AML multi-gene panel testing: A review and comparison of two gene panels.

BACKGROUND/OBJECTIVE: Risk adapted therapy is standard practice in Acute Myeloid Leukemia (AML). A common diagnostic approach involves focusing on a three gene panel (CEPBA, FLT3, and NPM1). However, a complete representation of prognostic and predictive factors in AML necessitates an expanded series of genes, due to the dynamic interactions present between concurrent mutations. Hence, the current study aims to describe the benefits of an expanded risk profile in an unselected cohort of AML cases. METHODS: The genomes of 11 randomly selected patients with AML were sequenced using next generation sequencing. A narrow three gene panel and broader 50 gene panel were contrasted. RESULTS: The expanded gene panel detected one additional pathogenic mutation in five patients and two pathogenic mutations in two patients, resulting in a change in their risk profile. Only 5/11 (45%) of AML patients demonstrated a pathogenic mutation on the 3 gene profile, however all patients had at least one detectable pathogenic mutation on the broader gene panel. The detection of a concurrent mutation by the expanded gene panel reversed the favorable risk profile for three patients. CONCLUSIONS: Detection of concurrent mutations enables rejection or validation of prognoses associated with NPM1 or CEBPA mutations. DNMT3a and TP53 mutations in AML have a pertinent prognostic and therapeutic value for patients and their addition enhances the current three gene panel. In our small study, the three gene panel changed the prognosis for three patients (3/11, 27%) with the detection of commonly occurring AML mutations.

Demonstration of a 3-dB directional coupler with enhanced robustness to gap variations for silicon wire waveguides.

We demonstrate a robust 3-dB directional coupler which has a narrow silicon wire core and a wide gap. Sensitivity to the gap variation is decreased to one tenth that of a conventional directional coupler. Better spectral stability due to the enhanced robustness to waveguide geometrical fluctuations was experimentally verified.

1 micros tunable delay using para-metric mixing and optical phase conjugation in Si waveguides: comment.

A recent report of 1 micros all-optical delay using silicon convertor elements in the 1550-nm band is analyzed.

Distress and social dysfunction following prostate cancer treatment: a longitudinal cross-cultural comparison of Japanese and American men.

We assessed the impact of bother with urinary and bowel dysfunction on social activities among men in Japan and the United States following primary therapy for localized prostate cancer. In paired longitudinal outcomes studies, we measured general and disease-specific health-related quality of life in 400 Japanese and 427 American men who underwent radical prostatectomy or brachytherapy for localized prostate cancer. Outcomes included the social function domain of the Medical Outcomes Study Short Form-36 and the University of California, Los Angeles Prostate Cancer Index, all of which are scored 0-100. Participants completed the questionnaires before and 1, 12 and 24 months after treatment. Among men who reported any urinary bother, Japanese men had slightly better urinary function than American men (84 vs 77, P<0.01). Before brachytherapy, urinary bother was weakly correlated with social function in both the countries; after brachytherapy, urinary bother was strongly correlated with social function in American but not Japanese men. After brachytherapy, bowel dysfunction had a stronger correlation with social function in American than Japanese men (P<0.05). The bother associated with urinary and bowel dysfunction after surgery or brachytherapy for prostate cancer has a greater impact on social function in American men than in Japanese men.

Sexual function following radical prostatectomy: a prospective longitudinal study of cultural differences between Japanese and American men.

We conducted a cross-cultural comparison of the recovery of sexual function and bother during the first 2 years after radical prostatectomy (RP) between American and Japanese men. A total of 275 Japanese and 283 American men who underwent RP alone were prospectively enrolled into longitudinal cohort studies of health-related quality of life outcomes. Sexual function and bother (distress) were estimated with English and validated Japanese versions of the UCLA Prostate Cancer Index before RP and 1, 2-3, 4-6, 12, 18 and 24 months after RP. Each subject served as his own control. Japanese men reported lower sexual function scores at baseline, even after adjusted for age, prostate-specific antigen (PSA) and comorbidity (38 vs 61, P<0.001). The two groups had similar baseline sexual bother (70 vs 69, P=0.84). Japanese men had a smaller improvement in sexual function (beta=0.8 vs beta=5.3) and bother (beta=0.2 vs beta=2.9) over time than did the American men postoperatively, after adjusting for baseline score, age, baseline PSA and nerve-sparing. American men were more likely than Japanese men to regain their baseline sexual function by 24 months after surgery (hazard ratio (HR)=1.60; 95% confidence interval (CI)=1.06-2.42). In contrast, American men were less likely than Japanese men to return to baseline sexual bother (HR=0.57; 95% CI=0.44-0.75). This study demonstrates that Japanese and American men experience different patterns of recovery of their sexual function and bother after RP. Ethnicity may be a contributing factor.

Mapping of heme-binding domains in soluble guanylyl cyclase beta1 subunit.

Soluble guanylyl cyclase (sGC) is activated upon the interaction of NO with heme in the sGC beta1 subunit. To identify the domains contributing to heme-binding, we constructed a series of deletion mutants of the beta1 subunit, and evaluated their heme-binding capability. Deletion mutants consisting of residues 1-120 [beta1(1-120)] and 80-385 [beta1(80-385)] were the shortest mutants exhibiting heme binding among the C-terminal and N-terminal-truncated mutants, respectively. The region common to both beta1(1-120) and beta1(80-385), i.e., residues 80-120, is therefore essential for heme binding, although the residues 341-385 play an auxiliary role in heme binding. Two deletion mutants, beta1(80-195) and beta1(60-195), which include only the essential region, exhibited strong heme binding and spectral properties similar to those of the nitrosyl complex of native sGC. Thus, these heme-binding core proteins may serve as model proteins for future studies on the tertiary structure of the nitrosyl complex of sGC.

Hypertonicity rescues T cells from suppression by trauma-induced anti-inflammatory mediators.

Trauma causes the release of anti-inflammatory factors thought to cause infections by inhibiting T cells. We have found that hypertonic saline (HS) enhances functions of normal T cells. Here we studied if HS can rescue T cells from suppression by costimulating interleukin (IL)-2 production. Human peripheral blood mononuclear cells were treated with the immunosuppressive factors IL-4, IL-10, transforming growth factor (TGF)-beta(1), and PGE(2) and with serum of trauma patients and stimulated with phytohemagglutinin, and IL-2 production was measured. Costimulation with HS tripled IL-2 production of normal cells. IL-4, IL-10, TGF-beta(1), and PGE(2) suppressed IL-2 production with IC(50) of 500, 1, 36,000, and 0.01 pg/ml, respectively. Costimulation of suppressed cells with HS restored IL-2 production and increased IC(50) values >70-fold. Serum from trauma patients could completely suppress normal cells; however, costimulation with HS restored IL-2 production by up to 80% of the control response. These findings show that HS can restore the function of suppressed T cells, suggesting that HS resuscitation of trauma patients could reduce posttraumatic sepsis.

Three patients with isolated adrenocorticotropin deficiency presenting with neuroleptic malignant syndrome-like symptoms.

We report 3 patients with isolated adrenocorticotropin (ACTH) deficiency presenting with neuroleptic malignant syndrome (NMS)-like symptoms. All patients were in their 60's or 70's and showed consciousness disturbance, a high-grade fever, extrapyramydal signs, and muscle enzyme elevations, which met the criteria for NMS. Also, they all showed hyponatremia induced by isolated ACTH deficiency. In addition to the standard therapy for NMS, corticosteroid supplement therapy was effective in all patients. There thus appear to be subjects with isolated ACTH deficiency among patients presenting with NMS-like symptoms, and adrenal and pituitary function should be checked in NMS patients with hyponatremia.

[Maze procedure for atrial fibrillation associated with aortic valve disease in an elderly patient: report of a case].

The choice of a valve substitute in elderly patients remains controversial. Moreover, the combined use of the maze procedure in elderly patients raises further discussion. We report a case of bioprosthetic aortic valve replacement concomitant with the maze procedure in a 74-year-old man. With symptom of orthopnea and short of breath, he was diagnosed as aortic stenosis and regurgitation with atrial fibrillation. We performed the bioprosthesis aortic valve replacement and the maze procedure in this patient. He was extubated next day and discharged on the fifteenth day after the operation without any complications. Postoperatively he gained a sinus regular rhythm and A wave of transmitral flow was detected by Doppler echocardiography. Now, he enjoys his better quality of life without any drugs including warfarin. Although combined aortic valve replacement and maze procedure are more invasive for elderly patients, these procedures provides better quality of life after the operation.

New antifungal 1,2,4-triazoles with difluoro(substituted sulfonyl)methyl moiety.

New 1,2,4-triazoles (2) having a difluoro(substituted sulfonyl)methyl moiety were designed and synthesized via alpha,alpha-difluoro-alpha-(substituted thio)acetophenones (3). Compounds (2) showed potent antifungal activities against C. albicans, C. krusei, A. flavus and A. fumigatus in vitro and against C. albicans in vivo for oral and i.v. administrations. Especially, (-)-2a, (-)-2b and (-)-2d showed potent antifungal activities.

Hypertonic saline infusion: can it regulate human neutrophil function?

The down-regulation of neutrophil adhesion molecule expression after hemorrhagic shock may reduce neutrophil-mediated organ injury. Hypertonic saline (HS) blocks neutrophil activation, and HS infusion in animals reduces organ injury. In this study, we investigated whether HS infusion in healthy human volunteers can affect neutrophil function. Healthy human volunteers were administered either 4 mL/kg of a 7.5% HS (n = 6) or normal saline (NS, 0.9%; n = 5) over 15 min. Mean arterial pressure (MAP) and plasma sodium levels were measured. Blood samples were obtained before and 1 h after fluid administration. Cells were stimulated with fMLP or left untreated. Neutrophil phagocytosis and expression of CD11b and L-selectin was determined with flow cytometry. HS infusion caused a 7 +/- 2 mM rise in plasma Na+ levels that was sustained at 6 +/- 1 mM for 60 min. MAP was affected only in one subject. HS and NS infusion had little effect on neutrophil phagocytosis. After HS infusion, CD1lb expression of unstimulated neutrophils was 26 +/- 6% lower than before HS infusion, and that of fMLP-stimulated cells was 12 +/- 2% lower compared to pre-infusion values. NS infusion had no significant effects on neutrophil CD11b expression. L-selectin expression of unstimulated cells after HS infusion was 9 +/- 3% higher than in the pre-infusion samples. These data suggest that HS infusion could indeed affect human neutrophils by suppressing CD11b expression. Although modest in healthy subjects, this effect may be more pronounced in trauma patients where reduced neutrophil-endothelial cell interactions might lessen neutrophil-mediated tissue damage.

Acute profound sensorineural hearing loss as the initial manifestation of acute leukemia--report of a case.

This paper reports an unusual case in which acute lymphocytic leukemia presented acute profound sensorineural hearing loss as the initial manifestation of the disease. The patient is a 55-year-old woman who complained of left hearing loss of sudden onset. Pure tone audiometry revealed profound sensorineural hearing loss of the left ear at mid and low frequencies. The patient was tentatively diagnosed as idiopathic sudden deafness and admitted for the treatment, but her laboratory data indicated that she was at an advanced stage of leukemia. The patient's hearing loss did not improve subjectively until she deceased 1 year after the admission. The mechanism producing acute hearing loss in leukemic patients is reviewed and discussed, and the importance of differentiating possible underlying diseases before we diagnose idiopathic sudden deafness is stressed.

alpha,alpha-gem-Difluorination of alpha-(alkylthio)acetophenone derivatives with N-fluoropyridinium salts.

The alpha,alpha-gem-difluorination of 2',4'-difluoro-alpha-(methylthio)acetophenone (1a) with N-fluoropyridinium salts gave 2',4',alpha,alpha-tetrafluoro-alpha-(methylthio)acetophenone (3a). This reaction was accelerated by the addition of zinc chloride, zinc bromide or anhydrous iron(III) chloride, and higher yields than the reaction without additives were obtained. The gem-difluorination reaction using FP-T300 in the presence of zinc bromide was applicable to other alpha-(alkylthio)acetophenone derivatives (1).

Does the timing of hypertonic saline resuscitation affect its potential to prevent lung damage?

Hypertonic saline (HS) resuscitation has been reported to prevent lung damage by suppressing neutrophil activation in animal models. Data on the effectiveness of HS to prevent organ damage in the clinical setting are inconsistent. We investigated whether the timing of HS administration relative to neutrophil activation could affect its potential to block neutrophil responses. Different likely clinical circumstances were simulated in vitro by exposing human neutrophils to HS at different time points before and after activation with N-formyl-methionyl-leucyl-phenylalanine (fMLP). The in vivo effect of using HS as a secondary resuscitation fluid was determined with a mouse model of hemorrhage. BALB/c mice were hemorrhaged (40 +/- 5 mmHg) for 1 h and partially resuscitated with HS or Lactated Ringer's (LR) 20 min before completing resuscitation with LR or HS, respectively. Neutrophil activation parameters were determined 2 h after complete resuscitation and lung damage was assessed after 24 h. The length of exposure to physiologically relevant HS levels (20 mM) determined the suppressive effect on in vitro neutrophil superoxide formation. HS treatment caused a transient state of suppression during which neutrophil activation was suppressed; however, HS was unable to suppress cells that were stimulated with fMLP before HS was added. Accordingly, in vivo lung damage was greater in animals that received HS after they had been partially resuscitated with LR compared to mice that received HS before LR (P < 0.05). We conclude that timing of exposure to HS affects neutrophil responses in vitro and may reduce the potential of HS resuscitation to prevent lung injury in vivo.

[A successful case of hybrid therapy for the left main trunk and triple coronary vessel lesions with acute myocardial infarction and cardiogenic shock].

A 86-year-patient who had acute myocardial infarction and critical cardiogenic shock was diagnosed to have the left main trunk (LMT) and triple vessel disease. Emergent coronary artery bypass grafting to the left anterior descending artery was performed using saphenous vein graft without cardiopulmonary bypass through median sternotomy. On the 41st postoperative day, catheter intervention was performed to the remaining lesions by stenting of LMT and percutaneous transluminal coronary angioplasty to the right coronary artery lesions. Tl scintigraphy showed remarkable reduction of myocardial ischemia. Hybrid therapy is the effective new strategy for critical cases which cannot be successfully and securely treated by medical or surgical approach alone.

Bis-N-nitroso-caged nitric oxides: photochemistry and biological performance test by rat aorta vasorelaxation.

Three new caged nitric oxides (NOs)-BNN3, BNN5Na, and BNN5M were tested for biological use. BNNs have a strong ultraviolet (UV) absorption band (lambda(max): 300 nm, epsilon: 13.5 mM(-1) cm (-1)) extended to 420 nm and produce NO upon irradiation with 300-360 nm light in quantum yields about 2. A photoexcited BNN molecule yields two NOs with time constants of less than 10 ns for phase 1 and less than 20 micros for phase 2 at 37 degrees C, suggesting usefulness of BNNs for measuring in vivo and in vitro fast NO reactions. Upon irradiating with UV light, caged nitric oxides-loaded rat aortic strips maintained in a state of active tonic contraction effectively relaxed ( < 3 microM BNN5M loading solution concentration). BNN3 is incorporated in the lipid membrane. BNN5Na, insoluble in organic solvents but water soluble, localizes in the water phase. BNN5M, is muscle-cell-permeable and hydrolysed to BNN5Na to remain in cytosol. BNNs were thermally stable and demonstrated no observable toxicity.

Hypertonicity regulates the function of human neutrophils by modulating chemoattractant receptor signaling and activating mitogen-activated protein kinase p38.

Excessive neutrophil activation causes posttraumatic complications, which may be reduced with hypertonic saline (HS) resuscitation. We tested if this is because of modulated neutrophil function by HS. Clinically relevant hypertonicity (10-25 mM) suppressed degranulation and superoxide formation in response to fMLP and blocked the activation of the mitogen activated protein kinases (MAPK) ERK1/2 and p38, but did not affect Ca2+ mobilization. HS did not suppress oxidative burst in response to phorbol myristate acetate (PMA). This indicates that HS suppresses neutrophil function by intercepting signal pathways upstream of or apart from PKC. HS activated p38 by itself and enhanced degranulation in response to PKC activation. This enhancement was reduced by inhibition of p38 with SB203580, suggesting that p38 up-regulation participates in HS-induced enhancements of degranulation. HS had similar effects on the degranulation of cells that were previously stimulated with fMLP, but had no effect on its own, suggesting that HS enhancement of degranulation requires another signal. We conclude that depending on other stimuli, HS can suppress neutrophil activation by intercepting multiple receptor signals or augment degranulation by enhancing p38 signaling. In patients HS resuscitation may reduce posttraumatic complications by preventing neutrophil activation via chemotactic factors released during reperfusion.

[Retrovesical leiomyosarcoma responsive to preoperative chemoradiotherapy: a case report].

A 70-year-old man with dysuria was referred to our hospital. Computed tomography scan and magnetic resonance imaging demonstrated a large solid tumor in the retrovesical space. Transurethral needle biopsy revealed leiomyosarcoma. Since the size of the tumor decreased markedly by intraarterial chemotherapy with cisplatin, methotrexate and pirarubicin, in combination with radiotherapy (40 Gy), surgical extirpation of the tumor was performed. Neither infiltration to the adjacent organs or lymph node metastasis was recognized. The patient had been free of recurrence for 12 months after operation.

Self-switching of optical pulses in dispersion-imbalanced nonlinear loop mirrors.

We report a novel nonlinear filter that transmits and shortens incident pulses while rejecting cw background as well as resonant continuum. A relative extinction of 22dB is reported for the cw background.

[A case report of pseudo-false aneurysm of the left ventricle perforated into the right ventricle].

A 60-year-old diabetic women with acute inferior myocardial infarction was admitted to our hospital. An echocardiogram suggested a left ventricular false aneurysm. A left ventricular cineangiogram showed the communication between the left ventricle and the right ventricle through a false aneurysm. At operation one week after the infarction, the pericardial space was free from adhesions. A pseudo-false aneurysm communicating to both ventricle was revealed. The defects were closed with patches and pledgetted mattress sutures. The pseudo-false aneurysm was obliterated with pledgetted mattress and running sutures. The postoperative course was uneventful and the patient was discharged without complication. We emphasize the importance of preoperative morphological and hemodynamic evaluation using a left ventricular cineangiogram in the case of post-myocardial infarction ventricular septal perforation.