Myosin motor Myo1c and its receptor NEMO/IKK-γ promote TNF-α–induced serine307 phosphorylation of IRS-1

Tumor necrosis factor-α (TNF-α) signaling through the IκB kinase (IKK) complex attenuates insulin action via the phosphorylation of insulin receptor substrate 1 (IRS-1) at Ser307. However, the precise molecular mechanism by which the IKK complex phosphorylates IRS-1 is unknown. In this study, we report nuclear factor κB essential modulator (NEMO)/IKK-γ subunit accumulation in membrane ruffles followed by an interaction with IRS-1. This intracellular trafficking of NEMO requires insulin, an intact actin cytoskeletal network, and the motor protein Myo1c. Increased Myo1c expression enhanced the NEMO–IRS-1 interaction, which is essential for TNF-α– induced phosphorylation of Ser307–IRS-1. In contrast, dominant inhibitory Myo1c cargo domain expression diminished this interaction and inhibited IRS-1 phosphorylation. NEMO expression also enhanced TNF-α–induced Ser307–IRS-1 phosphorylation and inhibited glucose uptake. In contrast, a deletion mutant of NEMO lacking the IKK-β–binding domain or silencing NEMO blocked the TNF-α signal. Thus, motor protein Myo1c and its receptor protein NEMO act cooperatively to form the IKK–IRS-1 complex and function in TNF-α–induced insulin resistance

Cutaneous T-cell-attracting chemokine as a novel biomarker for predicting prognosis of idiopathic pulmonary fibrosis: a prospective observational study

[Background] Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease that leads to respiratory failure and death. Although there is a greater understanding of the etiology of this disease, accurately predicting the disease course in individual patients is still not possible. This study aimed to evaluate serum cytokines/chemokines as potential biomarkers that can predict outcomes in IPF patients. [Methods] A multi-institutional prospective two-stage discovery and validation design using two independent cohorts was adopted. For the discovery analysis, serum samples from 100 IPF patients and 32 healthy controls were examined using an unbiased, multiplex immunoassay of 48 cytokines/chemokines. The serum cytokine/chemokine values were compared between IPF patients and controls; the association between multiplex measurements and survival time was evaluated in IPF patients. In the validation analysis, the cytokines/chemokines identified in the discovery analysis were examined in serum samples from another 81 IPF patients to verify the ability of these cytokines/chemokines to predict survival. Immunohistochemical assessment of IPF-derived lung samples was also performed to determine where this novel biomarker is expressed. [Results] In the discovery cohort, 18 cytokines/chemokines were significantly elevated in sera from IPF patients compared with those from controls. Interleukin-1 receptor alpha (IL-1Rα), interleukin-8 (IL-8), macrophage inflammatory protein 1 alpha (MIP-1α), and cutaneous T-cell-attracting chemokine (CTACK) were associated with survival: IL-1Rα, hazard ratio (HR) = 1.04 per 10 units, 95% confidence interval (95% CI) 1.01–1.07; IL-8, HR = 1.04, 95% CI 1.01–1.08; MIP-1α, HR = 1.19, 95% CI 1.00–1.36; and CTACK, HR = 1.12 per 100 units, 95% CI 1.02–1.21. A replication analysis was performed only for CTACK because others were previously reported to be potential biomarkers of interstitial lung diseases. In the validation cohort, CTACK was associated with survival: HR = 1.14 per 100 units, 95% CI 1.01–1.28. Immunohistochemistry revealed the expression of CTACK and CC chemokine receptor 10 (a ligand of CTACK) in airway and type II alveolar epithelial cells of IPF patients but not in those of controls. [Conclusions] CTACK is a novel prognostic biomarker of IPF

Rationale and Design of a Prospective, Multicentre, Stop Tyrosine Kinase Inhibitor Trial of Paediatric Patients with Chronic Myeloid Leukaemia with Sustained Complete Molecular Response (STKI-14)

Chronic myeloid leukaemia (CML) is a relatively rare disease in children, accounting for 2–3% of all paediatric leukaemia cases. Generally, children with CML can avoid hematopoietic stem cell transplantation and achieve molecular responses with tyrosine kinase inhibitors (TKI). However, CML stem cells are thought to survive in many patients, even after TKI treatment. Many aspects of the toxic effects of prolonged exposure to TKIs during childhood remain unclear, particularly those regarding growth impairment. This lack of clarity underscores the importance of the present clinical trial, which aims to clarify the feasibility of treatment-free remission (TFR) in children following TKI treatment. We aim to examine the long-term out-comes and complications of TKIs before and after cessation to better understand the unknown complications that could arise in adulthood. This trial targets patients who were diagnosed with CML at an age younger than 20 years, were in the chronic or accelerated phase at initial diagnosis and remained in complete molecular remission for at least 2 years after TKI administration. We will examine the utility of TKI cessation and assess the treatment results of patients who resumed TKI therapy after losing a major molecular response. We will also investigate factors related to the feasibility of a TFR after TKI cessation

High-Risk Neuroblastoma with Metastases to Bilateral Kidneys at Diagnosis

Renal metastasis at diagnosis with neuroblastoma is rare. We present a 14-month-old boy who was diagnosed with high-risk neuroblastoma with multiple metastases, including bilateral kidneys. He received five cycles of induction chemotherapy and high-dose chemotherapy with autologous peripheral blood stem cell transplantation. All of the lesions shrank, and magnetic resonance imaging indicated that some of the metastases had disappeared. However, there were residual masses in the bilateral kidneys, and histological examination revealed the presence of tumor cells. Therefore, the patient underwent unrelated cord blood stem cell transplantation, which involved killer-ligand incompatibility in the graft-versus-host direction, in addition to human leukocyte antigen C and DRB1 mismatches. Three months later, tumor progression occurred from the residual mass in the sacral canal and a new lesion in the pancreas. Although tumor progression could not be controlled by additional chemotherapy and local radiotherapy, the metastatic nodules in bilateral kidneys did not increase in size before his death. To the best of our knowledge, this is the first report of neuroblastoma with bilateral renal metastases in the English medical literature. In addition, this case suggests that the combination of chemotherapy and immunotherapy may inhibit the progression of the renal lesions under certain conditions

Clock Gene Dysregulation Induced by Chronic ER Stress Disrupts β-cell Function

In Wfs1−/− Ay/a islets, in association with endoplasmic reticulum (ER) stress, D-site-binding protein (Dbp) expression decreased and Nuclear Factor IL-3 (Nfil3)/E4 Promoter-binding protein 4 (E4bp4) expression increased, leading to reduced DBP transcriptional activity. Similar alterations were observed with chemically-induced ER stress. Transgenic mice expressing E4BP4 under the control of the mouse insulin I gene promoter (MIP), in which E4BP4 in β-cells is expected to compete with DBP for D-box, displayed remarkable glucose intolerance with severely impaired insulin secretion. Basal ATP/ADP ratios in MIP-E4BP4 islets were elevated without the circadian oscillations observed in wild-type islets. Neither elevation of the ATP/ADP ratio nor an intracellular Ca2+ response was observed after glucose stimulation. RNA expressions of genes involved in insulin secretion gradually increase in wild-type islets early in the feeding period. In MIP-E4BP4 islets, however, these increases were not observed. Thus, molecular clock output DBP transcriptional activity, susceptible to ER stress, plays pivotal roles in β-cell priming for insulin release by regulating β-cell metabolism and gene expressions. Because ER stress is also involved in the β-cell failure in more common Type-2 diabetes, understanding the currently identified ER stress-associated mechanisms warrants novel therapeutic and preventive strategies for both rare form and common diabetes

The Usefulness of T1-Weighted Magnetic Resonance Images for Diagnosis of Acute Leukemia Manifesting Musculoskeletal Symptoms prior to Appearance of Peripheral Blood Abnormalities

The patients with acute leukemia occasionally present with musculoskeletal symptoms initially, including bone pain, joint pain, muscular pain, and functional impairment. Without abnormal findings of peripheral blood cell counts or smear, the correct diagnosis tends to be delayed. Magnetic resonance imaging is often performed to examine musculoskeletal abnormalities; it can simultaneously reveal the bone marrow composition with high anatomical resolution and excellent soft tissue contrast. We present 4 pediatric patients who were initially diagnosed with acute pyogenic osteomyelitis or arthritis, based on the elevated white blood cell counts and/or C-reactive protein in addition to the localized high signal intensity on T2-weighted magnetic resonance images. Finally, they were diagnosed with B-cell precursor acute lymphoblastic leukemia by bone marrow examination. The period between the onset of musculoskeletal symptoms and the diagnosis of leukemia ranged from 20 days to 6 months. In all cases, the T1-weighted magnetic resonance images taken prior to detection of peripheral blood abnormality revealed diffuse low signal intensity of the bone marrow in regions adjacent or contralateral to localized musculoskeletal symptoms. These findings should raise the suspicion of leukemia even without abnormalities in peripheral blood

Allogeneic hematopoietic stem cell transplantation for the treatment of BCR-ABL1-negative atypical chronic myeloid leukemia and chronic neutrophil leukemia: A retrospective nationwide study in Japan

Atypical chronic myeloid leukemia(aCML)and chronic neutrophilic leukemia(CNL)are rare BCR-ABL1 fusion gene-negative myeloid neoplasms with a predominance of neutrophils. Since no standard therapeutic strategy currently exists for these diseases,we retrospectively evaluated the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for aCML and CNL. Data from 14 aCML and 5 CNL patients as their diagnoses were collected using a nationwide survey. Allo-HSCT was performed between 2003 and 2014. Preconditioning regimens included myeloablative (n = 15),reduced-intensity (n = 3), and non-myeloablative (n = 1) regimens. Transplanted stem cells were obtained from HLA-matched related donors (n = 5) and alternative donors (n = 14). Neutrophil engraftment was successfully achieved in 17 patients. One-year overall survival rates (OS) were 54.4% (95% confidence interval [CI], 24.8 to 76.7%) and 40.0% (95% CI, 5.2 to 75.3%) in patients with aCML and CNL, respectively. Among aCML patients, 1-year OS were 76.2% (95% CI, 33.2 to 93.5%) and 20.0% (95% CI, 0.8 to 58.2%) in patients with <5% myeloblasts (n = 9) and ?5% myeloblasts (n = 5) in peripheral blood before allo-HSCT, respectively. These results suggest that allo-HSCT achieves long-term survival in patients with aCML and CNL. Better pre-transplant management is required to improve the outcomes of aCML patients with ?5% blasts in peripheral blood