A novel irreversible FLT3 inhibitor, FF-10101, shows excellent efficacy against AML cells with FLT3 mutations.

An activating mutation of Fms-like tyrosine kinase 3 (FLT3) is the most frequent genetic alteration associated with poor prognosis in acute myeloid leukemia (AML). Although many FLT3 inhibitors have been clinically developed, no first-generation inhibitors have demonstrated clinical efficacy by monotherapy, due to poor pharmacokinetics or unfavorable safety profiles possibly associated with low selectivity against FLT3 kinase. Recently, a selective FLT3 inhibitor, quizartinib, demonstrated favorable outcomes in clinical studies. However, several resistant mutations emerged during the disease progression. To overcome these problems, we developed a novel FLT3 inhibitor, FF-10101, designed to possess selective and irreversible FLT3 inhibition. The co-crystal structure of FLT3 protein bound to FF-10101 revealed the formation of a covalent bond between FF-10101 and the cysteine residue at 695 of FLT3. The unique binding brought high selectivity and inhibitory activity against FLT3 kinase. FF-10101 showed potent growth inhibitory effects on human AML cell lines harboring FLT3 internal tandem duplication (FLT3-ITD), MOLM-13, MOLM-14, and MV4-11, and all tested types of mutant FLT3-expressing 32D cells including quizartinib-resistant mutations at D835, Y842, and F691 residues in the FLT3 kinase domain. In mouse subcutaneous implantation models, orally administered FF-10101 showed significant growth inhibitory effect on FLT3-ITD-D835Y- and FLT3-ITD-F691L-expressing 32D cells. Furthermore, FF-10101 potently inhibited growth of primary AML cells harboring either FLT3-ITD or FLT3-D835 mutation in vitro and in vivo. These results indicate that FF-10101 is a promising agent for the treatment of patients with AML with FLT3 mutations, including the activation loop mutations clinically identified as quizartinib-resistant mutations.

Cysteine inhibits the fibrillisation and cytotoxicity of amyloid-ß 40 and 42: implications for the contribution of the thiophilic interaction.

Inhibitors of amyloid fibril formation have been at the centre of intense research efforts for the prevention of amyloidosis. Here, we hypothesise that a specific non-covalent interaction, the thiophilic interaction between the side chain of an aromatic residue in a polypeptide and a sulphur atom of the compound, effectively inhibits amyloid fibril formation. Fluorescence spectroscopy and transmission electron microscopy revealed that sulphur compounds, particularly Cys, inhibit the fibrillisation of amyloid-ß 1-40 (Aß40) and 1-42 (Aß42). Interestingly, aggregates of Aß40 and Aß42 induced by Cys were less cytotoxic than those induced by catechin, which is the most typical inhibitor of amyloid fibril formation. Because the essential amino acid, Cys, is an abundant molecule in the blood and cytosol, our data provide a new basis for the prevention of amyloid-related diseases and the elucidation of the mechanism of these diseases.

[Left to right ratio of transcranial color-coded sonography for monitoring hyperperfusion syndrome after carotid artery stenting: a case report].

Hyperperfusion syndrome is a significant complication after carotid endarterectomy (CEA) or carotid artery stenting (CAS). A few reports have shown that an increase in the ratio of mean flow velocity (MFV) of the middle cerebral artery (MCA) of the affected side by transcranial color-coded sonography (TCCS) is useful for the evaluation of hyperperfusion after CEA or CAS. We report a case of hyperperfusion syndrome after CAS in which not only the increased ratio of the affected side based on preoperative mean flow velocity, but also the left to right ratio (L/R ratio) was useful for monitoring hyperperfusion. A 48-year-old man was admitted to our hospital because of cerebral infarction of the right internal carotid artery (ICA) due to stenosis of the right ICA at origin. The preoperative L/R ratio of MFV of the MCA by TCCS was 0.58. We performed CAS and the patient then developed hyperperfusion syndrome with epilepsy and was intubated under the management of strict blood control. We performed TCCS daily and the patient was extubated when the L/R ratio of MFV of the MCA decreased to 1.1 from a maximum of 2.6, although the increased ratio of MFV of the MCA of the affected side was still higher than 1.4. The patient went home without any complications from hyperperfusion. When there is preoperative laterality of cerebral blood flow, the L/R ratio of MFV by TCCS can be useful for monitoring hyperperfusion after CEA or CAS.

One-dimensional protein-based nanoparticles induce lipid bilayer disruption: carbon nanotube conjugates and amyloid fibrils.

Along with recent progress of nanotechnology, concern has risen about biological impacts of nanoparticles deriving from their interaction with cell membranes. Nanoparticles tend to adsorb proteins in vivo. Therefore, the physical properties of the conjugates to cell membranes must be investigated to elucidate and assess their properties. We examined whether one-dimensional protein-based nanoparticles induce liposome leakage in physiological saline. Carbon nanotube conjugates with adsorbed lysozyme interacted with the liposome through electrostatic interaction, leading to liposome leakage. Surprisingly, amyloid fibrils of lysozyme resembled the conjugate in terms of their effects on liposome leakage. Results described herein provide new insight into the interaction between nanoparticles and cell membranes in terms of their shape, mechanical properties, and noncovalent interactions.

Surgical treatment of intracranial VA dissecting aneurysm.

OBJECT: Intracranial VA dissections are reported to cause headache, brain stem infarction, and SAH with an associated high morbidity and mortality. We aimed to clarify both the clinical characteristics and effectual treatment of intracranial VA dissections, and to present a retrospective analysis of our experience in the treatment. MATERIAL AND METHOD: Between 1995 and 2007 we experienced 62 VA dissections in our institution. Fourteen of 62 (23%) cases of VA dissections were associated with aneurysm, and received surgical treatment. Five of fourteen cases presented with SAH, 8/14 cases with ischemia, 1/14 cases with headache. RESULTS: In the hemorrhagic group, internal trapping of aneurysm (ITA) was successfully performed in four cases. In one case, bypass surgery was followed by ITA, while one case with treatment-related complication was observed. But Glasgow Outcome Scale (GOS) of almost all cases was severe; 2/5 cases showed good recovery (GR), and 3/5 cases had severe disability. In the non-hemorrhagic group, proximal clipping or trapping was performed in 4/9 cases. Bypass surgery followed by proximal clipping or trapping was performed in 2/9 cases, and ITA in 1/9 case. One case showed treatment-related complication. GOS was GR in all cases. CONCLUSION: Outcome in the hemorrhagic group was more severe as compared to the non-hemorrhagic group. The surgical strategy should be planned according to the location of the aneurysm and the origin of PICA.

[A case of filter wire protection induced carotid artery stenosis after CAS].

A 64-year-old man with asymptomatic severe ICA stenosis was treated by conventional CAS with Angioguard XP filter wire system. Follow-up angiography was performed six months later, to demonstrate severe localized stenosis in the part where the filter was deployed. Following angiography, stent-assisted angioplasty was performed successfully. We report a rare case of carotid artery stenosis induced by filter wire protection after CAS.

[A Japanese hospital reports long-term survival for 10 years after carotid endarterectomy].

BACKGROUND: Several reports in Western countries have demonstrated the net benefit and an acceptable long-term survival of carotid endarterectomy (CEA) for severe carotid stenosis. However, long-term follow-up after CEA for carotid stenosis is not well-documented in Japan. The aim of this study was to determine long-term outcomes of CEA in our hospital. METHODS: 38 consecutive patients underwent 42 CEAs at the Kyushu Medical Center between May, 1994 and December, 1998. Survival follow-up was conducted in December 2008 and the incidence of late stroke was investigated in all surviving patients. RESULTS: A total of 37 CEAs in 30 patients (83.3%) were registered. There were 28 males and 2 females, 25 symptomatic and 5 years asymptomatic, mean ages 68+/-7 years. Survival rate after CEA was 80.0% after 5 and 53.3% after 10-years, respectively. The 10 year survival ratio free from cerebral infarction was 36.7%. CONCLUSIONS: For the patients in this study, CEA is associated with an acceptable long-term survival as well as a satisfactory benefical effect in stroke prevention.

[A case of parental artery occlusion for a non-ruptured giant thrombosed aneurysm at the right vertebral artery using a goose neck snare to hold a guiding catheter].

The stabilization of a guiding catheter is one of the important factors for achieving successful endovascular treatments. However, obtaining sufficient stabilization is sometimes difficult due to the tortuousity of the approach route. A goose neck snare is useful not only for the retrieval of intravascular foreign bodies but also for holding a guiding catheter. This report presents a case of parental artery occlusion for a non-ruptured giant thrombosed aneurysm occurring in the right vertebral artery using a goose neck snare to hold a guiding catheter.

Characteristic sonographic findings of early restenosis after carotid endarterectomy.

OBJECTIVE: Restenosis of the carotid artery after carotid endarterectomy (CEA) is a major complication. The frequency, time of occurrence, and tissue characteristics of carotid restenosis were assessed with sonography. METHODS: Two hundred sixteen patients who had CEA for carotid stenosis were studied; follow-up sonography and magnetic resonance angiography were done 2 weeks, 3 months, and then every year after CEA. On sonography, restenosis was defined as an internal carotid artery (ICA) with a peak systolic velocity of 170 cm/s or greater or a maximum area of stenosis of 90% or greater. RESULTS: During 605 artery-years of follow-up, 18 patients (7.5%) were found to have restenosis on sonography: 4 at 3 months, 11 at 1 year, and 3 at 2 years after CEA. At the time that restenosis was detected, in all 18 ICAs the peak systolic velocity exceeded 200 cm/s and had more than doubled since the last measurement (mean +/- SD, 103 +/- 27 to 321 +/-107 cm/s), whereas the area of stenosis exceeded 90% in 6 patients, and magnetic resonance angiography revealed stenosis of 60% or greater in 8 patients. On sonography, all of the restenotic plaques were isoechoic and concentric. The restenosis was asymptomatic in 17 patients. Vascular risk factors or the severity of initial carotid stenosis before CEA were not associated with development of restenosis. Eleven patients had successful endovascular therapy, and the others received medical treatment. CONCLUSIONS: A marked increase in the flow velocity through an operated ICA is a good indication of restenosis. The isoechogenicity and concentricity of the restenotic plaques suggest that the restenosis is primarily the result of intimal hyperplasia.

[Strategy for management of carotid arterial stenosis: analysis of 293 consecutive patients in a Japanese cerebrovascular center].

Carotid arterial stenosis is a major risk factor for ischemic stroke and is increasing in Japan as the life-style has been westernized. The purpose of this study was to clarify the detailed process of diagnosis and treatment of patients with carotid arterial stenosis. Of the consecutive 1,889 hospitalized patients in our cerebrovascular center during 2001 and 2003, 293 patients had carotid stenosis 50% or more in diameter by the NASCET method; 82 patients were hospitalized during the acute stage of ischemic stroke and 211 patients with or without past history of ischemic stroke were admitted in the chronic stage. Among acute ischemic stroke patients, 62 patients (76%) had mild neurological symptoms of NIH Stroke Scale score < or = 4 on admission. As the initial treatment during the acute phase, all patients underwent antithrombotic medication; 33 of them underwent carotid endarterectomy (CEA) or carotid arterial stenting (CAS) in the chronic stage. Of 211 chronic patients, 123 (58%) did not have a history of symptomatic ischemic stroke, and instead had nonspecific symptoms, including carotid bruit, headache, and vertigo, or were diagnosed as having carotid artery stenosis by examinations of preoperative screenings. One hundred and thirty-five chronic patients underwent CEA/CAS and all the others except for a patient with serious gastrointestinal bleeding underwent anti-thrombotic medication. Statin treatment was chosen for 59 acute patients and 66 chronic patients. Because many patients with carotid arterial stenosis had mild symptoms during the acute phase or did not have ischemic episodes, we might overlook carotid lesions unless we performed screening examinations using ultrasound or magnetic resonance angiography.

Combined endovascular treatment for both intracranial aneurysm and symptomatic vasospasm.

BACKGROUND AND PURPOSE: The best strategy for treatment of subarachnoid hemorrhage due to ruptured cerebral aneurysm is obliteration of the aneurysm as soon as possible. Early surgery is desirable if the patient does not develop severe vasospasm or is clinically stable. However, if the patient has already developed severe vasospasm on admission, surgery may carry the risk of increasing the severity. We evaluated the safety and effectiveness of combined Guglielmi detachable coil (GDC) embolization and angioplasty in a single session for the treatment of ruptured aneurysms associated with symptomatic vasospasm. METHODS: From January 1992 to January 2001, 12 consecutive patients with ruptured aneurysms associated with symptomatic vasospasm were treated. Patients were classified as Hunt and Hess grade 2 (n = 1), 3 (n = 6), 4 (n = 4), or 5 (n = 1) and Fisher CT group 2 (n = 1), 3 (n = 10), or 4 (n = 1). They underwent GDC aneurysm occlusion and balloon angioplasty (n = 6), intraarterial papaverine infusion (n = 2), or both (n = 4) in a single session. In nine patients, aneurysm coil occlusion was performed first. RESULTS: Complete GDC occlusion was achieved in eight patients, a small neck remnant persisted in three, and embolization was incomplete in one patient. In all patients, angiographic improvement of vasospasm was obtained. In one patient, a thromboembolic complication occurred and was treated with urokinase. Clinical outcomes at discharge were good recovery in six, moderate disability in two, severe disability in three, or death in one. CONCLUSION: Endovascular treatment can be the first therapeutic option for ruptured aneurysms associated with severe vasospasm on admission. It offers some advantages over surgery in this setting, but these are balanced by the risk of thromboembolism.

Primary intraventricular hemorrhage from dural arteriovenous fistula.

Dural arteriovenous fistulas (AVFs) cause several types of intracranial hemorrhage, but rarely cause primary intraventricular hemorrhage (IVH). We report a 67-year-old man with sudden headache and a long history of a pulsatile bruit who developed intraventricular hemorrhage without any parenchymal hemorrhage. Cerebral angiogram revealed dural arteriovenous fistulas in transverse and sigmoid sinuses. Severe retrograde venous drainage seemed to have caused backward flow into the subependymal veins with their consequential rupture. Transvenous embolization was successful.

[Vascular reconstruction of tandem stenoses of the internal carotid artery].

We report a case treated successfully by carotid endarterectomy combined with endovascular stenting for tandem stenoses of the internal carotid artery. A 71-year-old man had tandem stenotic lesions affecting bifurcation and the petrous portion of the left internal carotid artery. Coronary stents were placed at the petrous portion of the internal carotid artery immediately after standard carotid endarterectomy. Endvascular techniques and surgery can be complementary in the management of patients suffering from such tandem lesions.

Cysteine inhibits amyloid fibrillation of lysozyme and directs the formation of small worm-like aggregates through non-covalent interactions.

In this article, we discuss the effects of amino acids on amyloid aggregation of lysozyme. l-cysteine (Cys) dramatically inhibited fibrillation of lysozyme, whereas other amino acids (including l-arginine) did not. In the presence of Cys, the aggregation pathway of lysozyme shifted from fibrillation to the formation of the small worm-like aggregates with unfolding. The interaction between Cys and lysozyme was observed to be non-covalent, suggesting that the thiophilic interaction between the thiol group on the side chain of Cys and the core sequence of lysozyme significantly contributes to the inhibition of amyloid aggregation. These findings provide a new basis for the design of a biocompatible additive to prevent amyloid fibrillation.

Three fatal cases of rapidly progressive infective endocarditis caused by Staphylococcus aureus: one case with huge vegetation.

Staphylococcus aureus (S. aureus) infective endocarditis (IE) is a severe disease with a high mortality despite intensive therapy. Three cases of S. aureus IE had a rapidly progressive fatal clinical course despite intensive antimicrobial therapy. One case was methicillin-sensitive S. aureus IE, which formed rapidly growing a huge vegetation on a prosthetic mitral valve, complicated with multiple systemic emboli. The other 2 cases were methicillin-resistant S. aureus IE without any predisposing heart disease.