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Infantile inflammatory myofibroblastic tumors: clinicopathological and molecular characterization of 12 cases
Inflammatory myofibroblastic tumors arising in infants are rare, poorly investigated and mostly reported as isolated cases or as a part of larger series thus, their clinicopathological and molecular features are essentially unknown. Archival files from two large pediatric institutions and a tumor registry were queried for pediatric inflammatory myofibroblastic tumors. Available material from patients ≤12 months of age was reviewed. Additional immunostains (ALK-1, D240, WT1) and ALK-FISH studies were performed as needed. Targeted anchored multiplex PCR with next-generation sequencing was done in all cases. A total of 12 of 131 infantile cases (mean 5.5 months) were identified (M:F of 2:1). Anatomic locations included intestinal/mesenteric (
n
= 6), head/neck (
n
= 3), and viscera (
n
= 3). Half of tumors showed a hypocellular myxoid pattern, perivascular condensation, and prominent vasculature with vague glomeruloid structures present in four of them. The remaining cases exhibited a more cellular pattern with minimal myxoid component. ALK-1 immunohistochemistry was positive in most cases (11/12) with cytoplasmic-diffuse (
n
= 6), cytoplasmic-granular (
n
= 2), and dot-like (
n
= 3) staining patterns.
ALK
fusion partners identified in five cases included
EML4
,
TPM4
,
RANBP2
, and a novel
KLC1
. Three inflammatory myofibroblastic tumors showed fusions with other kinases including
TFG-ROS1
and novel
FN1-ROS1
and
RBPMS-NTRK3
rearrangements. Favorable outcome was documented in most cases (10/11) with available follow-up (median 17 months) while three patients were successfully treated with crizotinib. In summary, infantile inflammatory myofibroblastic tumors are rare and can exhibit paucicellular, extensively myxoid/vascular morphology with peculiar immunophenotype mimicking other mesenchymal or vascular lesions. All tumors harbored kinase fusions involving
ALK
,
ROS1
, and
NTRK3
including three novel fusion partners (
KLC1
,
FN1
, and
RBPMS
, respectively). A favorable response to crizotinib seen in three cases supports its potential use in infants as seen in older patients. Awareness of these unusual morphologic, immunophenotypic, and molecular features is critical for appropriate diagnosis and optimized targeted therapy.
Journal Article
Intake of Protein Plus Carbohydrate during the First Two Hours after Exhaustive Cycling Improves Performance the following Day
Intake of protein immediately after exercise stimulates protein synthesis but improved recovery of performance is not consistently observed. The primary aim of the present study was to compare performance 18 h after exhaustive cycling in a randomized diet-controlled study (175 kJ·kg(-1) during 18 h) when subjects were supplemented with protein plus carbohydrate or carbohydrate only in a 2-h window starting immediately after exhaustive cycling. The second aim was to investigate the effect of no nutrition during the first 2 h and low total energy intake (113 kJ·kg(-1) during 18 h) on performance when protein intake was similar. Eight endurance-trained subjects cycled at 237±6 Watt (~72% VO2max) until exhaustion (TTE) on three occasions, and supplemented with 1.2 g carbohydrate·kg(-1)·h(-1) (CHO), 0.8 g carbohydrate + 0.4 g protein·kg(-1)·h(-1) (CHO+PRO) or placebo without energy (PLA). Intake of CHO+PROT increased plasma glucose, insulin, and branch chained amino acids, whereas CHO only increased glucose and insulin. Eighteen hours later, subjects performed another TTE at 237±6 Watt. TTE was increased after intake of CHO+PROT compared to CHO (63.5±4.4 vs 49.8±5.4 min; p<0.05). PLA reduced TTE to 42.8±5.1 min (p<0.05 vs CHO). Nitrogen balance was positive in CHO+PROT, and negative in CHO and PLA. In conclusion, performance was higher 18 h after exhaustive cycling with intake of CHO+PROT compared to an isocaloric amount of carbohydrate during the first 2 h post exercise. Intake of a similar amount of protein but less carbohydrate during the 18 h recovery period reduced performance.
Journal Article
What is new in pericytomatous, myoid, and myofibroblastic tumors?
Recent advances in molecular techniques in soft tissue pathology, including the widespread application of next-generation sequencing, have led to significant progress in our understanding of mesenchymal tumors. Recognition of the genetic signatures of these neoplasms not only clarifies the relationship of these entities but also provides a mechanism for more accurate diagnosis. More importantly, insight into the genetic underpinnings of these lesions may offer therapeutic targets for cases not amenable to surgical treatment. This review highlights the clinicopathologic features and novel molecular findings in pericytic, myoid, and myofibroblastic tumors.
Journal Article
International society of sports nutrition position stand: caffeine and performance
Position Statement: The position of The Society regarding caffeine supplementation and sport performance is summarized by the following seven points: 1.) Caffeine is effective for enhancing sport performance in trained athletes when consumed in low-to-moderate dosages (~3-6 mg/kg) and overall does not result in further enhancement in performance when consumed in higher dosages (≥ 9 mg/kg). 2.) Caffeine exerts a greater ergogenic effect when consumed in an anhydrous state as compared to coffee. 3.) It has been shown that caffeine can enhance vigilance during bouts of extended exhaustive exercise, as well as periods of sustained sleep deprivation. 4.) Caffeine is ergogenic for sustained maximal endurance exercise, and has been shown to be highly effective for time-trial performance. 5.) Caffeine supplementation is beneficial for high-intensity exercise, including team sports such as soccer and rugby, both of which are categorized by intermittent activity within a period of prolonged duration. 6.) The literature is equivocal when considering the effects of caffeine supplementation on strength-power performance, and additional research in this area is warranted. 7.) The scientific literature does not support caffeine-induced diuresis during exercise, or any harmful change in fluid balance that would negatively affect performance.
Journal Article
Co-ingestion of carbohydrate and whey protein increases fasted rates of muscle protein synthesis immediately after resistance exercise in rats
The objective of the study was to investigate whether co-ingestion of carbohydrate and protein as compared with protein alone augments muscle protein synthesis (MPS) during early exercise recovery. Two months old rats performed 10 repetitions of ladder climbing with 75% of body weight attached to their tails. Placebo (PLA), whey protein (WP), or whey protein plus carbohydrate (CP) was then given to rats by gavage. An additional group of sedentary rats (SED) was used as controls. Blood samples were collected immediately and at either 1 or 2 h after exercise. The flexor hallucis longus muscle was excised at 1 or 2 h post exercise for analysis of MPS and related signaling proteins. MPS was significantly increased by CP compared with PLA (p<0.05), and approached significance compared with WP at 1 h post exercise (p = 0.08). CP yielded a greater phosphorylation of mTOR compared with SED and PLA at 1 h post exercise and SED and WP at 2 h post exercise. CP also increased phosphorylation of p70S6K compared with SED at 1 and 2 h post exercise. 4E-BP1 phosphorylation was inhibited by PLA at 1 h but elevated by WP and CP at 2 h post exercise relative to SED. The phosphorylation of AMPK was elevated by exercise at 1 h post exercise, and this elevated level was sustained only in the WP group at 2 h. The phosphorylation of Akt, GSK3, and eIF2Bε were unchanged by treatments. Plasma insulin was transiently increased by CP at 1 h post exercise. In conclusion, post-exercise CP supplementation increases MPS post exercise relative to PLA and possibly WP, which may have been mediated by greater activation of the mTOR signaling pathway.
Journal Article
EWSR1-PATZ1-rearranged sarcoma: a report of nine cases of spindle and round cell neoplasms with predilection for thoracoabdominal soft tissues and frequent expression of neural and skeletal muscle markers
The knowledge of clinical features and, particularly, histopathological spectrum of EWSR1-PATZ1-rearranged spindle and round cell sarcomas (EPS) remains limited. For this reason, we report the largest clinicopathological study of EPS to date. Nine cases were collected, consisting of four males and five females ranging in age from 10 to 81 years (average: 49 years). Five tumors occurred in abdominal wall soft tissues, three in the thorax, and one in the back of the neck. Tumor sizes ranged from 2.5 to 18 cm (average 6.6 cm). Five patients had follow-up with an average of 38 months (range: 18–60 months). Two patients had no recurrence or metastasis 19 months after diagnosis. Four patients developed multifocal pleural or pulmonary metastasis and were treated variably by surgery, radiotherapy, and chemotherapy. The latter seemed to have little to no clinical benefit. One of the four patients was free of disease 60 months after diagnosis, two patients were alive with disease at 18 and 60 months, respectively. Morphologically, low, intermediate, and high-grade sarcomas composed of a variable mixture of spindled, ovoid, epithelioid, and round cells were seen. The architectural and stromal features also varied, resulting in a broad morphologic spectrum. Immunohistochemically, the following markers were most consistently expressed: S100-protein (7/9 cases), GFAP (7/8), MyoD1 (8/9), Pax-7 (4/5), desmin (7/9), and AE1/3 (4/9). By next-generation sequencing, all cases revealed EWSR1-PATZ1 gene fusion. In addition, 3/6 cases tested harbored CDKN2A deletion, while CDKN2B deletion and TP53 mutation were detected in one case each. Our findings confirm that EPS is a clinicopathologic entity, albeit with a broad morphologic spectrum. The uneventful outcome in some of our cases indicates that a subset of EPS might follow a more indolent clinical course than previously appreciated. Additional studies are needed to validate whether any morphological and/or molecular attributes have a prognostic impact.
Journal Article
Improved Inflammatory Balance of Human Skeletal Muscle during Exercise after Supplementations of the Ginseng-Based Steroid Rg1
The purpose of the study was to determine the effect of ginseng-based steroid Rg1 on TNF-alpha and IL-10 gene expression in human skeletal muscle against exercise challenge, as well as on its ergogenic outcomes. Randomized double-blind placebo-controlled crossover trials were performed, separated by a 4-week washout. Healthy young men were randomized into two groups and received capsule containing either 5 mg of Rg1 or Placebo one night and one hour before exercise. Muscle biopsies were conducted at baseline, immediately and 3 h after a standardized 60-min cycle ergometer exercise. While treatment differences in glycogen depletion rate of biopsied quadriceps muscle during exercise did not reach statistical significance, Rg1 supplementations enhanced post-exercise glycogen replenishment and increased citrate synthase activity in the skeletal muscle 3 h after exercise, concurrent with improved meal tolerance during recovery (P<0.05). Rg1 suppressed the exercise-induced increases in thiobarbituric acids reactive substance (TBARS) and reversed the increased TNF-alpha and decreased IL-10 mRNA of quadriceps muscle against the exercise challenge. PGC-1 alpha and GLUT4 mRNAs of exercised muscle were not affected by Rg1. Maximal aerobic capacity (VO2max) was not changed by Rg1. However, cycling time to exhaustion at 80% VO2max increased significantly by ~20% (P<0.05).
Our result suggests that Rg1 is an ergogenic component of ginseng, which can minimize unwanted lipid peroxidation of exercised human skeletal muscle, and attenuate pro-inflammatory shift under exercise challenge.
Journal Article
Development of a recombinant tetravalent dengue virus vaccine: Immunogenicity and efficacy studies in mice and monkeys
Truncated recombinant dengue virus envelope protein subunits (80E) are efficiently expressed using the
Drosophila Schneider-2 (S2) cell expression system. Binding of conformationally sensitive antibodies as well as X-ray crystal structural studies indicate that the recombinant 80E subunits are properly folded native-like proteins. Combining the 80E subunits from each of the four dengue serotypes with ISCOMATRIX
® adjuvant, an adjuvant selected from a set of adjuvants tested for maximal and long lasting immune responses, results in high titer virus neutralizing antibody responses. Immunization of mice with a mixture of all four 80E subunits and ISCOMATRIX
® adjuvant resulted in potent virus neutralizing antibody responses to each of the four serotypes. The responses to the components of the tetravalent mixture were equivalent to the responses to each of the subunits administered individually. In an effort to evaluate the potential protective efficacy of the
Drosophila expressed 80E, the dengue serotype 2 (DEN2-80E) subunit was tested in both the mouse and monkey challenge models. In both models protection against viral challenge was achieved with low doses of antigen in the vaccine formulation. In non-human primates, low doses of the tetravalent formulation induced good virus neutralizing antibody titers to all four serotypes and protection against challenge with the two dengue virus serotypes tested. In contrast to previous reports, where subunit vaccine candidates have generally failed to induce potent, protective responses, native-like soluble 80E proteins expressed in the
Drosophila S2 cells and administered with appropriate adjuvants are highly immunogenic and capable of eliciting protective responses in both mice and monkeys. These results support the development of a dengue virus tetravalent vaccine based on the four 80E subunits produced in the
Drosophila S2 cell expression system.
Journal Article
Postexercise Carbohydrate–Protein Supplementation Improves Subsequent Exercise Performance and Intracellular Signaling for Protein Synthesis
Ferguson-Stegall, L, McCleave, EL, Ding, Z, Doerner III, PG, Wang, B, Liao, Y-H, Kammer, L, Liu, Y, Hwang, J, Dessard, BM, and Ivy, JL. Postexercise carbohydrate-protein supplementation improves subsequent exercise performance and intracellular signaling for protein synthesis. J Strength Cond Res 25(5)1210-1224, 2011-Postexercise carbohydrate-protein (CHO + PRO) supplementation has been proposed to improve recovery and subsequent endurance performance compared to CHO supplementation. This study compared the effects of a CHO + PRO supplement in the form of chocolate milk (CM), isocaloric CHO, and placebo (PLA) on recovery and subsequent exercise performance. Ten cyclists performed 3 trials, cycling 1.5 hours at 70% o2max plus 10 minutes of intervals. They ingested supplements immediately postexercise and 2 hours into a 4-hour recovery. Biopsies were performed at recovery minutes 0, 45, and 240 (R0, R45, REnd). Postrecovery, subjects performed a 40-km time trial (TT). The TT time was faster in CM than in CHO and in PLA (79.43 ± 2.11 vs. 85.74 ± 3.44 and 86.92 ± 3.28 minutes, p ≤ 0.05). Muscle glycogen resynthesis was higher in CM and in CHO than in PLA (23.58 and 30.58 vs. 7.05 μmol·g wet weight, p ≤ 0.05). The mammalian target of rapamycin phosphorylation was greater at R45 in CM than in CHO or in PLA (174.4 ± 36.3 vs. 131.3 ± 28.1 and 73.7 ± 7.8% standard, p ≤ 0.05) and at REnd in CM than in PLA (94.5 ± 9.9 vs. 69.1 ± 3.8%, p ≤ 0.05). rpS6 phosphorylation was greater in CM than in PLA at R45 (41.0 ± 8.3 vs. 15.3 ± 2.9%, p ≤ 0.05) and REnd (16.8 ± 2.8 vs. 8.4 ± 1.9%, p ≤ 0.05). FOXO3A phosphorylation was greater at R45 in CM and in CHO than in PLA (84.7 ± 6.7 and 85.4 ± 4.7 vs. 69.2 ± 5.5%, p ≤ 0.05). These results indicate that postexercise CM supplementation can improve subsequent exercise performance and provide a greater intracellular signaling stimulus for PRO synthesis compared to CHO and placebo.
Journal Article