Response to “Immune-mediated cholangitis: is it always nivolumab’s fault?”

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Results of a phase II trial for high-risk neuroblastoma treatment protocol JN-H-07: a report from the Japan Childhood Cancer Group Neuroblastoma Committee (JNBSG)

Abstract

Background

The Japanese Children's Cancer Group (JCCG) Neuroblastoma Committee (JNBSG) conducted a phase II clinical trial for high-risk neuroblastoma treatment. We report the result of the protocol treatment and associated genomic aberration studies.

Methods

JN-H-07 was a single-arm, late phase II trial for high-risk neuroblastoma treatment with open enrollment from June 2007 to February 2009. Eligible patients underwent five courses of induction chemotherapy followed by high-dose chemotherapy with hematopoietic stem cell rescue. Surgery for the primary tumor was scheduled after three or four courses of induction chemotherapy. Radiotherapy was administered to the primary tumor site and to any bone metastases present at the end of induction chemotherapy.

Results

The estimated 3-year progression-free and overall survival rates of the 50 patients enrolled were 36.5 ± 7.0 and 69.5 ± 6.6%, respectively. High-dose chemotherapy caused severe toxicity including three treatment-related deaths. In response to this, the high-dose chemotherapy regimen was modified during the trial by infusing melphalan before administering carboplatin and etoposide. The modified high-dose chemotherapy regimen was less toxic. Univariate analysis revealed that patients younger than 547 days and patients whose tumor showed a whole chromosomal gains / losses pattern had a significantly poor prognosis. Notably, the progression-free survival of cases with MYCN amplification were not inferior to those without MYCN amplification.

Conclusions

The outcome of patients treated with the JN-H-07 protocol showed improvement over the results reported by previous studies conducted in Japan. Molecular and genetic profiling may enable a more precise stratification of the high-risk cohort.

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Revealing Synergistic Mechanism of Multiple Components in Gandi Capsule for Diabetic Nephropathy Therapeutics by Network Pharmacology

Gandi capsule, a traditional Chinese herbal medicinal formulation that consists of eight herbs, is used as a clinical therapy for diabetic nephropathy. To clarify the potential synergistic mechanism, this study adopted a network pharmacology strategy to screen the action targets that corresponded to the active components in the Gandi capsule. We first constructed a compound database of 315 components in the Gandi capsule and a target database of diabetic nephropathy, which included 155 target proteins. Six representative compounds were selected to dock with 99 proteins found in the UniProtKB database with their PDB code, and interaction networks between the active ingredients of the Gandi capsule and their targets were mapped out. Results revealed 47 proteins with a high affinity with at least one compound molecule in the Gandi capsule. The main action pathways closely related to the development of diabetic nephropathy were the TGF-β1, AMPK, insulin, TNF-α, and lipid metabolism pathways as per network pharmacology analysis. In the interaction network, ACC1, SOD2, COX2, PKC-B, IR, and ROCK1 proteins had the most frequent interactions with the six compounds. We performed visual molecular docking in silico and experimentally confirmed competitive component-protein binding by SPR and an enzyme activity test, which highlighted the relationships of wogonin to COX2 and SOD2, astragaloside IV to ACC1, and morroniside to ACC1. We concluded that the potential synergistic mechanism of the Gandi capsule resulted from high affinities with multiple proteins and intervention in multiple pathways in combination therapy of diabetic nephropathy.

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Rare mutations in apoptosis related genes APAF1, CASP9, and CASP3 contribute to human neural tube defects

Rare mutations in apoptosis related genes APAF1, CASP9, and CASP3 contribute to human neural tube defects

Rare mutations in apoptosis related genes <i>APAF1</i>, <i>CASP9</i>, and <i>CASP3</i> contribute to human neural tube defects, Published online: 30 April 2018; doi:10.1038/s41419-017-0096-2

Rare mutations in apoptosis related genes APAF1, CASP9, and CASP3 contribute to human neural tube defects

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The Role of Periostin in Capsule Formation on Silicone Implants

Although silicone implants are widely used in breast and other reconstructive surgeries, the limited biocompatibility of these materials leads to severe complications, including capsular contracture. Here, we aimed to clarify the relationship between periostin and the process of capsule formation after in vivo implantation. Seven-week-old wild-type (WT) C57BL/6 mice and periostin-deficient mice were used. Round silicone implants were inserted into a subcutaneous pocket on the dorsum of the mice. After 8 weeks, the fibrous capsule around the implant was harvested and histologically examined to estimate capsular thickness and the number of inflammatory cells. Additionally, immunohistochemical analysis (periostin, α-SMA, and collagen type I) and western blotting (CTGF, TGF-β, VEGF, and MPO) were performed for a more detailed analysis of capsule formation. The capsules in periostin-knockout mice (PN-KO) were significantly thinner than those in WT mice. PN-KO mice showed significantly lower numbers of inflammatory cells than WT mice. Fibrous tissue formation markers (α-SMA, periostin, collagen type I, and CTGF) were significantly reduced in PN-KO mice. We also confirmed that inflammatory reaction and angiogenesis indicators (TGF-β, MPO, and VEGF) had lower expression in PN-KO mice. Inhibition of periostin could be important for suppressing capsule formation on silicone implants after in vivo implantation.

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Response to “Immune-mediated cholangitis: is it always nivolumab’s fault?”

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Gundelia tournefortii Antidiabetic Efficacy: Chemical Composition and GLUT4 Translocation

In the present in vitro study, we tested the chemical composition, cytotoxicity and antidiabetic activity of two distinct extracts of wild Artichoke-like vegetable, Gundelia tournefortii: methanol and hexane. GC/MS phytochemical analysis of G. tournefortii methanol and hexane extracts revealed 39 compounds reported here for the first time in G. tournefortii out of the 45 detected compounds. Only Stigmasterol was present in both extracts. The efficacy of G. tournefortii extracts in enhancing glucose transporter 4 (GLUT4) translocation to the plasma membrane (PM) was tested in L6 muscle cells stably expressing myc-tagged GLUT4 (L6-GLUT4myc) using cell-ELISA test. Results obtained here indicate that methanol and hexane extracts were safe up to 250 μg/ml as measured with MTT and the LDH leakage assays. The methanol extract was the most efficient in GLUT4 translocation enhancement. It increased GLUT4 translocation at 63 μg/ml 1.5- and 2-fold relative to the control in the absence and presence of insulin, respectively. These findings indicate that G. tournefortii possesses antidiabetic activity in part by enhancing GLUT4 translocation to the PM in skeletal muscle.

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