From T cell “exhaustion” to anti-cancer immunity

The immune system has the potential to protect from malignant diseases for extended periods of time. Unfortunately, spontaneous immune responses are often inefficient. Significant effort is required to develop reliable, broadly applicable immunotherapies for cancer patients. A major innovation was transplantation with hematopoietic stem cells from genetically distinct donors for patients with hematologic malignancies. In this setting, donor T cells induce long-term remission by keeping cancer cells in check through powerful allogeneic graft-versus-leukemia effects. More recently, a long awaited breakthrough for patients with solid tissue cancers was achieved, by means of therapeutic blockade of T cell inhibitory receptors. In untreated cancer patients, T cells are dysfunctional and remain in a state of T cell "exhaustion". Nonetheless, they often retain a high potential for successful defense against cancer, indicating that many T cells are not entirely and irreversibly exhausted but can be mobilized to become highly functional. Novel antibody therapies that block inhibitory receptors can lead to strong activation of anti-tumor T cells, mediating clinically significant anti-cancer immunity for many years. Here we review these new treatments and the current knowledge on tumor antigen-specific T cells.

Exercise mode affects the time to achieve VO2max without influencing maximal exercise time at the intensity associated with VO2max in triathletes

The objective of this study was to analyze, in triathletes, the possible influence of the exercise mode (running x cycling) on time to exhaustion (TTE) and oxygen uptake (VO2) response during exercise performed at the intensity associated with the achievement of maximal oxygen uptake (IVO2max). Eleven male triathletes (21.8 +/- 3.8 yr) performed the following tests on different days on a motorized treadmill and on a cycle ergometer: 1) incremental tests in order to determine VO2max and IVO2max and, 2) constant work rate tests to exhaustion at IVO2max to determine TTE and to describe VO2 response (time to achieve VO2max-TAVO(2max) and time maintained at VO2max-TMVO2max). No differences were found in VO2max, TTE and TMVO2max obtained on the treadmill tests (63.7 +/- 4.7 ml.kg(-1).min(-1); 324.6 +/- 109.1 s; 178.9 +/- 93.6 s) and cycle ergometer tests (61.4 +/- 4.5 ml.kg(-1).min(-1); 390.4 +/- 114.4 s; 213.5 +/- 102.4 s). However, TAVO(2max) was influenced by exercise mode (145.7 +/- 25.3 vs. 176.8 +/- 20.1 s; in treadmill and cycle ergometer, respectively; p = 0.006). It is concluded that exercise modality affects the TAVO(2max) without influencing TTE and TMVO2max during exercise at IVO2max in triathletes.

Relationship Between Speed and Time in Running

The purpose of this study was to evaluate the effect of using different mathematical models to describe the relationship between treadmill running speed and time to exhaustion. All models generated a value for an aerobic parameter (critical speed; S(critical)). 35 university students performed 5-7 constant-speed 0%-slope treadmill tests at speeds that elicited exhaustion in similar to 3 min to similar to 10 min. Speed and time data were fitted using 3 models: (1) a 2-parameter hyperbolic model; (2) a 3-parameter hyperbolic model; and (3) a hybrid 3-parameter hyperbolic + exponential model. The 2-parameter model generated values for S(critical) (mean (+/- SD): 186 +/- 33 m.min(-1)) and anaerobic distance capacity (ADC; 251 +/- 122 m) with a high level of statistical certainty (i.e., with small SEEs). The 3-parameter models generated parameter estimates that were unrealistic in magnitude and/or associated with large SEEs and little statistical certainty. Therefore, it was concluded that, for the range of exercise durations used in the present study, the 2-parameter model is preferred because it provides a parsimonious description of the relationship between velocity and time to fatigue, and it produces parameters of known physiological significance, with excellent confidence.

Electromyographic fatigue threshold of the biceps brachii: The effect of endurance time

Muscle fatigue can be a limiting factor to determine index as the electromyographic fatigue threshold (EMGFT) due the alterations in motivation and disconfots. This way, the purpose of this study was to identify the right biceps brachii and left biceps brachii obtained from repetitive elbow flexions at each 10% of total time. Nine healthy subjects performed the exercise named biceps curl until exhaustion with 25%, 35%, and 45% of one repetition maximum, in three different days. EMG amplitude (root mean square - RMS) was obtained for concentric contractions during these load levels and correlated with time to determine the slope values for each load and them detemine the EMGFT. The EMGFT was obtained within of each 10% of total time and they were compared by analysis of variance. The results showed a progressive increase in RMS with time, for both muscles in all loads, characterizing the muscle fatigue process, and for the EMGFT values ware not found predominantly significant differences between the execution time, as well as between muscles (right biceps × left biceps). This protocol allowed to identify the EMGFT to both muscles during the biceps curl, which was similar at different percentage of total time, indicating the possibility to reduce the length of the contraction test without the need to maintain the contraction until exhaustion. Further studies are needed to evaluate the applicability of this method to determining the effects on performance.

Maximal power output during incremental cycling test is dependent on the curvature constant of the power-time relationship

The aim of this study was to investigate whether the maximal power output (Pmax) during an incremental test was dependent on the curvature constant (W') of the power-time relationship. Thirty healthy male subjects (maximal oxygen uptake = 3.58 ± 0.40 L·min(-1)) performed a ramp incremental cycling test to determine the maximal oxygen uptake and Pmax, and 4 constant work rate tests to exhaustion to estimate 2 parameters from the modeling of the power-time relationship (i.e., critical power (CP) and W'). Afterwards, the participants were ranked according to their magnitude of W'. The median third was excluded to form a high W' group (HIGH, n = 10), and a low W' group (LOW, n = 10). Maximal oxygen uptake (3.84 ± 0.50 vs. 3.49 ± 0.37 L·min(-1)) and CP (213 ± 22 vs. 200 ± 29 W) were not significantly different between HIGH and LOW, respectively. However, Pmax was significantly greater for the HIGH (337 ± 23 W) than for the LOW (299 ± 40 W). Thus, in physically active individuals with similar aerobic parameters, W' influences the Pmax during incremental testing.

Independent association of sleep quality, fatigue, and vital exhaustion with platelet count in patients with a previous venous thromboembolic event

Elevated platelet count might reflect increased inflammation as an etiological factor for venous thromboembolism (VTE). Poor sleep, fatigue, and exhaustion are all associated with inflammation and are also common sequelae of chronic psychological stress that previously predicted increased risk of VTE. We hypothesized that platelet count would be high in patients with VTE who sleep poorly and who are fatigued and exhausted. We investigated 205 patients scheduled for thrombophilia work-up > or =3 months after an objectively diagnosed venous thromboembolic event. They completed the Jenkins Sleep Questionnaire to rate subjective sleep quality and the short forms of the Multidimensional Fatigue Symptom Inventory and Maastricht Vital Exhaustion Questionnaire. Platelet count was determined by a mechanical Coulter counter. Analyses controlled for age, sex, body mass index, time since the index event, and medication. After taking into account these covariates, poorer sleep quality (p = 0.001; DeltaR(2)= 0.046), high fatigue (p = 0.008; DeltaR(2)= 0.032), and vital exhaustion (p = 0.050; DeltaR(2)= 0.017) were all associated with elevated platelet count. In addition, high level of fatigue mediated the relationship between poor sleep quality and elevated platelet count (p = 0.046). Poor sleep quality, high levels of fatigue, and vital exhaustion were identified as correlates of an elevated platelet count in patients with a previous episode of VTE. Given the emerging role of inflammatory processes in VTE, the findings suggest a mechanism through which behavioral and chronic psychological stressors might contribute to incident and recurrent venous thrombotic events.

Association of vital exhaustion and depressive symptoms with changes in fibrin D-dimer to acute psychosocial stress

OBJECTIVE: Vital exhaustion and depression are psychosocial risk factors of coronary artery disease. A hypercoagulable state in response to acute psychosocial stress contributes to atherothrombotic events. We aimed to investigate the hypothesis that vital exhaustion and depression correlate with stress-induced changes in the hypercoagulability marker D-dimer. METHODS: Thirty-eight healthy and nonsmoking school teachers (mean age 50+/-8 years, 55% women) completed the nine-item Maastricht Vital Exhaustion Questionnaire and the seven-item depression subscale of the Hospital Anxiety and Depression Scale. Within 1 week, subjects twice underwent the Trier Social Stress Test (i.e., preparation phase, mock job interview, and mental arithmetic that totaled 13 min). Plasma D-dimer levels were determined at five time points during the protocol. RESULTS: Vital exhaustion (P=.022; eta(2)=.080) and depressive symptoms (P=.011; eta(2)=.090) were associated with stress-induced changes in D-dimer levels over time controlling for sex and age. Elevated levels of vital exhaustion (r=-.46, P=.005) and of depression (r=-.51, P=.002) correlated with reduced D-dimer increase from pre-stress to immediately post-stress. Also, elevated vital exhaustion (r=.34, P=.044) and depression (r=.41, P=.013) were associated with increase (i.e., attenuated recovery) of D-dimer levels between 20 and 45 min post-stress. Controlling for stress hormone and blood pressure reactivity did not substantially alter these results. CONCLUSION: The findings suggest an attenuated immediate D-dimer stress response and delayed recovery of D-dimer levels post-stress with elevated vital exhaustion and depressive symptoms. In particular, the prolonged hypercoagulability after stress cessation might contribute to the atherothrombotic risk previously observed with vital exhaustion and depression, even at subclinical levels.

UsedSoft and the Big Bang Theory: Is the e-Exhaustion Meteor about to Strike?

Since the UsedSoft ruling of the CJEU in 2012, there has been the distinct feeling that – like the big bang - UsedSoft signals the start of a new beginning. As we enter this brave new world, the Copyright Directive will be read anew: misalignments in the treatment of physical and digital content will be resolved; accessibility and affordability for consumers will be heightened; and lock-in will be reduced as e-exhaustion takes hold. With UsedSoft as a precedent, the Court can do nothing but keep expanding its own ruling. For big bang theorists, it is only a matter of time until the digital first sale meteor strikes non-software downloads also. This paper looks at whether the UsedSoft ruling could indeed be the beginning of a wider doctrine of e-exhaustion, or if it is simply a one-shot comet restrained by provisions of the Computer Program Directive on which it was based. Fighting the latter corner, we have the strict word of the law; in the UsedSoft ruling, the Court appears to willingly bypass the international legal framework of the WCT. As far as expansion goes, the Copyright Directive was conceived specifically to implement the WCT, thus the legislative intent is clear. The Court would not, surely, invoke its modicum of creativity there also... With perhaps undue haste in a digital market of many unknowns, it seems this might well be the case. Provoking the big bang theory of e-exhaustion, the UsedSoft ruling can be read as distinctly purposive, but rather than having copyright norms in mind, the standard for the Court is the same free movement rules that underpin the exhaustion doctrine in the physical world. With an endowed sense of principled equivalence, the Court clearly wishes the tangible and intangible rules to be aligned. Against the backdrop of the European internal market, perhaps few legislative instruments would staunchly stand in its way. With firm objectives in mind, the UsedSoft ruling could be a rather disruptive meteor indeed.

Change in positive affect during outpatient cardiac rehabilitation predicts vital exhaustion in patients with coronary heart disease

Vital exhaustion is an acknowledged psychosocial risk factor of incident coronary heart disease (CHD) and recurrent CHD events. Little is known about trajectories in vital exhaustion in patients with CHD and the factors predicting this change. We hypothesized that vital exhaustion would decrease during outpatient cardiac rehabilitation and that an increase in positive affect over time would be associated with decreased vital exhaustion at discharge from cardiac rehabilitation. We also explored the role of the patient's sex in this context. Vital exhaustion was reduced during outpatient cardiac rehabilitation, especially in patients who experienced an increase in positive affect over time (p < .001). This relationship was significant in men (p < .001) but not in women (p = .11).

Debating food production at dinner time: Mainstream audiences are invited to debate the ethics of agricultural practices in Brazil

In the rural areas of Brazil, a farmer runs his agricultural empire with a fierce hand: he exploits his workers and the land to their limits. Lack of sustainable land management leads to the pollution of rivers, changes in rain patterns, and exhaustion of the soil.

Identification Of Corynebacterium Spp. Isolated From Bovine Intramammary Infections By Matrix-assisted Laser Desorption Ionization-time Of Flight Mass Spectrometry.

Corynebacterium species (spp.) are among the most frequently isolated pathogens associated with subclinical mastitis in dairy cows. However, simple, fast, and reliable methods for the identification of species of the genus Corynebacterium are not currently available. This study aimed to evaluate the usefulness of matrix-assisted laser desorption ionization/mass spectrometry (MALDI-TOF MS) for identifying Corynebacterium spp. isolated from the mammary glands of dairy cows. Corynebacterium spp. were isolated from milk samples via microbiological culture (n=180) and were analyzed by MALDI-TOF MS and 16S rRNA gene sequencing. Using MALDI-TOF MS methodology, 161 Corynebacterium spp. isolates (89.4%) were correctly identified at the species level, whereas 12 isolates (6.7%) were identified at the genus level. Most isolates that were identified at the species level with 16 S rRNA gene sequencing were identified as Corynebacterium bovis (n=156; 86.7%) were also identified as C. bovis with MALDI-TOF MS. Five Corynebacterium spp. isolates (2.8%) were not correctly identified at the species level with MALDI-TOF MS and 2 isolates (1.1%) were considered unidentified because despite having MALDI-TOF MS scores >2, only the genus level was correctly identified. Therefore, MALDI-TOF MS could serve as an alternative method for species-level diagnoses of bovine intramammary infections caused by Corynebacterium spp.

A Metabolomic Protocol For Plant Systematics By Matrix-assisted Laser-desorption/ionization Time-of Flight Mass Spectrometry.

Matrix-assisted laser desorption/ionization time-of flight mass spectrometry (MALDI-TOF MS) has been widely used for the identification and classification of microorganisms based on their proteomic fingerprints. However, the use of MALDI-TOF MS in plant research has been very limited. In the present study, a first protocol is proposed for metabolic fingerprinting by MALDI-TOF MS using three different MALDI matrices with subsequent multivariate data analysis by in-house algorithms implemented in the R environment for the taxonomic classification of plants from different genera, families and orders. By merging the data acquired with different matrices, different ionization modes and using careful algorithms and parameter selection, we demonstrate that a close taxonomic classification can be achieved based on plant metabolic fingerprints, with 92% similarity to the taxonomic classifications found in literature. The present work therefore highlights the great potential of applying MALDI-TOF MS for the taxonomic classification of plants and, furthermore, provides a preliminary foundation for future research.

Profile Of Phenolic Compounds Of Brazilian Virgin Olive Oils By Rapid Resolution Liquid Chromatography Coupled To Electrospray Ionisation Time-of-flight Mass Spectrometry (rrlc-esi-tof-ms).

In recent years, agronomical researchers began to cultivate several olive varieties in different regions of Brazil to produce virgin olive oil (VOO). Because there has been no reported data regarding the phenolic profile of the first Brazilian VOO, the aim of this work was to determine phenolic contents of these samples using rapid-resolution liquid chromatography coupled to electrospray ionisation time-of-flight mass spectrometry. 25 VOO samples from Arbequina, Koroneiki, Arbosana, Grappolo, Manzanilla, Coratina, Frantoio and MGS Mariense varieties from three different Brazilian states and two crops were analysed. It was possible to quantify 19 phenolic compounds belonging to different classes. The results indicated that Brazilian VOOs have high total phenolic content because the values were comparable with those from high-quality VOOs produced in other countries. VOOs from Coratina, Arbosana and Grappolo presented the highest total phenolic content. These data will be useful in the development and improvement of Brazilian VOO.

Adaptação de protocolos invasivos e não invasivos para avaliações aeróbias e anaeróbias específicas ao basquetebol feminino

OBJECTIVE: To adapted the critical velocity (CV), RAST test and lactate minimum (LM) to evaluation of female basketball players. METHODS: Twelve well-trained female basketball players (19 ± 1yrs) were submitted to four intensities running (10 - 14 km/h) at shuttle exercise until exhaustion, applied on alternate days. The linear model 'velocity vs. 1/tlim' was adopted to determine the aerobic (CV) and anaerobic (CCA) parameters. The lactate minimum test consisted of two phases: 1) hiperlactatemia induction using the RAST test and 2) incremental test composed by five shuttle run (20-m) at 7, 8, 9, 10, and 12 km/h. Blood samples were collected at the end of each stage. RESULTS: The velocity (vLM) and blood lactate concentration at LM were obtained by two polynomial adjustments: lactate vs. intensity (LM1) and lactate vs. time (LM2). ANOVA one-way, Student t-test and Pearson correlation were used for statistical analysis. The CV was obtained at 10.3 ± 0.2 km/h and the CCA estimated at 73.0 ± 3.4 m. The RAST was capable to induce the hiperlactatemia and to determine the Pmax (3.6 ± 0.2 W/kg), Pmed (2.8 ± 0.1 W/kg), Pmin (2.3 ± 0.1 W/kg) and FI (30 ± 3%). The vLM1 and vLM2 were obtained, respectively, at 9.47 ±0.13 km/h and 9.8 ± 0.13 km/h, and CV was higher than vLM1. CONCLUSION: The results suggest that the non-invasive model can be used to determine the aerobic and anaerobic parameters. Furthermore, the LM test adapted to basketball using RAST and progressive phase was effective to evaluate female athletes considering the specificity of modality, with high success rates observed in polynomial adjustment 'lactate vs. time' (LM2).