Phase I study of alpelisib (BYL719), an α-specific PI3K inhibitor, in Japanese patients with advanced solid tumors.

This phase I study aimed to determine tolerability and preliminary efficacy of single-agent alpelisib (BYL719) in Japanese patients with advanced solid malignancies. The primary objective of the study was to estimate the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of oral alpelisib in patients with advanced solid tumors who had progressed despite standard therapy. The expansion part included patients with PIK3CA mutation/amplification; safety, preliminary efficacy, pharmacokinetic (PK)/pharmacodynamic profile, and food effect on the PK profile of alpelisib at the MTD/RP2D were determined.

Phase I Study of Ceritinib (LDK378) in Japanese Patients with Advanced, Anaplastic Lymphoma Kinase-Rearranged Non-Small-Cell Lung Cancer or Other Tumors.

Introduction: Anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is sensitive to ALK inhibitors, but resistance develops. This study assessed the maximum-tolerated dose, safety, pharmacokinetics (PK), and antitumor activity of ceritinib, a novel ALK inhibitor (ALKi), in Japanese patients with ALK-rearranged malignancies.

Methods: This phase I, multicenter, open-label study (NCT01634763) enrolled adult patients with ALK-rearranged (by fluorescence in situ hybridization and/or immunohistochemistry) locally advanced/metastatic malignancy that had progressed despite standard therapy.

Phase I dose-escalation study of buparlisib (BKM120), an oral pan-class I PI3K inhibitor, in Japanese patients with advanced solid tumors.

Buparlisib (BKM120) is an oral pan-phosphatidylinositol 3-kinase inhibitor, targeting all four isoforms of class I PI3K (α, β, γ and δ). This open-label Phase I dose-escalation study was conducted to determine the maximum tolerated dose of continuous daily buparlisib in Japanese patients with advanced solid tumors. Secondary objectives included safety and tolerability, pharmacokinetics, antitumor activity and pharmacodynamic marker changes.

Novel MMP-9 substrates in cancer cells revealed by a label-free quantitative proteomics approach.

Matrix metalloproteinase-9 (MMP-9) is implicated in tumor metastasis as well as a variety of inflammatory and pathological processes. Although many substrates for MMP-9, including components of the extracellular matrix, soluble mediators such as chemokines, and cell surface molecules have been identified, we undertook a more comprehensive proteomics-based approach to identify new substrates to further understand how MMP-9 might contribute to tumor metastasis. Previous proteomics approaches to identify protease substrates have depended upon differential labeling of each sample.

Roles of matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases 1 in acute encephalopathy following prolonged febrile seizures.

Prolonged febrile seizures may be followed by acute encephalopathy with neurological sequelae. To investigate the function of the blood-brain-barrier (BBB) in acute encephalopathy following prolonged febrile seizures with neurological sequelae (AEPFS), the concentrations of serum matrix metalloproteinase-9 (MMP-9) and tissue inhibitors of metalloproteinases 1 (TIMP-1) were measured by ELISA in 10 children with AEPFS, 16 with prolonged febrile seizures without encephalopathy (PFS), 20 with simple febrile seizures (SFS), 23 with convulsive status epilepticus (CSE), and 18 with West syndrome. Serum MMP-9 levels in AEPFS and PFS patients were significantly higher than those in SPS and West syndrome patients and in controls, and those in CSE patients were significantly higher than in controls.

[Analysis of 11 patients with profound multiple disabilities who underwent laryngotracheal separation].

We examined the clinical usefulness of laryngotracheal separation surgery for patients with profound multiple disabilities (PMD). The subjects were 11 severely retarded children who experienced repeated incidents of aspiration pneumonia or who were enough to have aspiration pneumonia easily. A retrospective investigation of their medical records was performed regarding pre- and post-operative data, including the number of times sputum suctionings were required, the number of times pneumonia developed, respiratory conditions, and nutrition methods.

Serum and CSF levels of cytokines in acute encephalopathy following prolonged febrile seizures.

It is well known that an acute encephalopathy occasionally follows prolonged febrile seizures. We measured the concentrations of interferon-gamma, tumor necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2), IL-4, IL-6, IL-10, and soluble TNF receptor 1 (sTNFR1) in serum and CSF during the acute stage in 13 children with acute encephalopathy following prolonged febrile seizures (AEPFS) and 23 with prolonged febrile seizures without encephalopathy (PFS) to investigate the pathogenesis of AEPFS. Serum IL-6, IL-10, sTNFR1, and CSF IL-6 levels were significantly higher in AEPFS and PFS compared with control subjects.

West syndrome associated with mosaic Down syndrome.

We report a girl with West syndrome associated with mosaic Down syndrome. She had repetitive tonic spasms at 6 months and an electroencephalography (EEG) showed hypsarrhythmia. Her facial appearance was normal and she had no minor anomalies.

Serum levels of matrix metalloproteinase-9 and its tissue inhibitor (TIMP-1) in acute disseminated encephalomyelitis.

In multiple sclerosis, there have been many reports on matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). However, MMPs and TIMPs have not been reported in acute disseminated encephalomyelitis (ADEM). We determined the relationship between the serum concentrations of MMP-9 and TIMP-1 and activity of lesions on MRI in 14 patients with ADEM to investigate the roles of MMP-9 and TIMP-1 in the pathogenesis of ADEM.

[Low-dose therapy with carbamazepine for convulsions associated with mild gastroenteritis].

We investigated the effect of carbamazepine on convulsions associated with mild gastroenteritis. Sixteen infants and young children (aged 9 months to 3 years) who experienced repetitive convulsions associated with mild gastroenteritis were admitted to our hospital. We treated the sixteen affected patients with 5 mg/kg of carbamazepine once per day until the diarrhea had stopped.

Analysis of serum soluble CD40 ligand in patients with influenza virus-associated encephalopathy.

CD40 ligand (CD40L) is mainly expressed on activated platelets and CD4+T cells, and it can be cleaved from the cell surface, releasing a soluble CD40L (sCD40L). Most sCD40L is derived from activated platelets. A previous paper revealed that the platelet number of patients with influenza virus-associated encephalopathy (IE) was correlated with the outcome.

Analysis of cytokine levels in cerebrospinal fluid in mumps meningitis: comparison with echovirus type 30 meningitis.

Background: It is unclear whether or not the CSF cytokine profiles in viral meningitis differ with the kind of causative virus.

Methods: We measured the concentrations of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2), IL-4, IL-6, and IL-10 in CSF during the acute stage in 15 children with mumps meningitis (MM), and 34 with echovirus type 30 meningitis (EM).

Results: The CSF IFN-gamma, IL-2, IL-6, and IL-10 levels were elevated in MM, and the CSF IFN-gamma, IL-2, and IL-6 levels were elevated in EM.

CD44 binding through the hemopexin-like domain is critical for its shedding by membrane-type 1 matrix metalloproteinase.

Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a potent modulator of pericellular environment through its proteolytic activity and promotes migration, invasion, and proliferation of tumor cells. During cell migration, MT1-MMP binds to CD44H, a major hyaluronan receptor, through the hemopexin-like (HPX) domain and localizes at the migration front. MT1-MMP is also responsible for shedding CD44H, which supports CD44H-mediated cell migration.

IRSp53/Eps8 complex is important for positive regulation of Rac and cancer cell motility/invasiveness.

IRSp53 has been characterized as an adaptor protein that links Rho-family small GTPases, such as Rac, to reorganization of the actin cytoskeleton. Here, we search for other binding partners for the IRSp53 SH3 domain and identify Eps8 as the major binding protein in fibroblasts and various cancer cell lines. Eps8 has been shown to form a Rac-specific guanine nucleotide exchange factor complex with Abi-1 and Sos-1, which seems essential for ruffling formation induced by oncogenic Ras.

Constitutive and induced CD44 shedding by ADAM-like proteases and membrane-type 1 matrix metalloproteinase.

CD44 is a receptor for hyaluronan and mediates signaling that regulates complex cell behavior including cancer cell migration and invasion. Shedding of the extracellular portion of CD44 is the last step in the regulation of the molecule-releasing interaction between the ligand and cell. However, highly glycosylated forms of CD44 have hampered the identification of the exact cleavage sites for shedding and the responsible proteases.

Sequence-specific silencing of MT1-MMP expression suppresses tumor cell migration and invasion: importance of MT1-MMP as a therapeutic target for invasive tumors.

Membrane-type 1 matrix metalloproteinase (MT1-MMP/MMP-14) has been believed a key enzyme in tumor invasion, because it is expressed in a variety of malignant human tumors, and overexpression of the enzyme enhances the ability of cellular invasiveness. However, it has not necessarily been clarified whether the endogenously expressed MT1-MMP in human tumors plays a critical role in their invasiveness. We used RNA silencing technology to downregulate the endogenous MT1-MMP expression in human tumor cells (fibrosarcoma HT1080 and gastric carcinoma MKN-28 cell lines), and evaluated the effect on the invasion of a reconstituted basement membrane (Matrigel).