CD9 blockade suppresses disease progression of high-risk pediatric B-cell precursor acute lymphoblastic leukemia and enhances chemosensitivity.

CD9 has been implicated in cancer progression but its prognostic relevance and therapeutic potential in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are largely unknown. In a cohort of pediatric BCP-ALL patients, we found that CD9+ cases had a significantly lower 5-year relapse-free survival rate than CD9- cases. Multivariate analysis demonstrated that CD9 positivity independently predicted inferior survival outcomes, and could be applied with established prognostic features, including prednisone response and cytogenetic status, to refine patient stratification. Administration of CD9 antibody substantially suppressed disease progression in NOD/SCID mice xenografted with CD9+ cell lines and primary leukemic blasts from patients with high-risk and refractory BCP-ALL, without compromising hematopoietic stem cell engraftment. Combination of anti-CD9 with conventional chemotherapy further reduced leukemic burden and prolonged animal survival. Mechanistically, CD9 blockade inhibited leukemic cell proliferation, induced G0/G1 cell cycle arrest, activated p38, and enhanced chemotherapeutic agent-induced apoptosis. Further, CD9 physically interacted with integrin very late antigen-4, regulated affinity to vascular cell adhesion molecule-1, and was involved in leukemia-stroma interaction. Collectively, our study established CD9 as a new prognostic marker, validated the preclinical efficacy of CD9 antibody, and laid the foundation for clinical development of CD9-targeted therapy for high-risk and refractory pediatric BCP-ALL.

Do we need another symptom score for childhood eczema?

AIM: It is important to objectively measure the severity of atopic dermatitis (AD). This study aims to investigate correlations among various clinical severity scores and determine how a severity score based on symptoms alone performs. METHODS: A Chinese-translated symptom score based on Patient-Oriented Eczema Measure (POEM, a short-term subjective-symptom score), Scoring Atopic Dermatitis (SCORAD, a short-term subjective-symptom and objective-sign score), Nottingham Eczema Severity Score (NESS, a long-term subjective symptoms + objective signs), Children Dermatology Life Quality Index (CDLQI, a short-term subjective-symptom score), skin hydration (SH) and transepidermal water loss (TEWL) were compared and Spearman's rho correlations was evaluated. RESULTS: 126 sets of clinical scores from eczema patients (mean age: 11.4 ± 5.6 years; 34.7% male) were evaluated. The modified-POEM, objective SCORAD, NESS and CDLQI correlated well with each other. All round, best correlations were obtained with POEM: Objective SCORAD (rho = 0.7, p < 0.001), NESS (rho = 0.69, p < 0.001), SCORAD symptom of itch (rho = 0.75, p < 0.01), SCORAD symptom of sleep loss (rho = 0.64, p < 0.01), CDLQI (rho = 0.77, p < 0.001) and SH (rho= -0.043, p < 0.05). Linear stepwise-backward regression demonstrated that POEM was independently associated with CDLQI parameters of pruritus (B: 2.16; p = 0.018), activities (B: 1.80; p = 0.009), sleep disturbance (B: 2.78; p < 0.001) and NESS parameter of sleep disturbance (B: 1.02; p = 0.003). CONCLUSION: Clinical scores for acute, chronic, subjective symptoms and objective signs correlated well with each other. The symptom measures by modified POEM is easy to perform by parents or patients and correlated better with most other clinical scores, making it an all-round ideal symptom-based severity score for research.

Regulation of Circulating Hematopoietic Stem/Progenitor Cells in Preterm Infants with Septicemia.

Preterm infants are at high risk of developing severe sepsis. Circulating hematopoietic stem and progenitor cells (HSPCs; CD45+CD34+) have been suggested to play a vital role in the host immunological defense against invading pathogens. The objectives were to investigate the regulation of circulating HSPCs in preterm infants during infection episodes, and to assess the relationship of CD45+CD34+ cells with immunological mediators and differential leukocyte populations. First, we conducted a cross-sectional case-control study comparing these parameters among infected infants (n = 23), gestational and postnatal age-matched noninfected infants (n = 46), and "healthy" control (CTL) infants (n = 12). Second, we investigated the longitudinal change of CD45+CD34+ cell concentrations in infected infants before, during, and after an infection episode, and compared them with the other two groups. Our cross-sectional results showed that CD45+CD34+ cell count and percentage were significantly reduced in infected infants during systemic infection, compared with the noninfected or CTL infants. There were significant positive correlation between levels of CD45+CD34+ cells and lymphocytes or monocytes, and significant negative correlation between CD45+CD34+ cells and neutrophils or interleukin (IL)-6 in infected infants. Longitudinal analysis showed that changes of CD45+CD34+ cells at the onset of sepsis relative to levels 1 week prior and 1 week postsepsis in infected infants were significantly different from those changes in the corresponding time points for the other two groups. Our findings suggested that circulating HSPCs were dynamically regulated during septicemia and could play an important role in the defense mechanism, plausibly contributing to replenishment of leukocytes during sepsis in preterm infants.

Dysregulated expression of arginine metabolic enzymes in human intestinal tissues of necrotizing enterocolitis and response of CaCO2 cells to bacterial components.

The small intestine is the exclusive site of arginine synthesis in neonates. Low levels of circulating arginine have been associated with the occurrence of necrotizing enterocolitis (NEC) but the mechanism of arginine dysregulation has not been fully elucidated. We aimed to investigate (i) expressional changes of arginine synthesizing and catabolic enzymes in human intestinal tissues of NEC, spontaneous intestinal perforation (SIP) and noninflammatory surgical conditions (Surg-CTL) and to investigate the (ii) mechanisms of arginine dysregulation and enterocyte proliferation upon stimulation by bacterial components, arginine depletion, ARG1 overexpression and nitric oxide (NO) supplementation. Our results showed that expressions of arginine synthesizing enzymes ALDH18A1, ASL, ASS1, CPS1, GLS, OAT and PRODH were significantly decreased in NEC compared with Surg-CTL or SIP tissues. Catabolic enzyme ARG1 was increased (>100-fold) in NEC tissues and histologically demonstrated to be expressed by infiltrating neutrophils. No change in arginine metabolic enzymes was observed between SIP and Surg-CTL tissues. In CaCO2 cells, arginine metabolic enzymes were differentially dysregulated by lipopolysaccharide or lipoteichoic acid. Depletion of arginine reduced cell proliferation and this phenomenon could be partially rescued by NO. Overexpression of ARG1 also reduced enterocyte proliferation. We provided the first expressional profile of arginine metabolic enzymes at the tissue level of NEC. Our findings suggested that arginine homeostasis was severely disturbed and could be triggered by inflammatory responses of enterocytes and infiltrating neutrophils as well as bacterial components. Such reactions could reduce arginine and NO, resulting in mucosal damage. The benefit of arginine supplementation for NEC prophylaxis merits further clinical evaluation.