynamic processes driving this imbalance are unclear. This meta-analysis aimed to elucidate the mechanistic driver(s) of postoperative protein catabolism through stable isotope assessment of protein turnover before and after abdominal surgery.MethodsMeta-analysis was performed of randomized controlled trials and cohort studies in patients undergoing elective abdominal surgery that contained measurements of whole-body or skeletal muscle protein turnover using stable isotope tracer methodologies pre- and postoperatively. Postoperative changes in protein synthesis and breakdown were assessed through subgroup analysis of tracer methodology and perioperative care.ResultsSurgery elicited no overall change in protein synthesis [standardized mean difference (SMD) ?0.47, 95% confidence interval (CI): ?1.32, 0.39, p = 0.25]. However, subgroup analysis revealed significant suppressions via direct-incorporation methodology [SMD -1.53, 95%CI: ?2.89, ?0.17, p = 0.03] within skeletal muscle. Changes of this nature were not present among arterio-venous [SMD 0.61, 95%CI: ?1.48, 2.70, p = 0.58] or end-product [SMD -0.09, 95%CI: ?0.81, 0.64, p = 0.82] whole-body measures. Surgery resulted in no overall change in protein breakdown [SMD 0.63, 95%CI: ?0.06, 1.32, p = 0.07]. Yet, separation by tracer methodology illustrated significant increases in urinary end-products (urea/ammonia) [SMD 0.70, 95%CI: 0.38, 1.02, p < 0.001] that were not present among arterio-venous measures [SMD 0.67, 95%CI: ?1.05, 2.38, p = 0.45].ConclusionsElective abdominal surgery elicits suppressions in skeletal muscle protein synthesis that are not reflected on a whole-body level. Lack of uniform changes across whole-body tracer techniques are likely due to contribution from tissues other than skeletal muscle

Synchronous deficits in cumulative muscle protein synthesis and ribosomal biogenesis underlie age-related anabolic resistance to exercise in humans

Ageing is associated with impaired hypertrophic responses to resistance exercise training (RET). Here we investigated the aetiology of ‘anabolic resistance’ in older humans. Twenty healthy male individuals, 10 younger (Y; 23 ± 1 years) and 10 older (O; 69 ± 3 years), performed 6 weeks unilateral RET (6 × 8 repetitions, 75% of one repetition maximum (1-RM), 3 times per week). After baseline bilateral vastus lateralis (VL) muscle biopsies, subjects consumed 150 ml D2O (70 atom%; thereafter 50 ml week−1), further bilateral VL muscle biopsies were taken at 3 and 6 weeks to quantify muscle protein synthesis (MPS) via gas chromatography–pyrolysis–isotope ratio mass spectrometry. After RET, 1-RM increased in Y (+35 ± 4%) and O (+25 ± 3%; P < 0.01), while MVC increased in Y (+21 ± 5%; P < 0.01) but not O (+6 ± 3%; not significant (NS)). In comparison to Y, O displayed blunted RET-induced increases in muscle thickness (at 3 and 6 weeks, respectively, Y: +8 ± 1% and +11 ± 2%, P < 0.01; O: +2.6 ± 1% and +3.5 ± 2%, NS). While ‘basal’ longer term MPS was identical between Y and O (∼1.35 ± 0.1% day−1), MPS increased in response to RET only in Y (3 weeks, Y: 1.61 ± 0.1% day−1; O: 1.49 ± 0.1% day−1). Consistent with this, O exhibited inferior ribosomal biogenesis (RNA:DNA ratio and c-MYC induction: Y: +4 ± 2 fold change; O: +1.9 ± 1 fold change), translational efficiency (S6K1 phosphorylation, Y: +10 ± 4 fold change; O: +4 ± 2 fold change) and anabolic hormone milieu (testosterone, Y: 367 ± 19; O: 274 ± 19 ng dl−1 (all P < 0.05). Anabolic resistance is thus multifactorial

Self-Screening and Non-Physician Screening for Hypertension in Communities: A Systematic Review.

BACKGROUND: Community-based self-screening may provide opportunities to increase detection of hypertension, and identify raised blood pressure (BP) in populations who do not access healthcare. This systematic review aimed to evaluate the effectiveness of non-physician screening and self-screening of BP in community settings. METHODS: We searched the Cochrane Central Trials Register, Medline, Embase, CINAHL, and Science Citation Index & Conference Proceedings Citation Index-Science to November 2013 to identify studies reporting community-based self-screening or non-physician screening for hypertension in adults. Results were stratified by study site, screener, and the cut-off used to define high screening BP. RESULTS: We included 73 studies, which described screening in 9 settings, with pharmacies (22%) and public areas/retail (15%) most commonly described. We found high levels of heterogeneity in all analyses, despite stratification. The highest proportions of eligible participants screened were achieved by mobile units (range 21%-88%) and pharmacies (range 40%-90%). Self-screeners had similar median rates of high BP detection (25%-35%) to participants in studies using other screeners. Few (16%) studies reported referral to primary care after screening. However, where participants were referred, a median of 44% (range 17%-100%) received a new hypertension diagnosis or antihypertensive medication. CONCLUSIONS: Community-based non-physician or self-screening for raised BP can detect raised BP, which may lead to the identification of new cases of hypertension. However, current evidence is insufficient to recommend specific approaches or settings. Studies with good follow-up of patients to definitive diagnosis are needed.This article presents independent research funded by a National Institute for Health Research Programme Grant RP-PG-1209–10051.This is the final version of the article. It was first available from Oxford University Press via http://dx.doi.org/10.1093/ajh/hpv02