Thymic stromal-derived lymphopoietin induces proliferation of pre-B leukemia and antagonizes mTOR inhibitors, suggesting a role for interleukin-7Ralpha signaling

Understanding the pathogenesis of leukemia in the context of lymphopoiesis may reveal novel therapeutic targets. Previously, we have shown that mTOR inhibitors (MTI) show activity in vitro and in preclinical models of both human and murine precursor B acute lymphoblastic leukemia (pre-B ALL), inhibiting cell proliferation and inducing apoptosis. These MTI-mediated effects can be reversed by interleukin-7 (IL-7), an important regulator of early B-cell development. This observation led us to examine the contribution of signaling via the IL-7Ralpha chain, which is shared by the receptor complexes of IL-7 and thymic stromal-derived lymphopoietin (TSLP). TSLP is closely related to IL-7 and active in lymphopoiesis, but an effect of TSLP on leukemia cells has not been described. We examined the effect of TSLP on pre-B ALL cells and their response to MTIs. Here, we show that TSLP stimulates proliferation of pre-B ALL cell lines. TSLP also partially reverses the effects of MTI on proliferation, apoptosis, and ribosomal protein S6 and 4E-BP1 phosphorylation in cell lines, with similar biological effects seen in some primary human lymphoblast samples. These data show that TSLP can promote survival of pre-B ALL cells and antagonize the effects of MTIs. These findings suggest that IL-7Ralpha chain is responsible for transducing the survival signal that overcomes MTI-mediated growth inhibition in pre-B ALL. Thus, further exploration of the IL-7Ralpha pathway may identify potential therapeutic targets in the treatment of ALL. Our data illustrate that growth-factor-mediated signaling may provide one mechanism of MTI resistance.     

Impact of laparotomy and liver resection on the peritoneal concentrations of fibroblast growth factor 2, vascular endothelial growth factor and hepatocyte growth factor

Purpose: Some data have suggested that major surgery is associated with the post-operative growth of residual tumour masses but the mechanism of this is unknown. This study was designed to determine the relationship between intraperitoneal (IP) cytokine levels, and laparotomy in benign and malignant settings. Methods: Intraperitoneal fluid specimens were obtained at the start and at the end of laparotomy in patients with benign conditions (n=10) and in others undergoing resection of hepatic metastases from colorectal cancer (n=10). Using ELISA the concentration of the angiogenic cytokines, HGF, VEGF-A, VEGF-C, VEGF-D and FGF-2 was determined. Results: The data show that in 16 of 20 patients there was a significant increase (P=0.006) in the IP concentration of hepatocyte growth factor (HGF) but not in the other growth factors by the end of the operation. The mean increase in HGF concentration was 821.5 pg/ml (95% CI: 11.0–6,426.0). Neither the groups (malignant and non-malignant) nor the length of operation correlated with greater or lesser increases in HGF. Conclusion: The observation that the increase in HGF occurred in both the cancer and non-cancer groups suggests that it is the surgery rather than the disease that is associated with the increased cytokine concentration. As HGF is a potent endothelial, epithelial and mesenchymal mitogen the data highlight HGF as a potential target for anti-cancer treatments in the peri-operative period. However, investigators should closely monitor wound healing as this may be compromised by this new class of drugs.     

Extracorporeal Membrane Oxygenation for Acute Life-Threatening Neurogenic Pulmonary Edema following Rupture of an Intracranial Aneurysm

Neurogenic pulmonary edema (NPE) leading to cardiopulmonary dysfunction is a potentially life-threatening complication in patients with central nervous system lesions. This case report describes a 28-yr woman with life-threatening fulminant NPE, which was refractory to conventional respiratory treatment, following the rupture of an aneurysm. She was treated successfully with extracorporeal membrane oxygenation (ECMO), although ECMO therapy is generally contraindicated in neurological injuries such as brain trauma and diseases that are likely to require surgical intervention. The success of this treatment suggests that ECMO therapy should not be withheld from patients with life-threatening fulminant NPE after subarachnoid hemorrhage.     

Posterior Cervical Fixation with Nitinol Shape Memory Loop in the Anterior-Posterior Combined Approach for the Patients with Three Column Injury of the Cervical Spine : Preliminary Report

Objective

The authors reviewed clinical and radiological outcomes in patients with three column injury of the cervical spine who had undergone posterior cervical fixation using Nitinol shape memory alloy loop in the anterior-posterior combined approach.

Materials

Nine patients were surgically treated with anterior cervical fusion using an iliac bone graft and dynamic plate-screw system, and the posterior cervical fixation using Nitinol shape memory loop (Davydov™) at the same time. A retrospective review was performed. Clinical outcomes were assessed using the Frankel grading method. We reviewed the radiological parameters such as bony fusion rate, height of iliac bone graft strut, graft subsidence, cervical lordotic angle, and instrument related complication.

Results

Single-level fusion was performed in five patients, and two-level fusion in four. Solid bone fusion was presented in all cases after surgery. The mean height of graft strut was significantly decreased from 20.46±9.97 mm at immediate postoperative state to 18.87±8.60 mm at the final follow-up period (p<0.05). The mean cervical lordotic angle decreased from 13.83±11.84° to 11.37±6.03° at the immediate postoperative state but then, increased to 24.39±9.83° at the final follow-up period (p<0.05). There were no instrument related complications.

Conclusion

We suggest that the posterior cervical fixation using Nitinol shape memory alloy loop may be a simple and useful method, and be one of treatment options in anterior-posterior combined approach for the patients with the three column injury of the cervical spine.     

P300 development during adolescence: effects of DRD2 genotype.

OBJECTIVE: Young boys at high risk for alcoholism by having a family history of alcoholism (FH+) have lower amplitude of the visual P300 event-related scalp potential. They have also been reported to have a slowing in the rate of P300 amplitude change during adolescence. The present study examined whether the change in P300 amplitude during adolescence in sons of alcoholics and nonalcoholics is affected by D2 dopamine receptor (DRD2) polymorphism. METHODS: P300 was elicited with a visual discrimination task from 71 adolescent sons of alcoholics and social drinkers (Time 1, T1). The task was readministered 2 years later (Time 2, T2). Comparisons were made between boys who had the DRD2 A1 allele (A1+) and boys who did not (A1-), and between boys with one or both parents being alcoholic (FH+) and boys having no alcoholic parents (FH-). RESULTS: Discrimination task accuracy was lowest in the highest risk group (A1+, FH+) at T1, and highest in the lowest risk group (A1-, FH-) at T2, producing a significant interaction of allelic group x family history group x session. Reaction time was faster at T2 than T1, and this effect was larger in FH-boys (125 ms) than FH+boys (40 ms). Overall, the behavioral results suggest mild performance deficits on the discrimination task are associated with higher risk for alcoholism. In both testing sessions, P300 attained larger amplitudes in sons of nonalcoholics than sons of alcoholics. At T2 compared to T1, both the latency and amplitude of the P300 were decreased. However, while the developmental P300 latency effect was equivalent in both the A1+ and A1- allelic groups, the P300 amplitude reduction during adolescence, measured both in response to targets and in target minus non-target subtraction waveforms, was only found in boys with the A1- allele. CONCLUSION: Differences in the developmental course of P300 amplitude over the course of adolescence are dependent on DRD2 polymorphism. SIGNIFICANCE: These results suggest the importance of genetic determinants of the dopaminergic system in understanding the P300 as a risk marker for substance abuse using an integrative developmental perspective.     

A unique plasma proteomic profiling with imbalanced fibrinogen cascade in patients with Kawasaki disease

Kawasaki disease (KD) is the leading cause of acquired heart disease during childhood in the developed countries. The mechanism and biomarkers of KD remain to be determined. In this study, we sought to elucidate potential plasma proteomic markers in KD patients in comparison to that in febrile controls. Plasma samples from KD patients and febrile controls were subjected to two-dimensional polyacrylamide gel electrophoresis analysis. Differential protein displays between KD patients and febrile controls were determined. Fibrinogen beta and gamma chains, alpha-1-antitrypsin (A1AT), CD5 antigen-like precursor (CD5L), and clusterin were increased in KD patients, whereas immunoglobulin free light chains were decreased, as compared with controls. The differential protein displays were validated with enzyme-linked immunosorbent assay tests. We found higher fibrinogen-related proteins (fibrinogen, A1AT, clusterin, and CD5L), along with a lower level of the immunoglobulin free light chains that involve fibrin degradation in KD. Results from this study showing a unique proteomic profiling with abnormal fibrinogen cascade may afford a good biomarker of KD and a better strategy to prevent cardiovascular complications of KD by correcting abnormal fibrin deposition or degradation.     

Aberrant expressions of pathogenic phenotype in Alzheimer's diseased transgenic mice carrying NSE-controlled APPsw

Mutations in the APP gene lead to enhanced cleavage by the beta- and gamma-secretase, and increased Abeta formation, which are tightly associated with Alzheimer's disease (AD)-like neuropathological changes. To examine whether depositions of Abeta by APP mutations are increased, and if this is associated with potential pathogenic phenotypes, the APPsw was expressed in a transgenic line under the control of the neuron-specific enolase (NSE) promoter. A behavioral dysfunction was shown at 12 months, and intensive staining bands, with APP and Abeta-42 antibodies, were visible in the brains of transgenic mice. Of the MAPK family, both JNK and p38 were activated in the brains of transgenic mice, whereas there was no significant activation of the ERK. In parallel, tau phosphorylation was also enhanced in the transgenic relative to the control mice. Moreover, the Cox-2 levels, from Western blot and immunostaining, were increased in the brains of the transgenic line. Furthermore, there were significant caspase-3- and TUNEL-stained nuclei in the transgenic line compared to the age-matched control mice. Thus, these results suggest that NSE-controlled APPsw transgenic mice appear to be a more relevant model in neuropathological phenotypes of AD, and thus could be useful in developing new therapeutic treatments for targeting the aberrant phenotypes that appear in these mice.