Juvenile dermatomyositis associated with autoantibodies to small ubiquitin-like modifier activating enzyme: a report of 4 cases from North India and a review of literature

Immunologic Research - Juvenile dermatomyositis (JDM) is the commonest inflammatory myositis in children. The clinical phenotype is often characterized by the presence of myositis-specific...     

The Study of the Influence of Formulation and Process Variables on the Functional Attributes of Simvastatin–Phospholipid Complex

Purpose

The aim of the present study was to examine the influence of the formulation and process variables on the entrapment efficiency of simvastatin–phospholipid complex (SPC), prepared with a goal of improving the solubility and permeability of simvastatin.

Methods

The SPC was prepared using a solvent evaporation method. The influence of formulation and process variables on simvastatin entrapment was assessed using a central composite design. An additional SPC was prepared using the optimized variables from the developed quadratic model. This formulation was characterized for its physical–chemical properties. The functional attributes of the optimized SPC formulation were analyzed by apparent aqueous solubility analysis, in vitro dissolution studies, dissolution efficiency analysis, and ex vivo permeability studies.

Results

The factors studied were found to significantly influence the entrapment efficiency. The developed model was validated using the optimized levels of formulation and process variables. The physical–chemical characterization confirmed a formation of the complex. The optimized SPC demonstrated over 25-fold higher aqueous solubility of simvastatin, compared to that of pure simvastatin. The optimized SPC exhibited a significantly higher rate and extent of simvastatin dissolution (>98 %), compared to that of pure simvastatin (～16 %). The calculated dissolution efficiency was also found to be significantly higher for the SPC (～54 %), compared to that of pure simvastatin (～8 %). Finally, the optimized SPC exhibited a significantly higher simvastatin permeability (>78 %), compared to that of pure simvastatin (～11 %).

Conclusion

The present study shows that SPC can be a promising strategy for improving the delivery of simvastatin and similar drugs with low aqueous solubility.

     

A young boy with rash,arthritis, and developmental delay: Monogenic lupus due to DNASE2 gene defect

Monogenic causes are increasingly being recognized in patients with lupus, especially in early-onset disease. We herein report a boy with a novel mutation in the DNase 2 (DNASE2) gene presenting with monogenic lupus. A 6-year-old boy with a global developmental delay with microcephaly presented with chronic febrile illness with anemia, rash, polyarthritis, renal involvement, and hepatosplenomegaly. Laboratory investigations revealed positive antinuclear antibody, high anti-dsDNA antibody titers, hypocomplementemia, hypergammaglobulinemia, nephrotic range proteinuria, and diffuse proliferative glomerulonephritis. Magnetic resonance imaging of brain showed altered signal intensity in subcortical white matter in bilateral fronto-parieto-temporal lobes. Targeted next-generation sequencing revealed a novel pathogenic variant in DNASE2. He was treated with oral prednisolone, mycophenolate mofetil, cyclosporine, and hydroxychloroquine and is doing well on follow up. DNASE2 deficiency has been reported as a rare genetic cause of monogenic lupus. DNASE2 deficiency should be suspected in patients with early-onset lupus with polyarthritis, erythematous rash, and neurological involvement.     

Novel HER3/MUC4 oncogenic signaling aggravates the tumorigenic phenotypes of pancreatic cancer cells

Several studies have demonstrated that MUC4 is involved in progression and metastasis of pancreatic cancer (PC). Here, we report that HER3/MUC4 interaction in HER2 low cells is critical in driving pancreatic tumorigenesis. Upon HER2 knockdown, we observed elevated expression of HER3 and MUC4 and their interactions, which was confirmed by immunoprecipitation and bioinformatics analyses. In paired human PC tissues, higher percentage of HER3 positivity (10/33, 30.3%; p = 0.001) was observed than HER2 (5/33, 15.1%; p = 0.031), which was further confirmed in spontaneous mice (KPC; Kras^G12D; Trp53^R172H/+; Pdx-Cre) tumors of different weeks. Mechanistically, increased phosphorylation of ERK and expression of PI3K and c-Myc were observed in HER2 knockdown cells, suggesting a positive role for HER3/MUC4 in HER2 low cells. Further, HER2 knockdown resulted in increased proliferation, motility and tumorigenicity of PC cells. Consistently, transient knockdown of HER3 by siRNA in HER2 knockdown cells led to decreased proliferation. These observations led us to conclude that HER3 interacts with MUC4 to promote proliferation in HER2 low PC cells. Further, deficiency of both HER2 and HER3 leads to decreased proliferation of PC cells. Hence targeting these newly identified HER3/MUC4 signals would improve the PC patients survival by intercepting MUC4 mediated oncogenic signaling.