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Metastatic pheochromocytoma and paraganglioma (PPGL) have poor prognosis and limited therapeutic options. The recent advent of immunotherapies showing remarkable clinical efficacies against various cancer types offers the possibility of novel opportunities also for metastatic PPGL. Most PPGLs are pathogenically linked to inactivating mutations in genes encoding different succinate dehydrogenase (SDH) subunits. This causes activation of the hypoxia-inducible factor 2 (HIF2)-mediated transcriptional program in the absence of decreased intratumoral oxygen levels, a phenomenon known as pseudohypoxia. Genuine hypoxia in a tumor creates an immunosuppressive tumor microenvironment. However, the impact of pseudohypoxia in the immune landscape of tumors remains largely unexplored. In this study, tumoral expression of programmed death-ligand 1 (PD-L1) and HIF2α and tumor infiltration of CD8 T lymphocytes (CTLs) were examined in PPGL specimens from 102 patients. We assessed associations between PD-L1, CTL infiltration, HIF2α expression, and the mutational status of SDH genes. Our results show that high PD-L1 expression levels in tumor cells and CTL tumor infiltration were more frequent in metastatic than nonmetastatic PPGL. However, this phenotype was negatively associated with SDH mutations and high HIF2α protein expression. These data were validated by analysis of mRNA levels of genes expressing PD-L1, CD8, and HIF2α in PPGL included in The Cancer Genome Atlas database. Further, PD-L1 and CD8 expression was lower in norepinephrine than epinephrine-secreting PPGL. This in silico analysis also revealed the low PD-L1 or CD8 expression levels in tumors with inactivating mutations in VHL or activating mutations in the HIF2α-coding gene, EPAS1, which, together with SDH-mutated tumors, comprise the pseudohypoxic molecular subtype of PPGL. These findings suggest that pseudohypoxic tumor cells induce extrinsic signaling toward the immune cells promoting the development of an immunosuppressive environment. It also provides compelling support to explore the differential response of metastatic PPGL to immune checkpoint inhibitors. © 2022 The Authors. The Journal of Pathology published by John WileySons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Background/Aims: A weight-loss diet alone or combined with a progressive resistance training program induced different adaptations on cardiometabolic risk, i.e. regional changes in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) volume distribution patterns. We hypothesized that a heterogeneous adipose tissue metabolism may exist between visceral fat at different discal levels. Methods: Thirty-four obese women, aged 40–60 years, were randomized to three groups: a control group (n = 9), a diet group (WL; n = 12) with a caloric restriction of 500 kcal/day during 16 weeks, or a diet-plus-resistance-training group (WL+RT; n = 13) with the same caloric restriction and a 16-week resistance training of 2 sessions per week. Results: The association pattern between abdominal fat depots and glucose metabolism variables showed a change from the L4-L5 region (preintervention) to VAT L2-L3 and SAT L2-L3 in the WL and WL+RT groups, respectively. It is noteworthy that accumulation of fat in the midthigh was not characterized by a more favorable lipid profile or glucose metabolism. Conclusion: Our results reinforce the importance of considering L2-L3 images to predict insulin resistance after a weight-loss diet, alone or combined with resistance training.

The purpose of this investigation was to examine the influence of training frequency on performance and some physiological responses during a 6-day taper. After 18 weeks of training, 9 male middle-distance runners were assigned to a high frequency taper (HFT, n = 5) or a moderate frequency taper (MFT, n = 4), consisting of training daily or resting every third day of the taper. Taper consisted of an 80% nonlinear progressive reduction in high intensity interval training. Blood samples were obtained, and 800 m performance and peak blood lactate ([La] peak ) measured before and after taper. Performance improved significantly after HFT (121.8 +/- 4.7 vs 124.2 +/- 4.9 s, p < 0.05), but not after MFT (126.6 +/- 2.8 vs 127.1 +/- 2.1 s). Neutrophils (2.89 +/- 0.68 vs 2.56 +/- 0.61 10 (3) x mm(-3)), granulocytes (3.08 +/- 0.70 vs 2.77 +/- 0.66 10 (3) x mm(-3)), haptoglobin (79.7 +/- 47.9 vs 60.7 +/- 33.6 mg x dl(-1)), total testosterone (7.39 +/- 1.67 vs 5.52 +/- 0.88 microg x l(-1)) and [La] peak (15.5 +/- 1.5 vs 14.4 +/- 2.0 mmol x l(-1)) significantly increased with taper. [La] peak correlated with performance time before taper (r = -0.76, p < 0.05), and change in [La] peak with change in serum cortisol (r = -0.75, p < 0.05) and total testosterone:cortisol ratio (r = 0.82, p < 0.01). In conclusion, training daily during a 6-day taper brought about significant performance gains, whereas resting every third day did not. High [La] peak and a hormonal milieu propitious to anabolic processes seemed to be necessary for optimum performance.

Phenylketonuria is an inherited metabolic disorder caused by a defect in the hydroxylation of phenylalanine. Newborn screening is crucial for the diagnosis and treatment of this disease. A phenylalanine dehydrogenase-coupled enzymatic assay (Quantase) in microtiter plates for the screening of phenylketonuria was evaluated and compared with our routine method based on the modified fluorometric McCaman method. The test exhibited a linear calibration curve with a good slope as well as sufficient imprecision (< 10%), recovery (99.23 ± 4.86%) and limit of detection (54.5 μmol/l). One hundred and ninety dried blood spots were analysed by this enzymatic method and compared with McCaman's. Although Quantase (Teknovas, Bilbao, Spain) showed a phenylalanine mean level in dried blood spot 18.2 μmol/l higher than that obtained with our routine method, the agreement between both techniques was considered acceptable.

Malabsorption-maldigestion syndromes are commonly found in several gastrointestinal diseases. Quantitative measures of fecal nutrients are important tools for the detection and diagnosis of these syndromes. Adequate food intake is important in the nutrition of children, especially during the first year of life. We have analyzed 180 stools of healthy children, divided into four age groups, to obtain the reference intervals of the major nutrients such as water, fat, nitrogen, sugar, and starch. Quantification of the nutrients was done by means of a near-infrared analyzer (Fenir 8820). Results show that this instrument exhibits a low coefficient of variation for all the nutrients except for starch. Fecal water, fat, nitrogen, and sugar concentrations ranged from 68.7 to 96.1 g/100 g, 0 to 14.5 g/100 g, 1.3 to 2.3 g/100 g, and 0.7 to 3.8 g/100 g, respectively. The results for the starch analyses were not acceptable because of instrument limitations. Near-infrared reflectance spectroscopy appears to be an alternative to standard chemical methods.

Increased circulating adiponectin and insulin sensitivity are usually observed after body fat loss induced by a weight-loss diet. Progressive resistance training (PRT) without a concomitant weight-loss diet significantly decreases visceral fat, thus improving insulin sensitivity. Therefore, the purpose of this study was to ascertain the effects of combined 16-week PRT and weight-loss diet on circulating adiponectin and insulin sensitivity index. Thirty-four obese (BMI: 30-40 kg/m(2)) women, aged 40-60 year, were randomized to three groups: a control group (C; n = 9); a diet group (WL; n = 12) with a caloric restriction of 500 kcal/d; and a diet plus resistance training group (WL+RT; n = 13) with the same caloric restriction as group WL and a 16-week supervised whole body PRT of two sessions/week. Both WL and WL+RT groups showed similar decreases in body mass (-6.3% and -7.7%) and visceral fat (-19.9% and -20.5%). WL resulted in an expected increase in circulating levels of adiponectin (P = 0.07) and insulin sensitivity. However, circulating total adiponectin decreased (P < 0.05) in WL+RT group, whereas an improvement in different cardiovascular risk factors (insulin sensitivity, low-density lipoprotein cholesterol (LDL-C), etc.) was observed. In conclusion, in obese women a 16-week combined PRT and weight-loss diet is accompanied by significant improvements in different cardiovascular risk factors in spite of a significant decrease of circulating adiponectin.

This study examined some physiological and performance responses to a 6-d taper, and the influence of training intensity and volume on these responses.After 15 wk of training, 8 well-trained male middle-distance runners were randomly assigned to either a moderate volume taper (MVT, N = 4) or a low volume taper (LVT, N = 4), consisting of either a 50% or a 75% progressive reduction in pretaper low intensity continuous training (LICT) and high intensity interval training (HIIT). Blood samples were obtained and 800-m running performance was measured before and after taper.Performance was not significantly enhanced by either taper protocol (post- vs pre-taper times 124.9 +/- 4.5 vs 126.1 +/- 4.2 s with LVT, 126.2 +/- 8.0 vs 125.7 +/- 6.6 s with MVT). For the entire group of 8 subjects, red cell count, hemoglobin (Hb), mean corpuscular volume and mean corpuscular Hb concentration significantly decreased with taper, while reticulocyte count increased. Performance changes for all subjects correlated with changes in postrace peak blood lactate concentration (r = 0.87, P0.01). Taper LICT correlated with changes in Hb (r = 0.77), hematocrit (r = 0.81), reticulocyte count (r = 0.73), creatine kinase (r = 0.72), and total testosterone (r = -0.78), and with posttaper red cell distribution width (r = -0.75) and lymphocyte count (r = -0.82). Taper HIIT correlated nonsignificantly with changes in red cell count (r = -0.66) and total testosterone (r = 0.68).It is concluded that taper-induced physiological changes in trained middle-distance runners are mainly hematological, and that distinct physiological changes are elicited from LICT and HIIT during taper. Middle-distance runners can progressively reduce their usual training volume by at least 75% during a 6-d taper.