Designing Sustainable Hydrophilic Interfaces via Feature Selection from Molecular Descriptors and Time-Domain Nuclear Magnetic Resonance Relaxation Curves.

Surface modification using hydrophilic polymer coatings is a sustainable approach for preventing membrane clogging due to foulant adhesion to water treatment membranes and reducing membrane-replacement frequency. Typically, both molecular descriptors and time-domain nuclear magnetic resonance (TD-NMR) data, which reveal physicochemical properties and polymer-chain dynamics, respectively, are required to predict the properties and understand the mechanisms of hydrophilic polymer coatings. However, studies on the selection of essential components from high-dimensional data and their application to the prediction of surface properties are scarce. Therefore, we developed a method for selecting features from combined high-dimensional molecular descriptors and TD-NMR data. The molecular descriptors of the monomers present in polyethylene terephthalate films were calculated using RDKit, an open-source chemoinformatics toolkit, and TD-NMR spectroscopy was performed over a wide time range using five-pulse sequences to investigate the mobility of the polymer chains. The model that analyzed the data using the random forest algorithm, after reducing the features using gradient boosting machine-based recursive feature elimination, achieved the highest prediction accuracy. The proposed method enables the extraction of important elements from both descriptors of surface properties and can contribute to the development of new sustainable materials and material-specific informatics methodologies encompassing multiple information modalities.

Incidence of sodium-glucose cotransporter-2 inhibitor-associated perioperative ketoacidosis in surgical patients: a prospective cohort study.

PURPOSE: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are commonly prescribed anti-diabetic medications with various beneficial effects; however, they have also been associated with ketoacidosis. The aim of this study was to determine the incidence of SGLT2i-associated perioperative ketoacidosis (SAPKA) in surgical patients. METHODS: We conducted a multicenter, prospective cohort study across 16 centers in Japan, enrolling surgical patients with diabetes who were prescribed SGLT2is between January 2021 and August 2022. Patients were monitored until the third postoperative day to screen for SAPKA, defined as urine ketone positivity with a blood pH of < 7.30 and HCO3 level ≤ 18.0 mEq/L, excluding cases of respiratory acidosis. RESULTS: In total, 759 of the 762 evaluated patients were included in the final analysis. Among these, three patients (0.40%) had urine ketones with a blood pH of < 7.30; however, blood gas analysis revealed respiratory acidosis in all three, and none of them was considered to have SAPKA. The estimated incidence of SGLT2i-associated postoperative ketoacidosis was 0% (95% confidence interval, 0%-0.4%). CONCLUSIONS: The observed incidence of SAPKA in our general surgical population was lower than expected. However, given that the study was observational in nature, interpretation of study results warrants careful considerations for biases.

Proof of concept testing of a positive reference material for in vivo and in vitro sensitization testing of medical devices.

In vivo skin sensitization tests are required to evaluate the biological safety of medical devices in contact with living organisms to provide safe medical care to patients. Negative and positive reference materials have been developed for biological tests of cytotoxicity, implantation, hemolysis, and in vitro skin irritation. However, skin sensitization tests are lacking. In this study, polyurethane sheets containing 1 wt/wt % 2,4-dinitrochlorobenzene (DNCB-PU) were developed and evaluated as a positive reference material for skin sensitization tests. DNCB-PU sheet extracts prepared with sesame oil elicited positive sensitization responses for in vivo sensitization potential in the guinea pig maximization test and the local lymph node assay. Furthermore, DNCB-PU sheet extracts prepared with water and acetonitrile, 10% fetal bovine serum-containing medium, or sesame oil elicited positive sensitization responses as alternatives to animal testing based on the amino acid derivative reactivity assay, human cell line activation test, and epidermal sensitization assay, respectively. These data suggest that the DNCB-PU sheet is an effective extractable positive reference material for in vivo and in vitro skin sensitization testing in medical devices. The formulation of this reference material will lead to the development of safer medical devices that contribute to patient safety.

[Surgical Results of Lumbar Degenerative Disease with Foot Drop].

Drop foot is associated with various diseases, such as peripheral nerve disease, lumbar degenerative disease, metabolic disease, and endocrine disease. Among lumbar degenerative diseases, lumbar disc herniation and lumbar canal stenosis are most commonly reported. We report the surgical outcomes of patients with drop foot caused by lumbar degenerative diseases. Between 2008 and 2018, we encountered 24 cases of drop foot in patients who underwent surgery of the lumbar lesion. The mean age was 69.5 years(49-88 years). Fourteen patients were male and ten were female. The mean time interval between the onset of drop foot and surgery was 51.5 days(from 7 days to 1 year). Drop foot, as a clinically significant muscle weakness, was defined at levels of manual muscle test(MMT)3 or lower. Responsible lesions for drop foot were canal stenosis at L4/5 in 8 cases, disc herniation at L4/5 in 10 cases, disc herniation at L5/S1 in 5 cases, and far-out syndrome in 1. One case involved drop foot bilaterally. Muscle weakness improved by surgery at levels of MMT 4 or greater in 16 cases(66.7%). Six cases of complete paresis or tibialis anterior muscle atrophy preoperatively resulted in no improvement;however, neuralgia was relieved in all. Twelve of 15 cases(80%)of lumbar disc herniation and 4 of 10 cases(40%)of lumbar canal stenosis resulted in improvement. Between disc herniation and canal stenosis, the surgical success rate was not statistically different. Age and the time interval between the onset and surgery were also not significant factors of the outcome. Surgical intervention seems to be beneficial even in cases of severe muscle weakness since pain relief can be expected, which leads to improvement in gait.

[A Case of Multiple Brain Lesions Associated with Hydrophilic Polymer Allergy after Coil Embolization that Showed Repeated Progression and Regression].

A 41-year-old woman underwent coil embolization for subarachnoid hemorrhage associated with a ruptured anterior cerebral artery(A1)aneurysm. Approximately 3 weeks later, MRI revealed right cerebral white matter changes with extensive edema and enhancement lesions. Even though she was asymptomatic, we suspected an allergic reaction to the hydrophilic coating polymer and initiated steroid treatment. After tapering and discontinuing the steroid treatment, follow-up MRI revealed development of white matter lesions;thus, steroid treatment was reinitiated. Progression and regression of the lesions occurred repeatedly, and she was radiologically stable at almost 1 year after coiling. We speculated that these white matter lesions were foreign body granulomas that reacted to the hydrophilic coating of the endovascular device. Overall, an allergic reaction to hydrophilic coating polymer could occur as a delayed complication after coil embolization and that progression and regression of the lesions could repeatedly occur in rare cases.

[Pseudoaneurysm of Neck External Carotid Artery Related to Chiropractic Manipulation].

A 55-year-old man presented with progressive pain and expanding swelling in his right neck. He had no history of trauma or infectious disease. The patient had undergone chiropractic manipulations once in a month and the last manipulation was done one day before the admission to our hospital. On examination by laryngeal endoscopy, a swelling was found on the posterior wall of the pharynx on the right side. The right piriform fossa was invisible. CT revealed hematoma in the posterior wall of the right oropharynx compressing the airway tract. Aneurysm-like enhanced lesion was also seen near the right common carotid artery. Ultrasound imaging revealed a fistula of approximately 1.2 mm at the posterior wall of the external carotid artery and inflow image of blood to the aneurysm of a diameter of approximately 12 mm. No dissection or stenosis of the artery was found. Jet inflow of blood into the aneurysm was confirmed by angiography. T1-weighted MR imaging revealed presence of hematoma on the posterior wall of the pharynx and the aneurysm was recognized by gadolinium-enhancement. We performed emergency surgery to remove the aneurysm while preserving the patency of the external carotid artery. The pin-hole fistula was sutured and the wall of the aneurysm was removed. Histopathological assessment of the rissue revealed pseudoaneurysm. The patient was discharged after 12 days without deficit. Progressively growing aneurysm of the external carotid artery is caused by various factors and early intervention is recommended. Although, currently, intravascular surgery is commonly indicated, direct surgery is also feasible and has advantages with regard to pathological diagnosis and complete repair of the parent artery.

A high-flow nasal cannula system with relatively low flow effectively washes out CO2 from the anatomical dead space in a sophisticated respiratory model made by a 3D printer.

BACKGROUND: Although clinical studies of the high-flow nasal cannula (HFNC) and its effect on positive end-expiratory pressure (PEEP) have been done, the washout effect has not been well evaluated. Therefore, we made an experimental respiratory model to evaluate the respiratory physiological effect of HFNC. METHODS: An airway model was made by a 3D printer using the craniocervical 3D-CT data of a healthy 32-year-old male. CO2 was infused into four respiratory lung models (normal-lung, open- and closed-mouth models; restrictive- and obstructive-lung, open-mouth models) to maintain the partial pressure of end-tidal CO2 (PETCO2) at 40 mmHg. HFNC flow was changed from 10 to 60 L/min. Capnograms were recorded at the upper pharynx, oral cavity, subglottic, and inlet sites of each lung model. RESULTS: With the normal-lung, open-mouth model, 10 L/min of HFNC flow decreased the subglottic PETCO2 to 30 mmHg. Increasing the HFNC flow did not further decrease the subglottic PETCO2. With the normal-lung, closed-mouth model, HFNC flow of 40 L/min was required to decrease the PETCO2 at all sites. Subglottic PETCO2 reached 30 mmHg with an HFNC flow of 60 L/min. In the obstructive-lung, open-mouth model, PETCO2 at all sites had the same trend as in the normal-lung, open-mouth model. In the restrictive-lung, open-mouth model, 20 L/min of HFNC flow decreased the subglottic PETCO2 to 25 mmHg, and it did not decrease further. As HFNC flow was increased, PEEP up to 7 cmH2O was gradually generated in the open-mouth models and up to 17 cmH2O in the normal-lung, closed-mouth model. CONCLUSIONS: The washout effect of the HFNC was effective with relatively low flow in the open-mouth models. The closed-mouth model needed more flow to generate a washout effect. Therefore, HFNC flow should be considered based on the need for the washout effect or PEEP.

Dexmedetomidine sedation during the nighttime reduced the incidence of postoperative atrial fibrillation in cardiovascular surgery patients after tracheal extubation.

BACKGROUND: Dexmedetomidine (Dex) provides sedation and analgesia by acting on central alpha-2 receptors and is suitable for use after extubation because it has little respiratory depression. Considering the sympathoinhibitory and anxiolytic action of Dex, there is the possibility that Dex might reduce the incidence of atrial fibrillation (AF), which is recognized as a common complication after cardiovascular surgery. We investigated whether the postoperative incidence of AF decreased in patients who received Dex only during the nighttime in the intensive care unit (ICU). METHODS: We retrospectively reviewed ICU charts to determine the incidence of AF and associated factors during the 2-day period after tracheal extubation in patients who underwent cardiovascular surgery from November 2009 to November 2010. The patients were divided into a Dex group (n = 16) and a non-Dex group (n = 29). RESULTS: There were no differences in AF risk factors except for diabetes between the two groups. The average rate of Dex administration was 0.3 ± 0.2 µg/kg/h. There were also no differences between the groups in heart rate during the daytime, central venous pressure, body temperature, white blood cell count, serum level of C-reactive protein, catecholamine use, beta-blocker use, and amount of fentanyl. AF developed in one patient in the Dex group (6.3 %) and ten patients in the non-Dex group (34.5 %) during the observation period, and the difference was significant (p = 0.035). None of the risk factors for AF was significantly associated with AF in univariate analysis; however, multivariate logistic regression analysis using age, Dex use, and beta-blocker use, extracted because their p values in univariate analysis were not exceeding 0.15, showed that Dex use was the only factor associated with the development of AF (p = 0.045, odds ratio 9.75 [1.05-90.8]). CONCLUSIONS: The results suggest that adequate sedation with Dex during the nighttime can reduce the incidence of AF in cardiovascular surgery patients after extubation.

Acute lymphoblastic leukemia in a girl with Wilson's disease.

Wilson's disease (WD) is an autosomal recessive defect in cellular copper transportation. Although acute lymphoblastic leukemia (ALL) is the most common form of childhood malignancy, only two cases of ALL associated with WD have been reported to date. One patient died of relapse and infection, and the other died of neutropenic sepsis during the treatment. We here describe the case of a 10-year-old girl with WD and ALL. Adverse events of chemotherapy, including liver toxicity and severe myelosuppression, necessitated adjustments in the chemotherapy doses. After completion of the treatment, the patient has remained in remission from ALL without progression of liver damage for 2 years. Severe treatment-related toxicity should be considered in chemotherapy for patients with WD.

Superior recovery profiles of propofol-based regimen as compared to isoflurane-based regimen in patients undergoing craniotomy for primary brain tumor excision: a retrospective study.

PURPOSE: Studies comparing the recovery profiles of isoflurane- and propofol-based anesthesia for major intracranial surgery have reported contradictory results. The aim of our study was to clarify the emergence status in both regimens by investigating uniformly managed neuroanesthesia cases. METHODS: The anesthesia database at Yamagata University Hospital covering the period 2002-2005 was retrospectively investigated for adult patients who underwent craniotomy for primary brain tumor excision. General anesthesia was provided by an isoflurane- (ISO group) or propofol-based (PROP group) regimen. Times to extubation and operating room (OR) discharge, perioperative consciousness levels, and perioperative variables were compared. RESULTS: Of the 202 surgeries performed during the study period, 77 and 82 patients were anesthetized with isoflurane and propofol, respectively. Demographic data were comparable between the two groups, although the American Society of Anesthesiology grade was worse in the PROP group. Extubation times [39.5 ± 14.6 min (ISO) vs. 29.5 ± 14.9 min (PROP); P < 0.001] and OR discharge times [67.2 ± 18.0 (ISO) vs. 53.9 ± 17.6 min (PROP); P < 0.001] were significantly shorter in the PROP, with significantly better immediate consciousness levels. The differences in levels of consciousness persisted for several hours postoperatively. PROP patients had significantly higher urine outputs and lower body temperatures during anesthesia. The incidences of shivering, nausea, vomiting, and convulsions were not significantly different between the groups. The time to discharge was similar between the groups. CONCLUSIONS: Propofol was associated with a better recovery profile and neurological condition than isoflurane, as indicated by shorter extubation and OR discharge times and better postoperative consciousness.

Fatigue in survivors of childhood acute lymphoblastic and myeloid leukemia in Japan.

BACKGROUND: Fatigue in cancer survivors is a serious problem in pediatric oncology, but reports on this issue are limited, especially in Asian countries. METHODS: Sixty-three patients with acute lymphoblastic leukemia and 18 patients with acute myeloid leukemia who attended a follow-up outpatient clinic were enrolled. Participants were required to be >8 years of age, in remission, and without any cancer treatment for at least the previous 1 year. A control group consisted of 243 subjects whose age and gender were matched with the patient group. A questionnaire consisting of 12 items was devised for fatigue measurement. RESULTS: Principal factor analysis identified three dimensions, defined as physical fatigue, decreased function, and altered mood. The mean total and the three fatigue dimension scores tended to be higher in the control group, but significant differences between the scores were seen only in the total and physical fatigue scores. Multiple regression analysis indicated an association of present older age or shorter duration after completion of treatment with total and physical fatigue, and an association of presence of total body irradiation with decreased function. CONCLUSION: Pediatric leukemia survivors in Japan experience equal or less fatigue compared with that of controls in different fatigue dimensions. Elucidation of underlying mechanisms of cancer-related fatigue including the differences of cultural background among different countries is necessary for future study of this issue.

Low-dose but not high-dose prostaglandin E(1) improves the histological outcome of severe forebrain ischemia in rats.

PURPOSE: Prostaglandin E(1) (PGE(1)) has been shown to provide short-term neuroprotection against various types of brain ischemia in a dose-dependent manner in mice. However, these findings were obtained from experiments performed without any control over physiological parameters. We performed an outcome study where physiological parameters were controlled in an attempt to confirm the dose-dependant neuroprotective effects of PGE(1). METHODS: A rat model of severe forebrain ischemia was used. Two doses of PGE(1) were administered during the pre-ischemic period, a low dose (LowPG group) and a high dose (HighPG group). Normotension was maintained in the LowPG group, while hypotension was induced in the HighPG group. In separate groups, normal saline (Control) or sodium nitroprusside (SNP) were infused to compare outcomes under similar blood pressure conditions. Histological outcomes in the hippocampal CA1 and entorhinal cortex were evaluated 5 days post-ischemia. RESULTS: HighPG resulted in hyperglycemia. The percentage of dead neurons in the hippocampal CA1 and entorhinal cortex were similar in the Control, SNP, and HighPG groups, the percentage being significantly attenuated in the LowPG group (CA1: Control = 92.8 +/- 2.4%, LowPG = 85.0 +/- 8.5%, HighPG = 95.3 +/- 2.4%, and SNP = 96.4 +/- 0.7%, P < 0.01; entorhinal cortex: Control = 73.8 +/- 4.0%, LowPG = 53.2 +/- 12.3%, HighPG = 72.1 +/- 12.6%, and SNP = 76.5 +/- 4.1%, P < 0.01). CONCLUSION: Pre-ischemic administration of low-dose PGE(1) in rats provided neuroprotection against severe forebrain ischemia. A dose dependency was not observed with PGE(1) dose and outcome.

[Efficacy of remifentanil for anesthetic management of awake craniotomy].

BACKGROUND: Remifentanil has strong analgesic fore tried to use remifentanil for anesthetic management of awake craniotomy (AC) and assessed its efficacy. METHODS: The patients underwent AC with general anesthesia by propofol (P group, n = 17), or by propofol and remifentanil (PR group, n = 13), and were analyzed retrospectively. We investigated (1) systolic blood pressure (SBP) and heart rate (HR) until first 60 minutes after starting the operation, (2) the time from cessation of anesthetics to awakening for brain mapping, and (3) anesthetic complications. RESULTS: The patients in PR group were infused remifentanil by 0.22 +/- 0.06 microg x kg(-1) x min(-1) and all needed controlled ventilation with laryngeal mask airway. The increase of HR after starting the operation was lower in PR group (P < 0.01). The time to awakening was not significant by defference between them. In anesthetic complications, the incidence of movement during the general anesthesia was more frequent in P group (P < 0.01). Other complications occurred similarly and were controllable. CONCLUSIONS: Remifentanil is effective for anesthetic management of AC. However, respiratory management is necessary.

Characterization of chronic idiopathic thrombocytopenic purpura in Japanese children: a retrospective multi-center study.

The objectives of this study are to clarify (1) the difference in demographic and clinical variables at initial presentation between acute and chronic idiopathic thrombocytopenic purpura (ITP), and (2) the prognostic factors of patients with chronic ITP. We conducted a retrospective analysis of 247 children with newly diagnosed ITP between April 1991 and March 2006 who visited one of the 12 hospitals belonging to the Kyoto University Pediatric Hematologic Study Group. 180 and 67 cases were classified as the acute type and as the chronic type, respectively. Older age, higher initial platelet count, positive medical history or concomitant medical diagnosis, the absence of preceding infection or vaccination, and the absence of an increase in immunoglobulin were risk factors for the chronicity. The prognostic factors in chronic ITP were evaluated in 53 patients after excluding patients receiving splenectomy or having insufficient follow-up data. The overall time required for 50% resolution in patients with chronic ITP was approximately 5.6 years. Age at presentation of less than 3 years and higher platelet counts at the time of chronic ITP diagnosis were good prognostic factors. On the other hand, gender, initial platelet counts, and preceding infection or vaccination were not associated with the prognosis.

[Airway and respiratory management for anesthesia in the patients with severe motor and intellectual disabilities].

BACKGROUND: For the management of general anesthesia in the patients with severe motor and intellectual disabilities, airway and respiratory disorders are severe and may cause fatal events. We retrospectively examined these risk factors. METHODS: We assessed adverse airway and respiratory events associated with anesthesia from perioperative and anesthetic records of these patients retrospectively. RESULTS: Forty-one cases (31 were for fundoplication, and 10 were for gastrostomy or jejunostomy) were involved. On anesthetic introduction, in 9 cases tracheal intubation was difficult (failed in 1 case). These and other 4 cases had developed pharyngeal and laryngeal edema. Manual ventilation by facemask was successful in all cases. During the postoperative period, pneumonia (5 cases), pleural effusion (1 case), and apnea (2 cases) occurred unexpectedly. CONCLUSIONS: Patients with severe motor and intellectual disabilities belong to the group with high risk for general anesthesia.

The dose-dependent effects of isoflurane on outcome from severe forebrain ischemia in the rat.

Isoflurane improves outcome against cerebral ischemia in the rat. However, the optimal neuroprotective concentration has not been defined. We examined the effects of different isoflurane concentrations on outcome from severe forebrain ischemia in the rat. Fasted rats were subjected to 0.5, 1.0, 1.5, 2.0, or 2.5 minimum alveolar concentration (MAC) isoflurane during 10 min bilateral carotid occlusion plus systemic hypotension. Each isoflurane concentration was administered only before ischemia. Arterial blood pressure was not pharmacologically manipulated. After ischemia, the anesthetic regimen was changed to fentanyl/nitrous oxide and maintained for 2 h. Pericranial temperature was maintained normothermic during the experiment. Neuromotor score, % dead hippocampal CA1 neurons, and cortical injury were measured 5 days postischemia. Preischemic arterial blood pressure decreased as MAC was increased. Animals administered >1.0 MAC frequently exhibited postischemic seizures resulting in increased mortality. There was no difference among MAC conditions for % dead CA1 neurons (93 approximately 95%). In the cortex, neuronal necrosis was less severe with 0.5 MAC and 1.0 MAC isoflurane relative to >1.0 MAC values. The neuromotor score in the 1.0 MAC isoflurane group was superior to the 2.5 MAC group. Dose-dependent effects of preischemic administration of isoflurane on histologic and behavioral outcome after severe forebrain ischemia were observed. Isoflurane MAC values <1.5 provided superior overall outcome relative to larger isoflurane concentrations.

Mitochondrial dysfunction is related to necrosis-like programmed cell death induced by A23187 in CEM cells.

We have previously reported that calcium ionophore A23187 differentially induces necrosis in CEM cells, a T-lymphoblastic leukemia cell line, and apoptosis in HL60 cells, a promyelocytic leukemia cell line. Stimulation with VP16, however, induces typical apoptosis in both cell lines. Necrosis in CEM cells, characterized by cell shrinkage and clustering, began within 5 min of treatment. Swelling of the mitochondria, lumpy chromatin condensation and intact plasma membranes were evident by electron microscopy. These A23187-mediated changes in CEM cells were suppressed by clonazepam or CGP37157, inhibitors of the mitochondrial Na(+)/Ca(2+) exchanger. The changes, however, were not affected by cyclosporin A, an inhibitor of the mitochondrial permeability transition pore. In both CEM and HL60 cells, intra-cellular calcium increased with similar amplitude within 1 min of treatment with 2 microM A23187. Intra-mitochondrial calcium increased with clonazepam pre-treatment alone in both CEM and HL60 cells. However, intra-mitochondrial calcium did not change drastically in response to A23187 in CEM or HL60 cells, either untreated or pre-treated with clonazepam. A23187 induces necrosis in CEM cells concurrent with mitochondrial dysfunction, which is independent of the mitochondrial permeability transition, but affected by intra-mitochondrial calcium, while HL60 cells lack these early changes. Differences in the responses to A23187 between these two cell lines might derive from differences in the susceptibility of the mitochondrial membrane to rapid increases in intra-cellular calcium.

Inhibition of leukemic cell growth by a novel anti-cancer drug (GUT-70) from calophyllum brasiliense that acts by induction of apoptosis.

During our search for cancer chemopreventing compounds derived from plant sources, we discovered that the natural product GUT-70, isolated from the stem bark of Calophyllum brasiliense collected in Brazil, significantly inhibits the growth of leukemic cells. GUT-70, characterized as a tricyclic coumarin, 5-methoxy-2,2-dimethyl-6-(2-methyl-1-oxo-2-butenyl) -10-propyl-2H,8H-benzo[1,2-b;3,4-b']dipyran-8-one (C(23)H(26)O(5)), inhibited all 6 human leukemic cell lines evaluated, including the P-glycoprotein overexpressing cell line, in a concentration and time-dependent manner with IC(50) values from 2-5 microM. Furthermore, GUT-70 did not inhibit colony formation by normal hematopoietic progenitors up to 30 microM and also did not inhibit the proliferation of normal human hepatocytes up to 30 microM. GUT-70 activated the caspase 2, 3, 8 and 9, and induced the apoptosis in leukemic cells, which was inhibited by caspase inhibitors. GUT-70 induced anti-leukemic effects independent of the p53-p2l(WAFl/CIP1) pathway and increased the overall expression of p27(KIP1) and p57(KIP2), to stop the cell cycle at the G(1)/S transition. Thus, a novel anti-cancer drug, GUT-70 isolated from the stem bark of C. brasiliense induces caspase-mediated and p53-independent apoptosis to overcome multidrug resistance and may become a potent leukemia therapeutics.

Stem cell factor/c-kit signaling promotes the survival, migration, and capillary tube formation of human umbilical vein endothelial cells.

c-kit receptor tyrosine kinase is a marker of progenitor cells, which differentiate into blood and/or vascular endothelial cells, and has an important role in the amplification/mobilization of progenitor cells. c-kit is expressed in mature endothelial cells, but its role there is unclear. Stem cell factor, a c-kit ligand, dose-dependently promoted survival, migration, and capillary tube formation of human umbilical vein endothelial cells. These effects mimicked those of vascular endothelial growth factor, except that stem cell factor did not sufficiently support proliferation of these cells. After exposing cells to this factor, Akt, Erk1/2, and c-kit were immediately (

A novel mechanism for imatinib mesylate-induced cell death of BCR-ABL-positive human leukemic cells: caspase-independent, necrosis-like programmed cell death mediated by serine protease activity.

Caspase-independent programmed cell death can exhibit either an apoptosis-like or a necrosis-like morphology. The ABL kinase inhibitor, imatinib mesylate, has been reported to induce apoptosis of BCR-ABL-positive cells in a caspase-dependent fashion. We investigated whether caspases alone were the mediators of imatinib mesylate-induced cell death. In contrast to previous reports, we found that a broad caspase inhibitor, zVAD-fmk, failed to prevent the death of imatinib mesylate-treated BCR-ABL-positive human leukemic cells. Moreover, zVAD-fmk-preincubated, imatinib mesylate-treated cells exhibited a necrosis-like morphology characterized by cellular pyknosis, cytoplasmic vacuolization, and the absence of nuclear signs of apoptosis. These cells manifested a loss of the mitochondrial transmembrane potential, indicating the mitochondrial involvement in this caspase-independent necrosis. We excluded the participation of several mitochondrial factors possibly involved in caspase-independent cell death such as apoptosis-inducing factor, endonuclease G, and reactive oxygen species. However, we observed the mitochondrial release of the serine protease Omi/HtrA2 into the cytosol of the cells treated with imatinib mesylate or zVAD-fmk plus imatinib mesylate. Furthermore, serine protease inhibitors prevented the caspase-independent necrosis. Taken together, our results suggest that imatinib mesylate induces a caspase-independent, necrosis-like programmed cell death mediated by the serine protease activity of Omi/HtrA2.