ABL1 and ABL2 promote medulloblastoma leptomeningeal dissemination.

Background: Medulloblastoma is the most common malignant pediatric brain tumor, and leptomeningeal dissemination (LMD) of medulloblastoma both portends a poorer prognosis at diagnosis and is incurable at recurrence. The biological mechanisms underlying LMD are unclear. The Abelson (ABL) tyrosine kinase family members, ABL1 and ABL2, have been implicated in cancer cell migration, invasion, adhesion, metastasis, and chemotherapy resistance, and are upstream mediators of the oncogene c-MYC in fibroblasts and lung cancer cells. However, their role in medulloblastoma has not yet been explored. The purpose of this work was to elucidate the role of ABL1/2 in medulloblastoma LMD. Methods: ABL1 and ABL2 mRNA expression of patient specimens was analyzed. shRNA knockdowns of ABL1/2 and pharmacologic inhibition of ABL1/2 were used for in vitro and in vivo analyses of medulloblastoma LMD. RNA sequencing of ABL1/2 genetic knockdown versus scrambled control medulloblastoma was completed. Results: ABL1/2 mRNA is highly expressed in human medulloblastoma and pharmacologic inhibition of ABL kinases resulted in cytotoxicity. Knockdown of ABL1/2 resulted in decreased adhesion of medulloblastoma cells to the extracellular matrix protein, vitronectin (P = .0013), and significantly decreased tumor burden in a mouse model of medulloblastoma LMD with improved overall survival (P = .0044). Furthermore, both pharmacologic inhibition of ABL1/2 and ABL1/2 knockdown resulted in decreased expression of c-MYC, identifying a putative signaling pathway, and genes/pathways related to oncogenesis and neurodevelopment were differentially expressed between ABL1/2 knockdown and control medulloblastoma cells. Conclusions: ABL1 and ABL2 have potential roles in medulloblastoma LMD upstream of c-MYC expression.

Magnetite nanoparticles as a kinetically favorable source of iron to enhance GBM response to chemoradiosensitization with pharmacological ascorbate.

Ferumoxytol (FMX) is an FDA-approved magnetite (Fe3O4) nanoparticle used to treat iron deficiency anemia that can also be used as an MR imaging agent in patients that can't receive gadolinium. Pharmacological ascorbate (P-AscH-; IV delivery; plasma levels ≈ 20 mM) has shown promise as an adjuvant to standard of care chemo-radiotherapy in glioblastoma (GBM). Since ascorbate toxicity mediated by H2O2 is enhanced by Fe redox cycling, the current study determined if ascorbate catalyzed the release of ferrous iron (Fe2+) from FMX for enhancing GBM responses to chemo-radiotherapy. Ascorbate interacted with Fe3O4 in FMX to produce redox-active Fe2+ while simultaneously generating increased H2O2 fluxes, that selectively enhanced GBM cell killing (relative to normal human astrocytes) as opposed to a more catalytically active Fe complex (EDTA-Fe3+) in an H2O2 - dependent manner. In vivo, FMX was able to improve GBM xenograft tumor control when combined with pharmacological ascorbate and chemoradiation in U251 tumors that were unresponsive to pharmacological ascorbate therapy. These data support the hypothesis that FMX combined with P-AscH- represents a novel combined modality therapeutic approach to enhance cancer cell selective chemoradiosentization in the management of glioblastoma.

Engineered exosomes targeting MYC reverse the proneural-mesenchymal transition and extend survival of glioblastoma.

Dysregulated Myc signaling is a key oncogenic pathway in glioblastoma multiforme (GBM). Yet, effective therapeutic targeting of Myc continues to be challenging. Here, we demonstrate that exosomes generated from human bone marrow mesenchymal stem cells (MSCs) engineered to encapsulate siRNAs targeting Myc (iExo-Myc) localize to orthotopic GBM tumors in mice. Treatment of late stage GBM tumors with iExo-Myc inhibits proliferation and angiogenesis, suppresses tumor growth, and extends survival. Transcriptional profiling of tumors reveals that the mesenchymal transition and estrogen receptor signaling pathways are impacted by Myc inhibition. Single nuclei RNA sequencing (snRNA-seq) shows that iExo-Myc treatment induces transcriptional repression of multiple growth factor and interleukin signaling pathways, triggering a mesenchymal to proneural transition and shifting the cellular landscape of the tumor. These data confirm that Myc is an effective anti-glioma target and that iExo-Myc offers a feasible, readily translational strategy to inhibit challenging oncogene targets for the treatment of brain tumors.

Linkages between soil carbon, soil fertility and nitrogen fixation in Acacia senegal plantations of varying age in Sudan.

BACKGROUND: Over the last decades sub-Saharan Africa has experienced severe land degradation and food security challenges linked to loss of soil fertility and soil organic matter (SOM), recurrent drought and increasing population. Although primary production in drylands is strictly limited by water availability, nutrient deficiencies, particularly of nitrogen (N) and phosphorus (P), are also considered limiting factors for plant growth. It is known that SOM (often measured as soil organic carbon (SOC)) is a key indicator of soil fertility, therefore, management practices that increase SOM contents, such as increasing tree cover, can be expected to improve soil fertility. The objectives of this study were to investigate the effect of Acacia senegal (Senegalia senegal) trees on soil nitrogen, phosphorus and potassium (K) in relation to SOC, the potential of A. senegal for N2 fixation, and to identify possible N and P ecosystem limitations. METHODS: Soil nutrient (total N, P, K and available P and exchangeable K) concentrations and stocks were determined for the 0-10, 10-20,20-30 and 30-50 cm layers of A. senegal plantations of varying age (ranging from 7 to 24-years-old) and adjacent grasslands (reference) at two sites in semi-arid areas of Sudan. At both sites, three plots were established in each grassland and plantation. The potential of A. senegal for N2 fixation in relation to plantations age was assessed using δ15N isotopic abundances and nutrient limitations assessed using C:N:P stoichiometry. RESULTS: Soil concentrations of all studied nutrients were relatively low but were significantly and directly correlated to SOC concentrations. SOC and nutrient concentrations were the highest in the topsoil (0-10 cm) and increased with plantations age. Acacia foliage δ15N values were >6‰ and varied little with plantations age. Soil C:N and C:P ratios did not differ between grassland and plantations and only 0-10 cm layer N:P ratios showed significant differences between grassland and plantations. DISCUSSION: The results indicated that soil fertility in the Sahel region is strongly related to SOM contents and therefore highlighting the importance of trees in the landscape. The higher mineral nutrient concentrations in the topsoil of the plantations may be an indication of 'nutrient uplift' by the deeper roots. The high foliar δ15N values indicated that N2 fixation was not an important contributor to soil N contents in the plantations. The accretion of soil N cannot be explained by deposition but may be related to inputs of excreted N brought into the area annually by grazing and browsing animals. The soil C:N:P stoichiometry indicated that the plantations may be limited by P and the grasslands limited by N.

Perioperative renal protection in patients with obstructive jaundice using drug combinations.

BACKGROUND/AIMS: The effectiveness of dopamine alone or in combination with mannitol or furosemide in preventing postoperative renal dysfunction in patients with obstructive jaundice was assessed in this study. METHODOLOGY: Forty patients having obstructive jaundice were randomly allocated into 4 equal groups. Preoperative hydration was performed by infusing all patients 1L of 5% dextrose the night before surgery and another 1L in the morning before surgery. Intra- and postoperative maintenance of adequate intravascular volume was assured by fluid and blood replacement guided by the monitoring of central venous pressure urine output and blood pressure. The 1st group was kept as a control. The other 3 groups received dopamine 2.5 micrograms/kg/min for 2 postoperative days starting before surgery. The 2nd group was maintained on dopamine alone, while mannitol (0.25 g/kg), every 12 hours for 2 postoperative days, was added to the 3rd group. Similarly furosemide (1 mg/kg) every 12 hours for 2 postoperative days, was infused to the patients of the 4th group. Postoperative renal functions were assessed by 24-hour urine output, serum creatinine, creatinine clearance and urine to plasma osmolality ratio. RESULTS: All these tests did not show significant changes in the 1st, 2nd and 7th postoperative days. Only transient decreased creatinine clearance and elevated serum creatinine were observed in the patients of the 4th group in the 1st and 2nd postoperative days. This may be attributed to fluid imbalance induced by furosemide in these patients who were older than the other groups. CONCLUSIONS: The study showed that careful attention to perioperative hydration is the cornerstone in preserving adequate renal function following surgery in patients with obstructive jaundice. Administration of dopamine alone or in combination with mannitol or furosemide did not confer more renal protection.

Human ochratoxicosis and nephropathy in Egypt: a preliminary study.

This preliminary study was designed in a trial to delineate the size of the problem of ochratoxicosis and its relation to genesis of lesions mounting to end stage renal disease (ESRD) or urothelial tumors in Egypt. This study comprised five groups of patients having renal diseases of different presentations; they are: patients with (ESRD) under conservative medical treatment (group 1), patients with (ESRD) under treatment with regular hemodialysis (group 2), renal allograft recipients (group 3), patients with nephrotic syndrome (group 4) and patients with urothelial tumors (group 5). In addition, two reference groups: potential related donors for renal transplantation (group 6) and healthy control with negative family history of renal disease (group 7). For all groups, laboratory, radiological and histopathological evaluation of kidney status were carried out coupled with determination of ochratoxin A level in serum, in urine and in biopsy specimens of patients with urothelial tumors. High ochratoxin serum levels were found in patients with ESRD (groups 1 and 2) (P < 0.01), higher serum levels were detected in the group without dialysis (group 1) in comparison with the reference groups possibly due to ochratoxin. A clearance by dialysis. Ochratoxin A was detected in serum and urine of renal transplant recipients (group 3) (P < 0.01) and especially higher levels were found in patients with nephrotic syndrome (group 4) (P < 0.001). For the group with urothelial tumor (group 5), positive serum, urine and tissue biopsy specimens for ochratoxin levels were found (P < 0.01). The results could lead to the conclusion that ochratoxin A could be correlated to the genesis of renal disease leading to (ESRD) or causing urothelial cancer. A thorough and in depth study of the problem of ochratoxicosis and renal disease causation in Egypt is now recommended.

Passive smoking and lower respiratory tract illnesses in children

The relationship between household tobacco smoke exposure and wheezing and nonwheezing lower respiratory tract illnesses in young children was investigated using both a questionnaire and the urinary cotinine/creatinine ratio to assess passive smoking. A case-control study was conducted on 60 children [</= 5 years] with lower respiratory tract illnesses and 40 control children. The results showed that household passive smoking may be a predisposing and/or aggravating factor for lower respiratory tract illnesses in young children whether wheezing or nonwheezing, infective or noninfective. Parents' assessment of their own level of smoking may be inaccurate and objective biochemical measures of passive smoking are needed to identify its risks

Digital subtraction angiography in potential live-kidney donors: a study of 1000 cases.

Intravenous digital subtraction angiography (IV-DSA) combined with excretory urography (IVU) were utilized to study the renal anatomy of 1000 potential live-kidney donors. In the entire series, 712 donors (71.2%) had bilateral single renal arteries, whereas 255 (25.5%) had unilateral multiple, 26 (2.6%) had bilateral multiple, and 7 (0.7%) had unilateral hypoplastic or absent renal arteries determined by IV-DSA. Major renal abnormalities that might be potentially significant for safe renal donation were detected in 76 donors (7.6%) by combined IV-DSA and IVU studies. In 10% of the potential donors, intraarterial digital subtraction angiography (IA-DSA) was required because of the equivocal results of IV-DSA. Of the 1000 potential donors, 700 underwent nephrectomy and the number of renal arteries at nephrectomy was compared with both IV-DSA and IA-DSA reports. Analysis of data revealed a sensitivity of 96% vs 95%, a specificity of 57% vs 75% and an overall accuracy 93% vs 90% for IV-DSA and IA-DSA, respectively, both IV-DSA and IA-DSA were accurate enough in identification of single renal arteries. However, the accuracy of IA-DSA was better than that of IV-DSA in visualization of double (84% vs 64%) and triple (66% vs 33%) renal arteries. It is concluded that IV-DSA combined with IVU is an effective technique for the evaluation of potential kidney donors. In cases where IV-DSA is equivocal, we recommend confirming IA-DSA.

Tetracycline sclerotherapy for testicular hydroceles in renal transplant recipients.

OBJECTIVES: To study the efficacy of tetracycline sclerotherapy in renal transplant recipients with symptomatic hydroceles. METHODS: A total of 21 patients with symptomatic hydroceles following renal transplantation underwent aspiration of hydrocele and injection of tetracycline hydrochloride. Sclerosant solution was prepared by dissolving 1 g tetracycline hydrochloride powder in 10 mL 1% lidocaine. The amount of sclerosant used depended on the volume of the sac: 5 mL for a sac containing up to 100 mL and 2.5 mL of sclerosant was added for each increase of 100 mL in sac volume. RESULTS: Twelve patients (57%) required only one treatment and 9 patients (43%) had up to 3 injections. The larger the hydrocele, the more treatments were required. The resolution of hydrocele was complete in 12 patients (57%) and partial in 7 (33%) with 2 (10%) failures. Pain at injection was observed in one third of the patients. No major complications (fever, hematoma, infections, abscess, or scrotal necrosis) occurred in any patient. No changes in the structure or size of the testicles were found by ultrasound during an average follow-up period of 35 months. CONCLUSIONS: Tetracycline sclerotherapy is a safe, effective, and economical form of out-patient therapy that can be recommended as primary treatment for hydroceles in patients who have undergone renal transplantation.

Alterations of plasma free amino acids in nephrotic syndrome.

In order to assess the plasma amino acid pattern in nephrotics, we studied 19 nephrotic patients in good general and nutritional conditions. The results were compared with those of 8 healthy controls of matched age and sex. A highly significant rise of plasma glutamic acid and hydroxyproline was detected in nephrotics. When the latter group is divided into 2 subgroups according to the serum creatinine level, the rise in plasma values of both amino acids was detected in both subgroups compared to the controls, while an insignificant rise was detected in cases with elevated serum creatinine compared to those with normal serum level. So we conclude that there is an alteration in the amino acid pattern in nephrotics, and that this alteration occurs early, before the rise in serum creatinine.

Anticardiolipin antibodies in children on chronic haemodialysis.

IgG and IgM anticardiolipin antibody (Ab) concentrations were determined in serum samples of 48 children with end-stage renal disease (ESRD) on haemodialysis using ELISA technique in an attempt to analyse their possible role in the occurrence of thrombosis of the vascular access. Ten normal healthy children were studied as a control group. The positivity of anticardiolipin Ab isotypes both IgM and IgG was high in children with ESRD on haemodialysis. Children with positive anticardiolipin Ab had significantly higher incidence of prior thrombosis of vascular access. Also, these antibodies should be considered as markers of high risk for fistula thrombosis.