Biomedical subjects
Publications and source records attributed to Y Minami.
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Atrial rupture without other major injury following blunt chest trauma is rare, but carries high mortality rate. Here we report 3 cases of blunt atrial rupture. All patients presented with hypotension and loss of consciousness. Echocardiography and computed tomography (CT) demonstrated pericardial effusion in all cases. All patients underwent surgery with a median sternotomy. Tear of the right atrium was seen in 2 patients, and no remarkable tear was seen in 1 patient. One of the 3 patients underwent surgery using cardiopulmonary bypass because he showed cardiogenic shock. Pericardiocentesis before the operation was not effective. All patients were discharged uneventfully. Echocardiography and CT were useful for diagnosis of cardiac rupture. In most reported cases, the cardiac tear has been repaired without using cardiopulmonary bypass. However, it is difficult to diagnose location of the tear, therefore, the repair became safer using cardiopulmonary bypass for the patients with cardiogenic shock. This article has described the mechanisms and generation of blunt chest trauma lesions.
The antioncogenic Chk2 kinase plays a crucial role in DNA damage-induced cell-cycle checkpoint regulation. Here we show that Chk2 associates with the oncogenic protein Wip1 (wild-type p53-inducible phosphatase 1) (PPM1D), a p53-inducible protein phosphatase. Phosphorylation of Chk2 at threonine68 (Thr68), a critical event for Chk2 activation, which is normally induced by DNA damage or overexpression of Chk2, is inhibited by expression of wild-type (WT), but not a phosphatase-deficient mutant (D314A) of Wip1 in cultured cells. Furthermore, an in vitro phosphatase assay revealed that Wip1 (WT), but not Wip1 (D314A), dephosphorylates Thr68 on phosphorylated Chk2 in vitro, resulting in the inhibition of Chk2 kinase activity toward glutathione S-transferase-Cdc25C. Moreover, inhibition of Wip1 expression by RNA interference results in abnormally sustained Thr68 phosphorylation of Chk2 and increased susceptibility of cells in response to DNA damage, indicating that Wip1 acts as a negative regulator of Chk2 in response to DNA damage.
Restricted feeding-induced free-running oscillation of clock genes in the liver was studied in homozygous Clock-mutant (Clock/Clock) mice. Similar to wild-type mice, Clock/Clock mice showed robust food-anticipatory behavioral activity in accordance with a restricted feeding schedule. Also, the peak of all clock gene mRNAs tested was phase-advanced in the liver of Clock/Clock mice as well as wild-type mice, although the amplitude of clock gene expression was low in Clock/Clock mice. The food-anticipatory behavioral rhythm in Clock/Clock mice maintained a period similar to wild-type mice during 2-day fasting after the cessation of restricted feeding. However, during the fasting days after temporal feeding cues were removed, the oscillation of clock genes in the liver and heart, excluding the suprachiasmatic nuclei, appeared to result in arrhythmicity in Clock/Clock mice. Thus, although the CLOCK-based molecular mechanism is not required for the expression of food-anticipatory activity, intact CLOCK protein might be involved in sustaining several cycles of peripheral circadian oscillations after restricted feeding-induced resetting.
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BACKGROUND: Re-expansion pulmonary oedema is a rare complication caused by rapid re-expansion of a chronically collapsed lung. Several cases of pulmonary oedema associated with one-lung ventilation (OLV) have been reported recently. Elevated levels of pro-inflammatory cytokines in pulmonary oedema fluid are suggested to play important roles in its development. Activation of cytokines after re-expansion of collapsed lung during OLV has not been thoroughly investigated. Here we investigated the effects of re-expansion of the collapsed lung on pulmonary oedema formation and pro-inflammatory cytokine expression. METHODS: Lungs isolated from female white Japanese rabbits were perfused and divided into a basal (BAS) group (n=7, baseline measurement alone), a control (CONT) group (n=9, ventilated without lung collapse for 120 min) and an atelectasis (ATEL) group (n=9, lung collapsed for 55 min followed by re-expansion and ventilation for 65 min). Pulmonary vascular resistance (PVR) and the coefficient of filtration (Kfc) were measured at baseline and 60 and 120 min. At the end of perfusion, bronchoalveolar lavage fluid/plasma protein ratio (B/P), wet/dry lung weight ratio (W/D) and mRNA expressions of tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and myeloperoxidase (MPO) were determined. RESULTS: TNF-alpha and IL-1beta mRNA were significantly up-regulated in lungs of the ATEL group compared with BAS and CONT, though no significant differences were noted in PVR, Kfc, B/P and W/D within and between groups. MPO increased at 120 min in CONT and ATEL groups. CONCLUSION: Pro-inflammatory cytokines were up-regulated upon re-expansion and ventilation after short-period lung collapse, though no changes were noted in pulmonary capillary permeability.
The tumor suppressor Chk2 kinase plays crucial roles in regulating cell-cycle checkpoints and apoptosis following DNA damage. We investigated the expression levels of the genes encoding Chk2 and several cell-cycle regulators in nine cell lines from lymphoid malignancies, including three Hodgkin's lymphoma (HL) lines. We found that all HL cell lines exhibited a drastic reduction in Chk2 expression without any apparent mutation of the Chk2 gene. However, expression of Chk2 in HL cells was restored following treatment with the histone deacetylase inhibitors trichostatin A (TsA) and sodium butyrate (SB), or with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5Aza-dC). Chromatin-immunoprecipitation (Chip) assays revealed that treatment of HL cells with TsA, SB or 5Aza-dC resulted in increased levels of acetylated histones H3 and H4, and decreased levels of dimethylated H3 lysine 9 at the Chk2 promoter. These results indicate that expression of the Chk2 gene is downregulated in HL cells via epigenetic mechanisms.
BACKGROUND: Recently, the novel antimicrobial peptide named dermcidin (DCD) was reported in human eccrine sweat glands. OBJECTIVES: We investigated the expression of DCD in a variety of cutaneous tumours in order to assess the usefulness of the monoclonal antibody (G-81), which recognizes a fragment of DCD. PATIENTS/METHODS: We studied the immunoreactivity of the G-81 antibody on 197 cutaneous tumours. RESULTS: A total of 13 of 26 cutaneous mixed tumours showed substantial immunoreactivity. In contrast all the following cases were completely unreactive: (i) epithelial tumours (seborrhoeic keratosis, squamous cell carcinoma, Bowen's disease, actinic keratosis, genital Paget's disease); (ii) follicular tumours (basal cell carcinoma, trichilemmoma, trichoepithelioma, trichoblastoma, keratoacanthoma, proliferating trichilemmal tumour, pilomatricoma); (iii) melanocytic tumours (malignant melanoma, naevus cell naevus, Spitz naevus, blue naevus); (iv) neural tumours (schwannoma, neurofibroma, Merkel cell neoplasm); (v) mesenchymal tumours (soft fibroma, dermatofibroma, dermatofibrosarcoma protuberans, vascular leiomyoma, leiomyosarcoma, lipoma, juvenile xanthogranuloma, angiomyoma); and (vi) other sweat gland tumours (poroid neoplasms, syringoma, cylindroma, clear cell hidradenoma, spiradenoma, syringoid eccrine carcinoma, mucinous carcinoma, apocrine cystadenoma, syringocystadenoma papilliferum, apocrine adenocarcinoma). Twenty-six cutaneous mixed tumours were considered from histopathological findings to be the apocrine type, but 13 of 26 mixed tumours contained some DCD-immunopositive cells that possibly differentiate into eccrine secretory glands. CONCLUSIONS: We found the expression of DCD in tubular structures of 50% of cutaneous mixed tumours with apocrine differentiation. These results suggest that a number of cutaneous mixed tumours show both eccrine and apocrine differentiation in the same neoplasm.
A 39-year old woman with antiphospholipid antibody positive systemic lupus erythematosus (SLE) was admitted to our department because of high fever, liver dysfunction and high level of C-reactive protein. At hospitalization, there was no anemia or jaundice. A tumor was palpable in the epigastric region, and there was tenderness in this region, but no muscular defense. There were no findings which indicated disease activity of SLE. The result of abdominal ultrasonography showed that there was a giant tumor, which occupied the majority of the left lobule of the liver, and a nonuniform ultrasound image was observed inside the tumor. The result of dynamic computed tomography (CT) showed peripheral globular enhancement, and enhancement then extended to the tumor center with time. Consequently, the patient was diagnosed with multiple hepatic hemangiomas. After admission, anemia rapidly deteriorated, and platelet count tended to decline. Therefore, intratumor hemorrhage was suspected, and emergent angiography was performed. For hemostatic purposes, transcatheter arterial embolization (TAE) and extended left hepatic lobectomy were performed. In patients with autoimmune diseases such as SLE and antiphospholipid syndromes, when thrombocytopenia is observed, care should be paid to identifying its cause, considering thrombocytopenia may be induced by hemangioma, although these cases are extremely rare.
We successfully treated a patient with accelerated aortic regurgitation due to localized aortic dissection with mitral regurgitation causing congestive heart failure. A 58-year-old female, who had suffered from aortic regurgitation for more than 10 years, had acute heart failure due to acceleration of aortic regurgitation. The surgical findings showed prolapse of the aortic valve due to localized dissection in the sinus of Valsalva. We performed a Bentall operation and a mitral valve replacement, with a favorable outcome. The postoperative course was uneventful.
The main mammalian circadian pacemaker is located in the suprachiasmatic nucleus of the hypothalamus. Clock genes such as the mouse Period gene (mPer) play a role in this core clock mechanism in the mouse. With brief light exposure during the subjective night, the photic information, which is conveyed directly to the suprachiasmatic nucleus via the retinohypothalamic tract, results in mPer1 and mPer2 expression in the suprachiasmatic nucleus. Glutamate and pituitary adenylate cyclase-activating polypeptide (PACAP) are co-stored in the retinohypothalamic tract. Recent studies have suggested that not only glutamate but also PACAP are key players in the phase shift that occurs during subject night; however, research demonstrating a direct association between the PACAP-induced phase shift and mPer gene expression has yet to be conducted. In the present study, PACAP (200 pmol) injected into the lateral ventricle during subjective night (circadian time 16; circadian time 12, onset of locomotor activity) caused a moderate phase delay associated with moderate expression of mPer1 and only slight expression of mPer2 in the mouse suprachiasmatic nucleus. PACAP-induced mPer1 expression was also observed in the paraventricular nucleus and periventricular area of the hypothalamus. (+)MK-801 (0.5 mg/kg), an N-methyl-D-aspartate (NMDA) receptor antagonist, suppressed both the PACAP-induced phase delay and mPer1 expression. From these results we suggest that PACAP induces phase delays in the mouse circadian rhythm in association with an increase of mPer expression in the suprachiasmatic nucleus via the activation of NMDA receptors.
An internal tandem duplication of the juxtamembrane (JM) domain of FLT3, a family of ligand-activated receptor tyrosine kinases, has been found in 20% of cases of acute myeloid leukemia (AML), and this mutation is correlated with leukocytosis and a poor prognosis. As a therapeutic approach, we previously reported that herbimycin A (HA) inhibited the growth of tandemly duplicated FLT3 (TDFLT3)-transformed cells (Leukemia 2000; 14: 374). Here, we have investigated the mechanism behind the cytotoxicity of HA, an ansamycin derivative which is now known to target Hsp90. The treatment with HA or another Hsp90 inhibitor, radicicol, induced selective apoptosis in TDFLT3-transformed 32D cells (TDFLT3/32D). The tyrosine-phosphorylation of TDFLT3 was inhibited by HA, whereas FLT3 ligand-induced phosphorylation of wild-type FLT3 (WtFLT3) was not. The downstream signal molecules MAPK, Akt and STAT5a were also dephosphorylated by HA in TDFLT3/32D. Immunoprecipitation analysis showed that TDFLT3 but not WtFLT3 formed a complex with Hsp90, and that the HA treatment dissociated TDFLT3 from the Hsp90 chaperone complex. These findings imply that targeting of Hsp90 will facilitate the development of anti-TDFLT3 therapy, and that Hsp90 is closely involved in the oncogenic activation of FLT3.
The ubiquitin-proteasome system catalyses the immediate destruction of misfolded or impaired proteins generated in cells, but how this proteolytic machinery recognizes abnormality of cellular proteins for selective elimination remains elusive. Here, we report that the C-terminus of Hsc70-interacting protein (CHIP) with a U-box domain is an E3 ubiquitin-ligase collaborating with molecular chaperones Hsp90 and Hsc70. Thermally denatured firefly luciferase was multiubiquitylated by CHIP in the presence of E1 and E2 (Ubc4 or UbcH5c) in vitro, only when the unfolded substrate was captured by Hsp90 or Hsc70 and Hsp40. No ubiquitylating activity was detected in CHIP lacking the U-box region. CHIP efficiently ubiquitylated denatured luciferase trapped by the C-terminal region of Hsp90, which contains a CHIP binding site. CHIP also showed self-ubiquitylating activity independent of target ubiquitylation. Our results indicate that CHIP can be regarded as 'a quality-control E3' that selectively ubiquitylates unfolded protein(s) by collaborating with molecular chaperones.
Sixty-six replacing growth-type early lung adenocarcinomas, measuring 2 cm or less across their greatest dimension, were used to investigate allelic losses at eight loci on the eight chromosomes carrying the principal cancer-associated genes. In total, 2 (16.7%) of 12 type A tumors (localized bronchioloalveolar carcinoma, LBAC) and 11 (39.3%) of 28 type B tumors (LBAC with alveolar collapse), which correspond to early lung adenocarcinomas including cancers in situ, showed allelic losses in one or more of the regions examined. In contrast, 25 (96.2%) of 26 type C tumors (LBAC with active fibroblastic proliferation), which correspond to small but advanced tumors, showed allelic losses in one or more regions. The change in histology from type A to type C was characterized by a significant rise in the incidence of allelic losses (P < 0.01). Deletions of 3p, 17p, 18q, and 22q increased significantly during malignant progression. In type C tumors that showed heterogeneous histological features, the tumor cells in the central fibrotic areas exhibited more allelic losses than those in the peripheral bronchioloalveolar growths and were, therefore, considered to have progressed to a more advanced stage than the tumor cells in the peripheral regions.
Recently, we reported the mRNA localization of Ca(2+)/calmodulin-dependent protein kinase I beta 2 isoform (CaMKIbeta2) in the mouse nervous system. In the present study, polyclonal antibody against CaMKIbeta2 was generated and used to investigate the distribution of the enzyme within the central nervous system of the rat. Interestingly some differences were observed between the enzyme localization and previous mRNA detection [J. Neurochem. 268 (1999) 26512]. The strongest expression of the enzyme was found in pontine nuclei. Immunopositive fibers could be traced through the middle cerebellar peduncle until they reached the cerebellum. Quite strong staining could also be observed in almost all of the neurons in the neocortex, hippocampus, amygdala, hypothalamus, brainstem and cerebellum, including the nuclei of the cranial nerves and Purkinje cell layer of the cerebellar cortex which was not clearly detected in the previous in situ hybridization study. In the spinal cord, CaMKIbeta2 could be detected in the gray matter with stronger expression in the dorsal horn. CaMKIbeta2 showed very strong nuclear localization but was also present in the cytoplasm of some neurons. Such localization suggests that CaMKIbeta2 may be involved in many neuronal functions in the central nervous system, including the possibility of important roles in nuclear signal transduction.
To clarify functional roles of MDEG2 (mammalian degenerin-2), a modulatory subunit of proton-activated cation channels, in MDEG1/MDEG2 heteromer, we replaced the Gly481 residue in MDEG2 with cysteine or phenylalanine and characterized them electrophysiologically. Expression of MDEG1 in Xenopus oocytes elicited proton-activated cation currents that were rapidly desensitized. Co-expression of MDEG1 and MDEG2 (or MDEG2-G481C) displayed similar current traces as MDEG1 alone. In contrast, co-expression of MDEG1 and MDEG2-G481F dramatically attenuated desensitization of the proton-activated currents. Interestingly, the G481F mutation in MDEG2 did not alter other channel properties including maximal whole-cell currents, ionic selectivity, pH-sensitivity and affinity for amiloride. Thus, Gly481 in MDEG2 specifically controls inactivation process of the MDEG1/MDEG2 channel.
Fusion gene products such as PML-RARalpha and BCR-ABL generated by leukemia-specific chromosomal translocations have been identified as target molecules for the treatment of leukemia. Here we describe one possibility for extending the frontier of mechanism-based medicine for acute myeloid leukemia (AML). FLT3, a receptor tyrosine kinase (RTK) preferentially expressed in hematopoietic progenitor cells, frequently has a gain-of-function mutation in AML. To search for FLT3-targeted compounds, we screened the growth-inhibitory effects of several tyrosine kinase inhibitors (TKIs) on mutant FLT3-transformed 32D cells. Herbimycin A at a concentration of 0.1 microM markedly inhibited the growth of the transfectants but at that concentration was ineffective in parental 32D cells. It suppressed the constitutive tyrosine phosphorylation of the mutant FLT3, but not the phosphorylation of the ligand-stimulated wild-type FLT3. In mice transplanted with transformed 32D cells, the administration of herbimycin A completely prevented leukemia progression. Recent studies have indicated that herbimycin A binds directly with HSP90, a molecular chaperone, and destabilizes HSP90-associated proteins. Another HSP90 inhibitor, radicicol, also induced apoptosis selectively in transformed 32D cells. HSP90 is a promising target for the treatment of AML with mutant FLT3.
In mammals, the Ror-family receptor tyrosine kinases consist of two structurally related proteins, Ror1 and Ror2, characterized by the extracellular Frizzled-like cysteine-rich domain and membrane proximal kringle domains. As an attempt to gain insights into their roles in mouse development, expression patterns of Ror1 and Ror2 during early embryogenesis were examined and compared. Interestingly, at early stages, Ror1 and Ror2 exhibit similar expression patterns in the developing face, including the frontonasal process and pharyngeal arches, which are derived from cephalic neural crest cells. On the other hand, they exhibit different expression patterns in the developing limbs and brain, where the expression of Ror2 was detected broadly compared with that of Ror1. At a later stage, both genes are expressed in a similar fashion in the developing heart and lung, yet in a distinct manner in the brain and eye.