Reduced cardiopulmonary fitness in childhood acute lymphoblastic leukemia survivors

This journal suppl. entitled: Supplement: SIOP Abstratcs: 45th Congress of the International Society of Paediatric Oncology (SIOP) ... 2013Poster Session - Late Effects: abstract no. P-0478PURPOSE/OBJECTIVE: One in 600 adult individuals in USA is a survivor of childhood cancers. A number of chemotherapeutic agents are associated with long-term cardiopulmonary toxicities. Low cardiopulmonary fitness is a strong predictor of all-cause mortality, cardiovascular disease and functional limitations. The purpose of this study was to evaluate cardiopulmonary fitness in Chinese paediatric acute lymphoblastic leukemia (ALL) survivors and to identify high risk group for early behavioral modification. MATERIALS AND METHODS: Childhood ALL survivors were recruited. Cardiopulmonary fitness expressed as peak oxygen consumption (peak VO2) was measured. Exercise response of ALL survivors was compared to a group of age, gender and BMI matched healthy controls. Maximal effort was defined as a respiratory exchange ratio (RER) > 1.10 with clear signs of exhaustion RESULTS: Fifty-one survivors (27 males, 24 females) with a mean age of 18.3 +/- 4.5 years were included in the analysis. Peak VO2 was significantly reduced in survivors compared with controls (35.2 +/- 9.8 vs 39.9 +/- 11.9 mL x Kg -1 x min -1 respectively, p < 0.05). Survivors also had significantly lower peak heart rate (HR) (186 +/- 9 vs 192 +/- 11 bpm, p < 0.05) and greater heart rate reserve (HRR) (5.3 +/- 9.8 vs -0.9 +/- 11.5 bpm, p < 0.05) than controls. Sixty-seven percent of survivors (15 males, 19 females) failed to achieve a peak HR greater than 95% of predicted maximal HR, compared to 41% in the control group (p < 0.05). The mean duration from assessment and termination of treatment for survivors with suboptimal peak HR (n = 34) vs those who could achieved optimal peak HR (n = 17) was 8.9 +/- 3.5 and 12.2 +/- 4.7 years respectively (p < 0.05). ALL risk stratifications in these 2 groups were similar. CONCLUSIONS: Significant proportion of ALL long-term survivors had reduced cardiopulmonary fitness which was a negative risk factor or subsequent cardiovascular risk. Early behavioral modifications are probably justified in this group of patients

Analysis of interactions in a tapasin/class I complex provides a mechanism for peptide selection

We examined interactions in a soluble tapasin (TPN)/HLA-B(*)0801 complex to gain mechanistic insights into the functions of TPN. Results show that TPN acts as a chaperone by increasing the ratio of active-to-inactive peptide-deficient HLA-B(*)0801 molecules in solution. TPN causes peptides to associate and dissociate faster owing to its effect on widening the binding groove of HLA-B(*)0801 molecules. Our data indicate that a TPN-assisted mechanism of peptide selection relies on disruption of conserved hydrogen bonds at the C-terminal end of the groove. Peptide sequence-dependent interactions along the entire length of the groove also play a role in this mechanism. We suggest that TPN influences presentation of antigenic peptides according to a mechanistically complicated process in which bound candidate peptides that are unable to conformationally disengage TPN from class I molecules are excluded from the repertoire. Overall, these studies unify our understanding of the functions of TPN

Function of NKG2D in natural killer cell–mediated rejection of mouse bone marrow grafts

Irradiation-resistant natural killer (NK) cells in an F(1) recipient can reject parental bone marrow, and host NK cells can also prevent engraftment of allogeneic bone marrow. We show here that repopulating bone marrow cells in certain mouse strains expressed retinoic acid early inducible 1 proteins, which are ligands for the activating NKG2D NK cell receptor. Treatment with a neutralizing antibody to NKG2D prevented rejection of parental BALB/c bone marrow in (C57BL/6 x BALB/c) F(1) recipients and allowed engraftment of allogeneic BALB.B bone marrow in C57BL/6 recipients. Additionally, bone marrow from C57BL/6 mice transgenic for retinoic acid early inducible 1epsilon was rejected by syngeneic mice but was accepted after treatment with antibody to NKG2D. If other stem cells or tissues upregulate expression of NKG2D ligands after transplantation, NKG2D may contribute to graft rejection in immunocompetent hosts

Structural mechanism of ER retrieval of MHC class I by cowpox.

One of the hallmarks of viral immune evasion is the capacity to disrupt major histocompatibility complex class I (MHCI) antigen presentation to evade T-cell detection. Cowpox virus encoded protein CPXV203 blocks MHCI surface expression by exploiting the KDEL-receptor recycling pathway, and here we show that CPXV203 directly binds a wide array of fully assembled MHCI proteins, both classical and non-classical. Further, the stability of CPXV203/MHCI complexes is highly pH dependent, with dramatically increased affinities at the lower pH of the Golgi relative to the endoplasmic reticulum (ER). Crystallographic studies reveal that CPXV203 adopts a beta-sandwich fold similar to poxvirus chemokine binding proteins, and binds the same highly conserved MHCI determinants located under the peptide-binding platform that tapasin, CD8, and natural killer (NK)-receptors engage. Mutagenesis of the CPXV203/MHCI interface identified the importance of two CPXV203 His residues that confer low pH stabilization of the complex and are critical to ER retrieval of MHCI. These studies clarify mechanistically how CPXV203 coordinates with other cowpox proteins to thwart antigen presentation