Polymyxin B (PMB) is a cationic cyclic peptide that can selectively inhibit the growth of Gram-negative bacteria by disrupting the outer membrane permeability barrier through binding to ...lipopolysaccharide (LPS). Here, a fluorescent PMB derivative (PMB-Ds) was applied to visually confirm the vacuole as a direct lethal target of PMB against fungal cells, which lack LPS. PMB-Ds could be visualized in the normal rounded vacuolar membrane of Saccharomyces cerevisiae cells, suggesting the presence of a molecular ligand assisting the vacuole-targeting mobilization of the peptide in the organism. Vma1p, a cytoplasmic subunit constituent of the yeast vacuolar-type ATPase, was identified as one of the PMB-binding proteins by means of mass spectrometry. Mutant cells carrying a deletion of Vma1p but not those with deletions in two separate PMB-binding proteins were shown to be resistant to the vacuolar membrane disruptive action of PMB. Furthermore, the mutant cells were resistant to PMB lethality even when treated with PMB in combination with allicin, an allyl sulfur compound, which can selectively enhance the vacuole-targeting fungicidal activity of the peptide. In contrast, the parent cells were not made resistant to the vacuolar membrane disruptive action of PMB even if cells were pre-treated with bafilomycin A1, a specific inhibitor of the yeast vacuolar-type H+-ATPase. However, the parent cells were rendered more resistant to PMB consequent to Vma1p-GFP localization in the cytoplasm. These findings suggested a role for Vma1p in the vacuole-targeting fungicidal activity of PMB comparable to that of LPS in the outer membrane of Gram-negative bacteria.
A myocardial bridge (MB) that partially covers the course of the left anterior descending coronary artery (LAD) sometimes causes myocardial ischemia, primarily because of hemodynamic deterioration, ...but without atherosclerosis. However, the mechanism of occurrence of myocardial infarction (MI) as a result of an MB in patients with spontaneously developing atherosclerosis is unclear.
One hundred consecutive autopsied MI hearts either with MBs MI(+)MB(+) group; n=46 or without MBs (n=54) were obtained, as were 200 normal hearts, 100 with MBs MI(-)MB(+) group and 100 without MBs. By microscopy on LADs that were consecutively cross-sectioned at 5-mm intervals, the extent and distribution of LAD atherosclerosis were investigated histomorphometrically in conjunction with the anatomic properties of the MB, such as its thickness, length, and location and the MB muscle index (MB thickness multiplied by MB length), according to MI and MB status. In the MI(+)MB(+) group, the MB showed a significantly greater thickness and greater MB muscle index (P<0.05) than in the MI(-)MB(+) group. The intima-media ratio (intimal area/medial area) within 1.0 cm of the left coronary ostium was also greater (P<0.05) in the MI(+)MB(+) group than in the other groups. In addition, in the MI(+)MB(+) group, the location of the segment that exhibited the greatest intima-media ratio in the LAD proximal to the MB correlated significantly (P<0.001) with the location of the MB entrance, and furthermore, atherosclerosis progression in the LAD proximal to the MB was largest at 2.0 cm from the MB entrance.
In the proximal LAD with an MB, MB muscle index is associated with a shift of coronary disease more proximally, an effect that may increase the risk of MI.
Meiotic cells undergo two successive divisions without an intervening S phase. However, the mechanism of S-phase omission between the two meiotic divisions is largely unknown. Here we show that Wee1, ...a universal mitotic inhibitor, is absent in immature (but not mature) Xenopus oocytes, being down-regulated specifically during oogenesis; this down-regulation is most likely due to a translational repression. Even the modest ectopic expression of Wee1 in immature (meiosis I) oocytes can induce interphase nucleus reformation and DNA replication just after meiosis I. Thus, the presence of Wee1 during meiosis I converts the meiotic cell cycle into a mitotic-like cell cycle having S phase. In contrast, Myt1, a Wee1-related kinase, is present and directly involved in G(2) arrest of immature oocytes, but its ectopic expression has little effect on the meiotic cell cycle. These results strongly indicate that the absence of Wee1 in meiosis I ensures the meiotic cell cycle in Xenopus oocytes. Based on these results and the data published previously in other organisms, we suggest that absence of Wee1 may be a well-conserved mechanism for omitting interphase or S phase between the two meiotic divisions.
Diverticulitis in the terminal ileum is uncommon. Past reports suggested that conservative therapy may be feasible to treat terminal ileum diverticulitis without perforation; however, there is no ...consensus on the therapeutic strategy for small bowel diverticulitis. We present a 37-year-old man who was referred to our hospital for sudden onset of abdominal pain and nausea. He was diagnosed with diverticulitis in the terminal ileum by computed tomography (CT). Tazobactam/piperacillin hydrate (18 g/day) was administered. The antibiotic treatment was maintained for 7 days, and the symptoms disappeared after the treatment. Thirty-eight days after antibiotic therapy, he noticed severe abdominal pain again. He was diagnosed with diverticulitis in terminal ileum which was flare-up of inflammation. He was given antibiotic therapy again. Nine days after antibiotic therapy, laparoscopy assisted right hemicolectomy and resection of 20 cm of terminal ileum were performed. Histopathology report confirmed multiple ileal diverticulitis. He was discharged from our hospital 12 days after the surgery. Colonoscopy was performed two months after the surgery and it revealed no finding suggesting inflammatory bowel disease. Surgical treatment should be taken into account as a potential treatment option to manage the diverticulitis in the terminal ileum even though it is not perforated.
EP4, a prostaglandin E2 receptor, has shown an immunosuppressive activity on cancer cells. This first‐in‐human study evaluated ONO‐4578, a highly selective EP4 antagonist, as monotherapy and in ...combination with nivolumab in patients with advanced or metastatic solid tumors. A daily dose ranging from 30 mg to 100 mg of ONO‐4578 monotherapy and that ranging from 2 mg to 60 mg of ONO‐4578 with biweekly nivolumab 240 mg were administered. A total of 31 patients were enrolled, 10 receiving monotherapy and 21 receiving combination therapy. Overall, 26 patients experienced treatment‐related adverse events. Dose‐limiting toxicities were observed in three patients; one of six patients receiving 100 mg monotherapy developed grade 3 duodenal ulcer and two of six patients receiving 60 mg combination therapy developed either grade 3 erythema multiforme or grade 3 increased amylase and grade 4 increased lipase. One patient with small‐cell lung cancer who received 40 mg combination therapy had a partial response, and three patients with monotherapy and six patients with combination therapy had stable disease. Pharmacodynamics analyses showed that ONO‐4578 had EP4 antagonistic activity at doses as low as 2 mg. In conclusion, the maximum tolerated dose of ONO‐4578 alone or in combination with nivolumab was not reached. ONO‐4578 was well tolerated at the tested doses and showed signs of antitumor activity. Considering safety, efficacy, and pharmacokinetics/pharmacodynamics results, ONO‐4578 40 mg daily with nivolumab 240 mg biweekly was selected as the recommended dose for future clinical trials. (Registration: JapicCTI‐173,496 and NCT03155061).
ONO‐4578 is a selective antagonist of the EP4 receptor for prostaglandin E2. ONO‐4578 alone or in combination with nivolumab was well tolerated and showed signs of anti‐tumor activity in patients with advanced or metastatic solid tumors. Considering safety, efficacy, and pharmacokinetics/pharmacodynamics results, ONO‐4578 40 mg daily with nivolumab 240 mg biweekly was selected as the recommended dose for future clinical trials.
Intraventricular tumors may arise from a variety of cells in the region. There are some difficulties in diagnosing these tumors because of their histologically similar appearance. We analyzed ...intraventricular tumors, including central neurocytoma, oligodendroglioma, cerebral neuroblastoma, and cerebellar neuroblastoma, the neuronal characters of which were established based on their ultrastructural findings, except for oligodendroglioma. Central neurocytoma and cerebellar neuroblastoma showed synaptic formation, and cerebral neuroblastoma possessed immature neurites. Oligodendroglioma showed similar structures to that of a normal oligodendrocyte. Furthermore, we review the literature and evaluate the usefulness of analyzing ultrastructures.
AimsMalignant pleural mesothelioma with heterologous elements (such as osseous, cartilaginous or rhabdomyoblastic differentiation) is very rare. We tried to differentiate such mesothelioma cases from ...extraskeletal pleural osteosarcoma, which is very challenging.MethodsWe compared 10 malignant pleural mesotheliomas (three biphasic and seven sarcomatoid types) with two pleural osteosarcomas using clinicopathological and immunohistochemical methods, and also fluorescence in situ hybridisation (FISH) to examine for homozygous deletion of p16.ResultsThe median age was 72 years for mesotheliomas, and 69 years for osteosarcoma. For mesothelioma, eight cases were male and two were female. Growth was diffuse in all mesothelioma cases except case 10, where it was localised, as it was for the two osteosarcomas. Among mesothelioma cases, 80% displayed osteosarcomatous and 60% chondromatous elements, while 10% exhibited rhabdomyoblastic ones. Immunohistochemical labelling for calretinin and AE1/AE3 was present in 8/10 and 7/10 mesotheliomas, respectively, but in only one osteosarcoma. Loss of methylthioadenosine phosphorylase was seen in 5/7 mesotheliomas. FISH analysis revealed homozygous deletion of p16 in 5/8 mesothelioma and 2/2 osteosarcoma. Median survival was 6.5 months after biopsy or surgical operation in mesothelioma, and 12 months after operation in osteosarcoma.ConclusionsAlthough median survival was longer for osteosarcoma than for malignant mesothelioma, we could not differentiate mesothelioma from pleural osteosarcoma on the combined basis of clinicopathological and immunohistochemical data, and FISH analysis. However, diffuse growth was more frequent in mesothelioma than in osteosarcoma.
Epinastine hydrochloride (epinastine) is a second-generation histamine Hi-receptor antagonist widely used as an anti-allergic and anti-pruritic. To explore possible new aspects of the anti-pruritic ...mechanism of epinastine, in particular any effects on the peripheral nervous system, we examined epinastine's effects on sensory neurons using cultured murine dorsal root ganglion (DRG).
We performed a quantitative assessment of neurite growth and substance P (SP) release from isolated DRG in the presence versus the absence of epinastine. Mechanism(s) of epinastine’s effects on sensory neurons were detected by examining its neurotoxicity, inhibitory action on nerve growth factor (NGF), and modulatory function on NGFreceptors.
The percentage of DRG with outgrowing neurites, total number of neurites, and average extension length of neurites were decreased by epinastine in a concentration-dependent manner. Epinastine did not exhibit any evidence of neurotoxicity on sensory neurons, degradation and inactivation ability on NGF, or effects on expression of NGF receptors. Also, no effects on neural progenitor cells of the central nervous system in culture were observed. Epinastine suppressed capsaicin-induced SP release from DRG neurons in a dosedependent fashion.
The results demonstrate that epinastine has inhibitory effects on sensory neuronal growth, which may explain its clinical effects including potent anti-pruritic activity.
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