Programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are immunomodulatory molecules overexpressed in lymphomas and are promising immunotherapy targets for hematologic ...malignancies. However, studies of PD-1/PD-L1 overexpression and their clinical significance in aggressive pediatric non-Hodgkin lymphomas (NHLs) are limited. We assessed PD-1/PD-L1 overexpression using immunohistochemistry in 68 aggressive pediatric NHLs: ALK-positive anaplastic large cell lymphoma (ALK+ ALCL, n=8), Burkitt lymphoma (BL, n=27), and large B-cell lymphoma (LBCL) de novo LBCL (n=22) and diffuse LBCL arising as monomorphic post-transplant lymphoproliferative disorder (PTLD-DLBCL, n=11). In LBCL, correlations between PD-L1 overexpression and Epstein-Barr virus (EBV) status, cell of origin, stage, nodal status, overall survival (OS), and event-free survival (EFS) were examined. The genetic mechanisms of PD-L1 overexpression were investigated using targeted nextgeneration sequencing (NGS) and cytogenetic data. All ALK+ ALCL samples, 50.0% of de novo LBCLs (11/22), 72.7% of PTLD-DLBCLs (8/11), and no BLs overexpressed PD-L1. Overexpressed PD-L1 correlated with EBV-positivity (p=0.033) in LBCLs and lower EFS in de novo LBCL (p=0.017). NGS of select LBCLs revealed distinct somatic mutations and an ultrahypermutated PTLD-DLBCL. Most cases with 9p24.1 copy gains overexpressed PD-L1 although some cases had no discernible genetic drivers of PD-L1 overexpression. Overexpressed PD-L1 is common in pediatric LBCL, associated with EBV-positivity and 9p24.1 gains, and may have prognostic significance in de novo LBCL. Furthermore, diverse molecular mechanisms for PD-L1 overexpression in aggressive pediatric NHL can occur. Thus, additional studies exploring the therapeutic and prognostic significance and molecular mechanisms of PD-L1 overexpression in aggressive pediatric NHLs are warranted.
To characterise the assessment and management practices employed by Sports Dietitians when assessing and managing athletes at risk of low energy availability (LEA).
55 Sports Dietitians participated ...in an online questionnaire that captured the typical methods used to identify and manage LEA in athletic populations.
The questionnaire consisted of 27 questions which explored common methods used to identify and manage LEA, as well as dietary methods employed and barriers experienced by Sports Dietitians.
Broadly, the top 3 nutrition-related priorities for respondents were nutrition strategies to support training, competition, and recovery while ‘LEA’ was ranked fifth. ‘Dietary intake’, ‘menstrual function’ and ‘training load (km/week)’ were the primary methods used to assess LEA and respondents were ‘confident’ in their ability to correctly identify athletes at risk. Among support personnel, coaches were rarely a referral source for management of LEA but did present frequent communication difficulties. Respondents indicated athletes have concerns about undesirable changes in body composition when providing recommendations of increased energy intake for LEA management.
Sport Dietitians appear to recognise and prioritise LEA management in athletes, but assessments are limited to dietary intake and training load (km/week); with collaborative approaches to LEA management lacking. Sports Dietitian may be overconfident in their ability to identify LEA as only a limited number of assessment methods are commonly used. Access to reliable assessments methods and collaborative management approaches are needed to improve athlete care when suspected of LEA.
The application of continuous glucose monitors (CGMs) to measure interstitial glucose in athletic populations is limited by the lack of accepted athlete-specific reference values. The aim of this ...study was to develop athlete-specific reference ranges for glycemic variability under standardized diet and exercise conditions.
A total of 12 elite racewalkers (n = 7 men, 22.4 ± 3.5 years, VO
61.6 ± 7.3 mL kg
min
) completed two 4-d trials separated by 4-d. Athletes were provided a high-energy, high-carbohydrate diet (225 ± 1.6 kJ kg
day
, 8.4 ± 0.3 g kg
day
carbohydrate) and completed standardized daily exercise. The timing of food consumed and exercise undertaken were matched each day across the 4-d trials. Interstitial glucose data were collected via Freestyle Libre 2 CGMs. Glycemic variability was calculated as the mean amplitude of glycemic excursions (MAGEs), mean of daily differences (MODD), and standard deviation (SD).
Twenty-four hour MODD, MAGE, and SD for interstitial glucose were 12.6 ± 1.8 mg/dL (0.7 ± 0.1 mmol/L), 36.0 ± 5.4 mg/dL (2.0 ± 0.3 mmol/L), and 16.2 ± 1.8 mg/dL (0.9 ± 0.1 mmol/L), respectively. Twenty-four hour mean glucose (MG; 102.6 ± 5.4 mg/dL 5.7 ± 0.3 mmol/L) was higher than overnight (91.8 ± 5.4 mg/dL 5.1 ± 0.3 mmol/L;
< .0001) and was lower in women than men (99.0 ± 3.6 mg/dL 5.5 ± 0.2 mmol/L vs 104.4 ± 3.6 mg/dL 5.8 ± 0.2 mmol/L;
= .059, d = 1.4).
This study provides reference indices under standardized diet and exercise conditions for glycemic variability derived from CGMs in endurance athletes which are similar than previously reported for healthy individuals, despite strenuous daily training and a high daily energy and carbohydrate diet.
Background
Systemic forms of EBV‐associated T‐cell lymphoproliferative disorders of childhood (S‐EBV‐T‐LPD) comprise three major forms: EBV‐positive hemophagocytic lymphohistiocytosis (EBV‐HLH), ...systemic EBV‐positive T‐cell lymphoma (S‐EBV‐TCL), and systemic chronic active EBV infection (S‐CAEBV). These disorders occur rarely in children in Western countries. Here, we described eight children of such entities.
Design
Eight cases (six clinical and two autopsy) with S‐EBV‐T‐LPD of childhood were retrospectively identified from 1990 to 2015. Clinicopathologic parameters including histomorphology, immunophenotype, EBV studies, and T‐cell receptor gene rearrangement studies were recorded.
Results
Patients include five females and three males of Hispanic, Asian, and Caucasian origins with an age range of 14 months to 9 years. Fever, hepatosplenomegaly, cytopenias, abnormal EBV serologies, and very high EBV viral loads were common findings. Histologic findings showed EBV+ T‐cell infiltrates with variable degrees of architectural distortion and cytologic atypia ranging from no to mild cytologic atypia to overt lymphoma and tissue hemophagocytosis. All showed aberrant CD4+ or CD8+ T cells with dim to absent CD5, CD7, and CD3, and bright CD2 and CD45 by flow cytometry or loss of CD5 by immunohistochemistry. TCR gene rearrangement studies showed monoclonal rearrangements in all clinical cases (6/6). Outcomes were poor with treatment consisting of chemotherapy per the HLH‐94 or HLH‐2004 protocols with or without bone marrow transplant.
Conclusion
In this large pediatric clinicopathologic study of S‐EBV‐T‐LPD of childhood in the United States, EBV‐HLH, S‐EBV‐TCL, and S‐CAEBV show many overlapping features. Diagnosis is challenging, and overall outcome is poor using current HLH‐directed therapies.
Ascertaining the impact of uncharacterized perturbations on the cell is a fundamental problem in biology. Here, we describe how a single assay can be used to monitor hundreds of different cellular ...functions simultaneously. We constructed a reference database or “compendium” of expression profiles corresponding to 300 diverse mutations and chemical treatments in
S. cerevisiae, and we show that the cellular pathways affected can be determined by pattern matching, even among very subtle profiles. The utility of this approach is validated by examining profiles caused by deletions of uncharacterized genes: we identify and experimentally confirm that eight uncharacterized open reading frames encode proteins required for sterol metabolism, cell wall function, mitochondrial respiration, or protein synthesis. We also show that the compendium can be used to characterize pharmacological perturbations by identifying a novel target of the commonly used drug dyclonine.
This review discusses the potential value of tracking interstitial glucose with continuous glucose monitors (CGMs) in athletes, highlighting possible applications and important considerations in the ...collection and interpretation of interstitial glucose data. CGMs are sensors that provide real time, longitudinal tracking of interstitial glucose with a range of commercial monitors currently available. Recent advancements in CGM technology have led to the development of athlete-specific devices targeting glucose monitoring in sport. Although largely untested, the capacity of CGMs to capture the duration, magnitude, and frequency of interstitial glucose fluctuations every 1-15 min may present a unique opportunity to monitor fueling adequacy around competitive events and training sessions, with applications for applied research and sports nutrition practice. Indeed, manufacturers of athlete-specific devices market these products as a "fueling gauge," enabling athletes to "push their limits longer and get bigger gains." However, as glucose homeostasis is a complex phenomenon, extensive research is required to ascertain whether systemic glucose availability (estimated by CGM-derived interstitial glucose) has any meaning in relation to the intended purposes in sport. Whether CGMs will provide reliable and accurate information and enhance sports nutrition knowledge and practice is currently untested. Caveats around the use of CGMs include technical issues (dislodging of sensors during periods of surveillance, loss of data due to synchronization issues), practical issues (potential bans on their use in some sporting scenarios, expense), and challenges to the underpinning principles of data interpretation, which highlight the role of sports nutrition professionals to provide context and interpretation.
Benign middle ear tumors represent a rare group of neoplasms that vary widely in their pathology, anatomy, and clinical findings. These factors have made it difficult to establish guidelines for the ...resection of such tumors. Here we present 7 unique cases of these rare and diverse tumors and draw from our experience to recommend optimal surgical management. Based on our experience, a postauricular incision is necessary in nearly all cases. Mastoidectomy is required for tumors that extend into the mastoid cavity. Whenever exposure or hemostasis is believed to be inadequate with simple mastoidectomy, canal-wall-down mastoidectomy should be performed. Finally, disarticulation of the ossicular chain greatly facilitates tumor excision and should be performed early in the procedure.
This article features eight AAFCS-accredited academic units in higher education to illustrate how the Family and Consumer Sciences Body of Knowledge (FCS-BOK) can be integrated into program curricula ...and educational procedures or structures. Contributors represent the following educational
institutions (listed and presented in alphabetical order): California State University-Long Beach, Carson-Newman University, Illinois State University, Louisiana Tech University, Southeastern Louisiana University, Southern University at New Orleans, Stephen F. Austin State University,
and Tennessee Technological University.
Congenital pulmonary airway malformation (CPAM) is a developmental abnormality of the lung, which results from an abnormality of branching during fetal development of the lung. We report the case of ...an 18 year-old woman who developed Kirsten rat sarcoma virus (KRAS) mutation positive mucinous adenocarcinoma of the lung (AC) in association with mixed CPAM type 1 and 2. This case is unique as KRAS mutation positive AC is present in a setting of both CPAM 1 and 2 in the same lesion.
Antitumor T-cell responses raised by frontline therapies such as chemotherapy, radiation, tumor cell vaccines, and viroimmunotherapy tend to be weak, both quantitatively (low frequency) and ...qualitatively (low affinity). We show here that T cells that recognize tumor-associated antigens (TAAs) can directly kill tumor cells if used at high effector-to-target ratios. However, when these tumor-reactive T cells were present at suboptimal ratios, direct T cell–mediated tumor cell killing was reduced and the ability of tumor cells to evolve away from a co-applied therapy (oncolytic or suicide gene therapy) was promoted. This T cell–mediated increase in therapeutic resistance was associated with C to T transition mutations that are characteristic of APOBEC3 cytosine deaminase activity and was induced through a TNFα and PKC–dependent pathway. Short hairpin RNA inhibition of endogenous APOBEC3 reduced rates of tumor escape from oncolytic virus or suicide gene therapy to those seen in the absence of antitumor T-cell coculture. Conversely, overexpression of human APOBEC3B in tumor cells enhanced escape from suicide gene therapy and oncolytic virus therapy both
in vitro
and
in vivo
. Our data suggest that weak affinity or low frequency T-cell responses against tumor antigens may contribute to the ability of tumor cells to evolve away from frontline therapies. We conclude that immunotherapies need to be optimized as early as possible so that, if they do not kill the tumor completely, they do not promote treatment resistance.
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