Daisuke Niimori

Tsukushi controls the hair cycle by regulating TGF-β1 signaling.

The hair follicle contains stem/progenitor cells that supply progeny for skin development and the hair cycle. Several signaling molecules belonging to the Wnt, BMP, shh, and transforming growth factor β (TGF-β) signaling cascades are involved in the normal hair follicle cycle. However, the systemic mechanism of how these humoral factors are controlled remains largely unknown. Previously, we reported that Tsukushi (TSK), a member of the small leucine-rich repeat proteoglycan family, functions extracellularly as a key coordinator of multiple signaling networks. Here, we show that TSK is expressed at the restricted areas of hair follicle during the morphogenesis and the hair cycle. Targeted disruption of the TSK gene causes the hair cycle to be delayed with low levels of TGF-β1 and phosphorylated Smad2/3 (pSmad2/3) expression. Biochemical analysis indicates that TSK directly binds to TGF-β1. Our data suggest that TSK controls the hair cycle by regulating TGF-β1 signaling.

A validation of presepsin levels in kidney dysfunction patients: four case reports

Here, we measured presepsins (PSPs) in four patients with acute kidney injury (AKI) or chronic kidney disease (CKD) and discuss the relationship between PSP and kidney dysfunction.Case 1: an 83-year-old man was admitted to the ICU to manage postoperative respiratory failure with AKI. He had undergone resection for rectal cancer and ileal conduit replacement. On day 1 in the ICU, Escherichia coli (E. coli) was isolated by urine culture. PSP level (pg/ml) on day 2 was 2,745 without elevation of other conventional biomarkers. On day 6, the patient was diagnosed with severe sepsis, and E. coli was isolated by blood culture. By then, PSP had risen to 3,977, along with elevation of other conventional biomarkers. His kidney function recovered gradually after continuous administration of hemodiafiltration; however, PSP continued to rise up to 6,051, along with high systemic inflammatory response syndrome (SIRS) and Acute Physiology and Chronic Health Evaluation (APACHE) II values. The patient expired on day 13 due to multiple organ failure. Case 2: a 78-year-old woman with CKD on hemodialysis (HD) was admitted to the ICU after cardiovascular surgery. Continuous HD was administered postoperatively, and PSP ranged from 1,473–1,870 without signs of sepsis. Temporary elevation of other conventional biomarkers was observed postoperatively. Case 3: a 74-year-old woman with CKD on HD was admitted to the ICU after neurosurgery. She underwent intermittent HD postoperatively, and PSP ranged from 1,240–1,935 without sepsis symptoms. Temporary elevation of other conventional biomarkers was observed postoperatively. Case 4: a 62-year-old man with CKD was admitted to the ICU to control gastrointestinal bleeding. PSP was 606 without signs of infection or elevation of other conventional biomarkers. In cases 2, 3, and 4, bacteria were not isolated in blood cultures. Patients’ clinical prognoses were good, with low or moderate SIRS and APACHE II scores.PSP in kidney dysfunction patients will be high despite non-infectious conditions. Therefore, evaluation of PSP in kidney dysfunction patients will be difficult. Further investigation is needed to clarify the relationship between PSP and kidney dysfunction.

Tsukushi is involved in the wound healing by regulating the expression of cytokines and growth factors

During the wound-healing process, macrophages, fibroblasts, and myofibroblasts play a leading role in shifting from the inflammation phase to the proliferation phase, although little is known about the cell differentiation and molecular control mechanisms underlying these processes. Previously, we reported that Tsukushi (TSK), a member of the small leucine-rich repeat proteoglycan family, functions as a key extracellular coordinator of multiple signalling networks. In this study, we investigated the contribution of TSK to wound healing. Analysis of wound tissue in heterozygous TSK-lacZ knock-in mice revealed a pattern of sequential TSK expression from macrophages to myofibroblasts. Quantitative PCR and in vitro cell induction experiments showed that TSK controls macrophage function and myofibroblast differentiation by inhibiting TGF-β1 secreted from macrophages. Our results suggest TSK facilitates wound healing by maintaining inflammatory cell quiescence.

Matrin-3 is essential for fibroblast growth factor 2-dependent maintenance of neural stem cells.

To investigate the mechanisms underlying the maintenance of neural stem cells, we performed two-dimensional fluorescence-difference gel electrophoresis (2D-DIGE) targeting the nuclear phosphorylated proteins. Nuclear phosphorylated protein Matrin-3 was identified in neural stem cells (NSCs) after stimulation using fibroblast growth factor 2 (FGF2). Matrin-3 was expressed in the mouse embryonic subventricular and ventricular zones. Small interfering RNA (siRNA)-mediated knockdown of Matrin-3 caused neuronal differentiation of NSCs in vitro, and altered the cerebral layer structure of foetal brain in vivo. Transfection of Matrin-3 plasmids in which the serine 208 residue was point-mutated to alanine (Ser208Ala mutant Matrin3) and inhibition of Ataxia telangiectasia mutated kinase (ATM kinase), which phosphorylates Matrin-3 Ser208 residue, caused neuronal differentiation and decreased the proliferation of neurosphere-forming stem cells. Thus, our proteomic approach revealed that Matrin-3 phosphorylation was essential for FGF2-dependent maintenance of NSCs in vitro and in vivo.

Dabrafenib and trametinib combination therapy safely performed in a patient with metastatic melanoma after severe liver toxicity due to vemurafenib

Dear Editor, Despite a few reports of liver toxicity caused by the combination of vemurafenib and other optional treatments, severe liver toxicity due to vemurafenib monotherapy has not been reported to our knowledge. In this case, severe liver toxicity due to vemurafenib did not occur in dabrafenib and trametinib combination therapy. A 65-year-old woman with a history of fatty liver presented with a mass in her right popliteal and inguinal region, 9 years after undergoing surgery for a right-ankle melanoma. Because a biopsy performed on the popliteal mass revealed a BRAF mutated melanoma, we treated the patient with vemurafenib monotherapy. On day 5, she had elevated levels of amylase (382 IU/L) and lipase (789 IU/L), corresponding to grades 3 and 4 of the Common Terminology Criteria for Adverse Events, version 4.0. There were no signs of acute pancreatitis. Vemurafenib was immediately discontinued, and her amylase and lipase levels normalized by day 11. Thereafter, the patient restarted half-dose vemurafenib therapy and was discharged. Vemurafenib was effective and the tumors were decreasing in size. However, on day 37, the patient presented with worsening malaise and jaundice. Laboratory findings revealed abnormal prothrombin activity (47%), international normalized ratio (1.61), and abnormal levels of aspartate aminotransferase (AST; 1805 IU/L), alanine aminotransferase (ALT; 1047 IU/L) and total bilirubin (3.7 mg/dL), leading to a diagnosis of severe acute liver failure. The patient’s AST and ALT levels corresponded to grade 4. Methylprednisolone was initiated as an anti-inflammatory agent, and her liver enzymes and coagulation markers had almost normalized within 10 days; the patient was discharged on day 49 (Fig. 1a). After her liver enzyme levels normalized, the patient started a combination therapy using half doses of dabrafenib and trametinib. Five months after starting the combination therapy, she has not reported significant adverse effects and computed tomography shows stable disease.

Severe bacterial sepsis results in delayed diagnosis of tuberculous lymphadenitis in a rheumatoid arthritis patient treated with adalimumab

Although tumor necrosis factor (TNF)-α inhibitors are effective in patients with rheumatoid arthritis (RA), an increased risk of infections often becomes a serious problem. It is well known that TNF-α inhibitors increase the risk of tuberculosis, but extrapulmonary tuberculosis often induced by them is difficult to diagnose using routine imaging examinations. We described a case of delayed diagnosis of a tuberculous lymphadenitis in a patient with RA treated with TNF-α inhibitor because of the complications of severe bacterial sepsis. In this case, rescreening with the interferon-γ release assay and excisional biopsy were useful in confirming the diagnosis of extrapulmonary tuberculosis. In the case we presented, she had other risk factors, that is, advanced age at the start of anti- TNF-α treatment or concomitant use of corticosteroid, might contribute to the development of complex infections. We should keep in mind that careful follow-up and appropriate examinations are necessary in caring for patients administering immunosuppressive treatments including anti- TNF-α drugs.

Nuclear Phosphoproteomics Features the Novel Smoking Markers inMouse Lung Tissue Following Subacute Phase Exposure to TobaccoSmoke

Smoking is a risk factor of lung diseases including chronic obstructive pulmonary disease (COPD) and lung cancer. However, the molecular mechanisms inducing these diseases remain to be completely uncovered. In order to elucidate them, it is necessary to identify the signaling pathway activated by tobacco smoking exposure. Especially, it is important to identify nuclear phosphoproteins induced by tobacco smoking exposure because the signaling pathways are modified by phosphoproteins. This time, to identify nuclear phosphoproteins as novel smoking markers, nuclear phosphoproteimics of mouse lung tissue following tobacco smoking exposure was examined. Tobacco smoking exposure against mice was examined using the nose-only, flow-past inhalation exposure chamber system for one month. Phosphopeptides eluted from nuclear proteins of the tobacco exposured mice lungs were identified by mass spectrometry. The result showed that 77 phosphoproteins were totally identified. Among them, the semiquantitative analysis using ProteoIQ proteomic software revealed that five phosphoproteins showed the different expression patterns between control and tobacco exposure groups. Furthermore, the classification by biological functions of the identified proteins revealed that these proteins were related to inflammation, regeneration, repair, proliferation, differentiation, morphological change and nicotine or stress response. Finally, we founded advanced glycosylation end product-specific receptor (RAGE) and serine/threonine-protein kinase SNF1-like kinase 2 (SIK2) as novel smoking markers.

Infective Endocarditis Caused by Odontogenic Infection withDentinogenesis Imperfecta in Jeune Syndrome

Osteogenesis imperfecta is main symptom in an autosomal recessive Jeune syndrome. Odontogenic infection by dentinogenesis imperfecta and poor oral hygiene is not known and Infective Endocarditis (IE) as a life threatening complication is the first report in Jeune syndrome. Case: A 13-year-old female patient presented with fever, disturbed consciousness, and convulsion. She had Jeune syndrome with mitral regurgitation and mental retardation. Cerebral hemorrhage, vegetation of mitral valve and poor oral hygiene demonstrated clinical definite diagnosis of IE by Duke Criteria. Bacterial aneurysm would cause to be cerebral hemorrhage that was no worsening by Computed Tomography. Vancomycin or Linezolid was treated after MRSA was detected in blood culture. Decayed teeth were removed as source of IE. Consciousness level and inflammation response were improved and no sign of infection was confirmed by frequent echocardiogram and blood culture. Outcome: Patient was discharged the hospital after she had no symptoms with appropriate treatment. Conclusion: Observation of oral hygiene and consideration of IE as the differential diagnosis are beneficial in a severe infectious disease of unknown origin with osteogenesis imperfecta, Jeune syndrome. Antibiotics therapy, oral hygiene and teeth extraction are effective for IE caused by decayed teeth with dentinogenesis imperfecta.

Healthy baby delivered vaginally from a brain-dead mother: Healthy neonate from brain-dead mother

A pregnant (20 gestational weeks) 32‐year‐old woman was found in cardiac arrest. Spontaneous circulation returned after 15 min. She became brain dead on the 13th hospital day. The patient was in stable circulatory condition under nasal desmopressin and 20–30 mg/day of hydrocortisone. On the 92nd hospital day at gestational week 33 + 3 days, natural labor began and a healthy 2,130‐g girl (Apgar 6/8) was delivered vaginally with minimum assistance.