Saposin B Is a Human Coenzyme Q10-Binding/Transfer Protein

Coenzyme Q10 (CoQ10) is essential for ATP production in the mitochondria, and is an important antioxidant in every biomembrane and lipoprotein. Due to its hydrophobicity, a binding and transfer protein for CoQ10 is plausible, but none have yet been isolated and characterized. Here we purified a CoQ10-binding protein from human urine and identified it to be saposin B, a housekeeping protein necessary for sphingolipid hydrolysis in lysosomes. We confirmed that cellular saposin B binds CoQ10 in human sperm and the hepatoma cell line HepG2 by using saposin B monoclonal antibody. The molar ratios of CoQ10 to saposin B were estimated to be 0.22 in urine, 0.003 in HepG2, and 0.12 in sperm. We then confirmed that aqueous saposin B extracts CoQ10 from hexane to form a saposin B-CoQ10 complex. Lipid binding affinity to saposin B decreased in the following order: CoQ10>CoQ9>CoQ7>>α-tocopherol>>cholesterol (no binding). The CoQ10-binding affinity to saposin B increased with pH, with maximal binding seen at pH 7.4. On the other hand, the CoQ10-donating activity of the saposin B-CoQ10 complex to erythrocyte ghost membranes increased with decreasing pH. These results suggest that saposin B binds and transports CoQ10 in human cells

Disseminated nontuberculous mycobacterial infection in a patient with idiopathic CD4 lymphocytopenia and IFN-γ neutralizing antibodies: a case report

Abstract Background Disseminated nontuberculous mycobacterial (NTM) infection usually occurs in immunodeficient patients, such as those with human immunodeficiency virus infection and idiopathic CD4 lymphopenia. However, disseminated NTM diseases have also been reported in immunocompetent patients. Autoantibodies to interferon-gamma (IFN-γ) are known to be involved in disseminated NTM disease, although anti-IFN-γ antibodies are mainly seen in immunocompetent patients rather than those with immunodeficiency. Here, we report a rare case of disseminated NTM patient with idiopathic CD4 lymphopenia and anti-IFN-γ antibodies. Case presentation A 64-year-old Asian male presented with fever, back pain, anorexia and weight loss. Physical examination revealed subcutaneous masses in the forehead, sternoclavicular joint, and right inguinal region. Computed tomography showed multiple osteosclerotic changes with soft structures and osteolytic changes. Both blood and sputum cultures were positive for Mycobacterium intracellulare, confirming the presence of disseminated NTM infection. Histopathological evaluation of the subcutaneous mass in the right inguinal region showed numerous granulomas consisting of epithelioid cells with Langhans-type giant cells. He was diagnosed with idiopathic CD4 lymphocytopenia. Interestingly, he also had anti-IFN-γ autoantibodies with suppression of IFN-γ-dependent signal transducer and activator of transcription 1 (STAT1) phosphorylation. Two-drug combination therapy with clarithromycin and ethambutol was started for the NTM infection, which resulted in a favorable disease course. Conclusions In patients with disseminated NTM infection, idiopathic CD4 lymphocytopenia and anti-IFN-γ autoantibody-positive immunodeficiency can be coexisted. It is necessary to clarify the pathogenesis and clinical course of CD4 lymphocytopenic conditions and IFN-γ neutralizing antibody-positive in the disseminated NTM disease

Crystallization and preliminary crystallographic analysis of DtsR1, a carboxyltransferase subunit of acetyl-CoA carboxylase from Corynebacterium glutamicum

DtsR1, a carboxyltransferase subunit of acetyl-CoA carboxylase from C. glutamicum, was crystallized and phases were obtained by molecular replacement

Acute 40% exchange-transfusion with hemoglobin-vesicles in a mouse pneumonectomy model.

Hemoglobin vesicles (HbVs) function as a red blood cell (RBC) substitute and are composed of purified hemoglobin encapsulated in a phospholipid bilayer membrane. The performance of HbVs as a substitute for RBC transfusions was examined in a mouse model of pneumonectomy following acute 40% exchange-transfusion with HbVs.Before performing left pneumonectomies, 40% of the blood volume of mice was replaced with a) lactated Ringer's solution (control), b) 5% recombinant human serum albumin (rHSA), c) mouse RBCs shed in rHSA (mRBCs/rHSA), or d) HbV suspended in rHSA (HbV/rHSA). We compared postoperative a) survival, b) functional recovery, and c) histopathological, immunohistochemical, and inflammatory responses among the study groups.In the HbV/rHSA and mRBC/rHSA groups, all mice survived ≥7 days after pneumonectomy, whereas 100% of the control mice died within a few h and 50% of mice in the rHSA group died within 24 h after pneumonectomy. Immunohistochemical staining for hypoxia-inducible factor-1α showed that hepatic and renal hypoxic injuries were prominently mitigated by HbV and mRBCs.The oxygen-carrying performance of HbV was similar to that of mRBCs, even with impaired lung functions following pneumonectomy. HbV infusion did not interfere with the recovery from surgical injury. In the near future, HbVs could be used clinically as a substitute for the perioperative transfusion of RBCs, when or where donated RBCs are not immediately available

Mixed response to osimertinib and the beneficial effects of additional local therapy

Background Although non‐small cell lung cancers (NSCLCs) harboring EGFR mutations initially respond well to EGFR‐tyrosine kinase inhibitors (TKIs), they typically progress after approximately one year. The EGFR T790M mutation is the most common resistance mechanism. NSCLCs with T790M respond well to osimertinib; however, the heterogeneity of NSCLCs may limit the efficacy. Some patients exhibit a mixed response (MR), in which some lesions shrink and others progress, but little is known of the incidence and characteristics of such a response. We sought to determine the frequency and clinical course in MR patients. Methods We retrospectively reviewed the records of patients who had received osimertinib for NSCLC with EGFR T790M. Results Between April and December 2016, 48 patients were administered osimertinib. Seven patients (15%) exhibited one of two MR types: (i) progressive lesions that did not include the re‐biopsy site (5 patients), and (ii) progressive lesions that included the re‐biopsy site (2 patients). The most frequent progressive sites were liver and lung metastases (4 patients). Three patients continued osimertinib following an MR, one of whom had received local therapy for liver metastasis and achieved disease control on osimertinib for an additional four months. Conclusion An MR was detected in 15% of NSCLC patients with T790M. This finding suggests that several different resistance mechanisms are active within a single patient who develops resistance to EGFR‐TKIs. Osimertinib is basically effective for tumors that acquire resistance to EGFR‐TKIs as a result of T790M mutation. Therefore, additional local therapy may be beneficial for patients who develop an MR to osimertinib

Changes in serum concentrations of (A) TNF-α, (B) IL-6, (C) G-CSF, and (D) IFN-γ between the baseline period and the 7^th postoperative day (POD), in the indicated study groups.

<p>Values are shown as the mean ± SD. n = 10 in each group. *<i>P</i> < 0.05 versus baseline (Student’s t-test).</p

Hemoglobin vesicle (HbV) solution.

<p>HbVs were developed as artificial oxygen carriers in the form of liposomes containing concentrated hemoglobin, which can be preserved for years, used regardless of the blood type, and do not pose a risk of infection.</p

Changes in (A) hematocrit levels, (B) hemoglobin concentrations, (C) white blood cell counts, and (D) platelet counts between the baseline period and the 7^th postoperative day (POD) in the indicated study groups.

<p>Values are shown as the mean ± SD. <i>n</i> = 10 in each group. *<i>P</i> < 0.05 versus baseline (Student’s t-test), #<i>P</i> < 0.05 versus the rHSA group (Dunnett’s test).</p