Failure of T cells to protect against cancer is thought to result from lack of antigen recognition, chronic activation, and/or suppression by other cells. Using a mouse sarcoma model, we show that ...glucose consumption by tumors metabolically restricts T cells, leading to their dampened mTOR activity, glycolytic capacity, and IFN-γ production, thereby allowing tumor progression. We show that enhancing glycolysis in an antigenic “regressor” tumor is sufficient to override the protective ability of T cells to control tumor growth. We also show that checkpoint blockade antibodies against CTLA-4, PD-1, and PD-L1, which are used clinically, restore glucose in tumor microenvironment, permitting T cell glycolysis and IFN-γ production. Furthermore, we found that blocking PD-L1 directly on tumors dampens glycolysis by inhibiting mTOR activity and decreasing expression of glycolysis enzymes, reflecting a role for PD-L1 in tumor glucose utilization. Our results establish that tumor-imposed metabolic restrictions can mediate T cell hyporesponsiveness during cancer.
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•Tumor cells and TILs compete for glucose within the tumor niche•Metabolic competition can drive cancer progression•Checkpoint blockade antibodies alter the metabolic balance in a tumor•PD-L1 promotes Akt/mTOR activation and glycolysis in tumor cells
Glucose consumption by antigenic tumors can metabolically restrict T cells, directly dampening their effector function and allowing tumor progression. Checkpoint blockade therapy may correct this resource imbalance through a direct effect in the tumor cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Genetically modified T cells expressing chimeric antigen receptors (CARs) demonstrate robust responses against lineage restricted, non-essential targets in hematologic cancers. However, in solid ...tumors, the full potential of CAR T cell therapy is limited by the availability of cell surface antigens with sufficient cancer-specific expression. The majority of CAR targets have been normal self-antigens on dispensable hematopoietic tissues or overexpressed shared antigens. Here, we established that abnormal self-antigens can serve as targets for tumor rejection. We developed a CAR that recognized cancer-associated Tn glycoform of MUC1, a neoantigen expressed in a variety of cancers. Anti-Tn-MUC1 CAR T cells demonstrated target-specific cytotoxicity and successfully controlled tumor growth in xenograft models of T cell leukemia and pancreatic cancer. These findings demonstrate the therapeutic efficacy of CAR T cells directed against Tn-MUC1 and present aberrantly glycosylated antigens as a novel class of targets for tumor therapy with engineered T cells.
•Cancer cells of many tissues express an abnormal glycoform of MUC1, Tn-MUC1•Normal human tissue does not express detectable Tn-MUC1 on the cellular surface•CAR T cells are engineered to target Tn-MUC1 lyse tumor cells in vitro and in vivo•Abnormal glycoform epitopes are valid clinical targets for CAR T cells
Posey and colleagues developed a CAR T cell therapy to break immune tolerance to solid tumors by targeting an aberrantly glycosylated, cancer-specific glycoprotein in multiple cancer histotypes and demonstrated efficacy and safety in tumors as diverse as leukemia and pancreatic cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Conventional type 1 dendritic cells (cDC1)
are thought to perform antigen cross-presentation, which is required to prime CD8
T cells
, whereas cDC2 are specialized for priming CD4
T cells
. CD4
T ...cells are also considered to help CD8
T cell responses through a variety of mechanisms
, including a process whereby CD4
T cells 'license' cDC1 for CD8
T cell priming
. However, this model has not been directly tested in vivo or in the setting of help-dependent tumour rejection. Here we generated an Xcr1
mouse strain to evaluate the cellular interactions that mediate tumour rejection in a model requiring CD4
and CD8
T cells. As expected, tumour rejection required cDC1 and CD8
T cell priming required the expression of major histocompatibility class I molecules by cDC1. Unexpectedly, early priming of CD4
T cells against tumour-derived antigens also required cDC1, and this was not simply because they transport antigens to lymph nodes for processing by cDC2, as selective deletion of major histocompatibility class II molecules in cDC1 also prevented early CD4
T cell priming. Furthermore, deletion of either major histocompatibility class II or CD40 in cDC1 impaired tumour rejection, consistent with a role for cognate CD4
T cell interactions and CD40 signalling in cDC1 licensing. Finally, CD40 signalling in cDC1 was critical not only for CD8
T cell priming, but also for initial CD4
T cell activation. Thus, in the setting of tumour-derived antigens, cDC1 function as an autonomous platform capable of antigen processing and priming for both CD4
and CD8
T cells and of the direct orchestration of their cross-talk that is required for optimal anti-tumour immunity.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Aim
To determine the relationship between the Test of Infant Motor Performance (TIMP) at 3 months and cognitive, language, and motor outcomes on the Bayley Scales of Infant and Toddler Development, ...Third Edition (Bayley‐III) at 2 years of age in high‐risk infants born preterm.
Method
One hundred and six infants (47 females, 59 males) born at earlier than 31 weeks gestational age were prospectively tested with the TIMP at 10 to 15 weeks after term age and were assessed again with the Bayley‐III at 2 years corrected age. Sensitivity and specificity were calculated for various cut points of the TIMP z‐score and Bayley‐III composite scores of no more than 85.
Results
The TIMP z‐scores at 10 to 15 weeks of age were significantly associated with all three subscales on the Bayley‐III at 2 years of age (p<0.001). Using a TIMP z‐score cutoff of −0.5, specificity was relatively high for cognitive (87%), language (88%), and motor (89%) outcomes, but sensitivity was low (cognitive 41%, language 49%, motor 57%).
Interpretation
This study demonstrates that the TIMP is related to cognitive, language, and motor outcomes on the Bayley‐III at 2 years of age in high‐risk infants born preterm.
What this paper adds
The Test of Infant Motor Performance (TIMP) predicts Bayley Scales of Infant and Toddler Development, Third Edition outcomes at 2 years of age.
The TIMP is relatively good at discriminating between children who will and will not have typical development.
Resumen
La escala Infant Motor Performance a los 3 meses predice logros cognitivos, motores y de lenguaje en niños nacidos prematuros a los dos años de edad
Objetivo
Determinar la relación entre la escala Infant Motor Performance (TIMP) a los 3 meses y los logros cognitivos, motores y de lenguaje en la Escala Bayley de Desarrollo de Bebes y Niños, Tercera Edición (Bayley‐III) a los 2 años de edad en niños nacidos prematuros de alto riesgo.
Metodo
Ciento seis niños (47 femeninos, 59 masculinos) nacidos antes de las 31 semanas de edad gestacional fueron testeados prospectivamente con el TIMP entre las 10 y 15 semanas después de la edad de término y fueron evaluados nuevamente con la Bayley‐III a los 2 años de edad corregida. La Sensibilidad y Especificidad fueron calculados para varios puntos de corte del TIMP z‐score y puntajes compuestos de Bayley‐III de no más de 85.
Resultados
Los TIMP z‐scores entre las 10 y 15 semanas estuvieron significativamente asociadas con las tres subescalas en Bayley‐III a los 2 años (p<0,001). Usando un corte de 0,5 para el TIMP z‐score, la especificidad fue relativamente alta para los logros cognitivos (87%), de lenguaje (88%), y motores (89%), pero la sensibilidad fue baja (cognitivos 41%, de lenguaje 49%, motores 57%).
Interpretacion
Este estudio demuestra que el TIMP está relacionado con los logros cognitivos, de lenguaje y motores en la Bayley‐III a los 2 años en niños nacidos pretérmino de alto riesgo.
Resumo
O Teste do Infant Motor Performance (TIMP) aos 3 meses prediz resultados de linguagem, cognitivos e motores em lactenets nascidos prematuros aos 2 anos de idade
Objetivo
Determinar a relação entre o Teste do Desempenho Motor do Lactente (TIMP) aos 3 meses e os resultados de linguagem, cognitivos e motores segundo as Escala Bayley de Desenvolviemnto do Lactente e da Criança, terceira edição (Bayley‐III) aos 2 anos de idade em lactentes nascidos prematuros de alto risco.
Método
Cento e seis lactentes (47 do sexo feminino, 59 do sexo masculino) nascidos com < 31 semanas de idade gestacional foram prospectivamente testados com o TIMP nas 10 e 15 semanas após a idade termo, e avaliados novamente com a Bayley‐III aos 2 anos de idade corrigida. A sensibilidade e especificidade foram calculados para vários pontos de corte dos escores z da TIMP e escores compostos da Bayley‐III de até 85.
Resultados
Os escores z doTIMP nas 10 e 15 semanas de idade foram significativamente associados com todas as três subescalas da Bayley‐III aos 2 anos de idade (P<0,001). Usando o ponto de corte do escore z da TIMP de _0,5. A especificidade foi relativamente alta para os resultados cognitivos (87%), de linguagem (88%), e motores (89%), mas a sensibilidade foi baixa (cognitivo 41%, linguagem 49%, motor 57%).
Interpretação
Este estudo demonstra que o TIMP se relaciona com resultados cognitivos, de linguagem e motores na Bayley‐III aos 2 anos de idade em lactentes nascidos prematuros de alto risco.
What this paper adds
The Test of Infant Motor Performance (TIMP) predicts Bayley Scales of Infant and Toddler Development, Third Edition outcomes at 2 years of age.
The TIMP is relatively good at discriminating between children who will and will not have typical development.
This article's has been translated into Spanish and Portuguese.
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This article is commented on by Morgan on pages 1194–1195 of this issue.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Trauma-induced coagulopathy is a major driver of mortality following severe injury. Viscoelastic goal-directed resuscitation can reduce mortality after injury. The TEG 5000 system is widely used for ...viscoelastic testing. However, the TEG 6s system incorporates newer technology, with encouraging results in cardiovascular interventions. The purpose of this study was to validate the TEG 6s system for use in trauma patients.
Multicenter noninvasive observational study for method comparison conducted at 12 US Levels I and II trauma centers. Agreement between the TEG 6s and TEG 5000 systems was examined using citrated kaolin reaction time (CK.R), citrated functional fibrinogen maximum amplitude (CFF.MA), citrated kaolin percent clot lysis at 30 minutes (CK.LY30), citrated RapidTEG maximum amplitude (CRT.MA), and citrated kaolin maximum amplitude (CK.MA) parameters in adults meeting full or limited trauma team criteria. Blood was drawn ≤1 hour after admission. Assays were repeated in duplicate. Reliability (TEG 5000 vs. TEG 6s analyzers) and repeatability (interdevice comparison) was quantified. Linear regression was used to define the relationship between TEG 6s and TEG 5000 devices.
A total of 475 patients were enrolled. The cohort was predominantly male (68.6%) with a median age of 49 years. Regression line slope estimates (ß) and linear correlation estimates (p) were as follows: CK.R (ß = 1.05, ρ = 0.9), CFF.MA (ß = 0.99, ρ = 0.95), CK.LY30 (ß = 1.01, ρ = 0.91), CRT.MA (TEG 6s) versus CK.MA (TEG 5000) (ß = 1.06, ρ = 0.86) as well as versus CRT.MA (TEG 5000) (ß = 0.93, ρ = 0.93), indicating strong reliability between the devices. Overall, within-device repeatability was better for TEG 6s versus TEG 5000, particularly for CFF.MA and CK.LY30.
The TEG 6s device appears to be highly reliable for use in trauma patients, with close correlation to the TEG 5000 device and equivalent/improved within-device reliability. Given the potential advantages of using the TEG 6s device at the site of care, confirmation of agreement between the devices represents an important advance in diagnostic testing.
Diagnostic test, level II.
Reduction of native prion protein (PrP) levels in the brain is an attractive strategy for the treatment or prevention of human prion disease. Clinical development of any PrP-reducing therapeutic will ...require an appropriate pharmacodynamic biomarker: a practical and robust method for quantifying PrP, and reliably demonstrating its reduction in the central nervous system (CNS) of a living patient. Here we evaluate the potential of ELISA-based quantification of human PrP in human cerebrospinal fluid (CSF) to serve as a biomarker for PrP-reducing therapeutics. We show that CSF PrP is highly sensitive to plastic adsorption during handling and storage, but its loss can be minimized by the addition of detergent. We find that blood contamination does not affect CSF PrP levels, and that CSF PrP and hemoglobin are uncorrelated, together suggesting that CSF PrP is CNS derived, supporting its relevance for monitoring the tissue of interest and in keeping with high PrP abundance in brain relative to blood. In a cohort with controlled sample handling, CSF PrP exhibits good within-subject test–retest reliability (mean coefficient of variation, 13% in samples collected 8–11 wk apart), a sufficiently stable baseline to allow therapeutically meaningful reductions in brain PrP to be readily detected in CSF. Together, these findings supply a method for monitoring the effect of a PrP-reducing drug in the CNS, and will facilitate development of prion disease therapeutics with this mechanism of action.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
In this multicenter, randomized trial, the administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic–ischemic encephalopathy did not result in a lower risk of death ...or neurodevelopmental impairment at 22 to 36 months of age than placebo and was associated with a higher rate of serious adverse events.
To compare neurocognitive, language, executive function, academic achievement, neurologic and behavioral outcomes, and quality of life at age 10 years in children born extremely preterm who developed ...bronchopulmonary dysplasia (BPD) to children who did not develop BPD.
The Extremely Low Gestational Age Newborns study population included 863 children born extremely preterm whose BPD status before discharge was known had an IQ (Differential Ability Scales II DAS II) assessment at 10 years. We evaluated the association of BPD with any cognitive (DAS II), executive function (NEuroPSYchological Assessment II), academic achievement (Wechsler Individual Achievement Test-III and Oral and Written Language Scales OWLS) as well as social dysfunctions (Social Responsiveness Scale). We used logistic regression models, adjusting for potential confounding factors, to assess the strength of association between the severity of BPD and each outcomes.
Three hundred and seventy-two (43%) children were oxygen-dependent at 36 weeks postconception age, whereas an additional 78 (9%) were also oxygen- and ventilator-dependent. IQ scores 2 or more SDs below the expected mean (ie,
scores ≤-2) occurred twice as commonly among children who had BPD as among those who did not. Children with severe BPD consistently had the lowest scores on DAS II, OWLS, Wechsler Individual Achievement Test-III, NEuroPSYchological Assessment II, and Social Responsiveness Scale assessments.
Among 10-year-old children born extremely preterm, those who had BPD were at increased risk of cognitive, language, and executive dysfunctions; academic achievement limitations; social skill deficits; and low scores on assessments of health-related quality of life.
Respiratory distress syndrome increases the risk of death and bronchopulmonary dysplasia (BPD) in premature infants. Inhaled nitric oxide (iNO) may reduce these risks. Recent meta-analyses have ...suggested that iNO is effective only at doses higher than 5 ppm and in infants born to Black mothers. In a randomized, double-blinded, controlled trial, infants born before 32 0/7 weeks gestation, weighing <1500 g, and requiring respiratory support were assigned to receive iNO for either seven days (short iNO), or until 33 0/7 weeks PMA (long iNO). The primary outcome was death or BPD. A total of 273 patients were enrolled, of whom 83 receiving long iNO (61.5%) experienced the primary outcome, compared with 65 (47.1%) receiving short iNO (relative risk (RR) 1.37; 95% confidence interval (CI), 1.06-1.79;
= 0.017). This increase was due solely to increased BPD in infants weighing 750-999 g (RR 1.33, 95% CI 1.07-1.66,
= 0.009). However, there was no difference in the numbers of infants requiring supplemental oxygen at 40 weeks PMA. Among infants < 750 g, long-iNO-treated infants had a lower cumulative probability of death (χ
5.12,
= 0.02). Long iNO increased the primary outcome in non-Black infants (RR 1.93, 95% CI 1.20-3.24) but not in Black infants. Understanding how maternal racial identity determines responses of premature infants to iNO may help narrow the gap in health outcomes between Black and non-Black infants.
Earlier use of in-hospital plasma, platelets, and red blood cells (RBCs) has improved survival in trauma patients with severe hemorrhage. Retrospective studies have associated improved early survival ...with prehospital blood product transfusion (PHT). We hypothesized that PHT of plasma and/or RBCs would result in improved survival after injury in patients transported by helicopter.
Adult trauma patients transported by helicopter from the scene to nine Level 1 trauma centers were prospectively observed from January to November 2015. Five helicopter systems had plasma and/or RBCs, whereas the other four helicopter systems used only crystalloid resuscitation. All patients meeting predetermined high-risk criteria were analyzed. Patients receiving PHT were compared with patients not receiving PHT. Our primary analysis compared mortality at 3 hours, 24 hours, and 30 days, using logistic regression to adjust for confounders and site heterogeneity to model patients who were matched on propensity scores.
Twenty-five thousand one hundred eighteen trauma patients were admitted, 2,341 (9%) were transported by helicopter, of which 1,058 (45%) met the highest-risk criteria. Five hundred eighty-five of 1,058 patients were flown on helicopters carrying blood products. In the systems with blood available, prehospital median systolic blood pressure (125 vs 128) and Glasgow Coma Scale (7 vs 14) was significantly lower, whereas median Injury Severity Score was significantly higher (21 vs 14). Unadjusted mortality was significantly higher in the systems with blood products available, at 3 hours (8.4% vs 3.6%), 24 hours (12.6% vs 8.9%), and 30 days (19.3% vs 13.3%). Twenty-four percent of eligible patients received a PHT. A median of 1 unit of RBCs and plasma were transfused prehospital. Of patients receiving PHT, 24% received only plasma, 7% received only RBCs, and 69% received both. In the propensity score matching analysis (n = 109), PHT was not significantly associated with mortality at any time point, although only 10% of the high-risk sample were able to be matched.
Because of the unexpected imbalance in systolic blood pressure, Glasgow Coma Scale, and Injury Severity Score between systems with and without blood products on helicopters, matching was limited, and the results of this study are inconclusive. With few units transfused to each patient and small outcome differences between groups, it is likely large, multicenter, randomized studies will be required to detect survival differences in this important population.
Level II.
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