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Computational Fluid Dynamics (CFD) is becoming more and more popular in various fields of engineering due to improvement of turbulence model and availability of high performance computing system. In bluff body and bridge aerodynamics fields CFD is applied to predict the aerodynamic response for reconfirming experimental results and revealing the flow mechanism. Accurate prediction of response largely depends on the accurate generation of grid system having converged solution. However, conventional grid convergence test takes much time to obtain the desired grid system. It becomes even worse for a beginner or user having lack of experience. In this paper, a strategy was proposed and demonstrated for faster generation of accurate and converged grid system for two-dimensional bluff bodies. First, the strategy was proposed and demonstrated by conducting simulation for a square rectangular cylinder at Reynolds number ( R ) of 1.22 × 10. An equation was derived to initialize the first grid height ( y) and a Growth Factor (GF) was recommended to expand the grid away from the target body to obtain a grid system having converged solution. The strategy was checked and examined by conducting standard grid convergence test and by comparing solution of various aerodynamic parameters with past experimental works. Finally, the strategy was applied for an elongated rectangular cylinder and for a streamlined bridge deck for further checking the performance of the strategy and found to be efficient enough for faster and quick generation of accurate and converged grid system. [ABSTRACT FROM AUTHOR]

Somatic mutations in the gene encoding the catalytic subunit of protein phosphatase 6 (Ppp6c) have been identified in malignant melanoma and are thought to function as a driver in B-raf- or N-ras-driven tumorigenesis. To assess the role of Ppp6c in carcinogenesis, we generated skin keratinocyte-specific Ppp6c conditional knockout mice and performed two-stage skin carcinogenesis analysis. Ppp6c deficiency induced papilloma formation with 7,12-dimethylbenz (a) anthracene (DMBA) only, and development of those papillomas was significantly accelerated compared with that seen following DMBA/TPA (12-O-tetradecanoylphorbol 13-acetate) treatment of wild-type mice. NF-κB activation either by tumor necrosis factor (TNF)-α or interleukin (IL)-1β was enhanced in Ppp6c-deficient keratinocytes. Overall, we conclude that Ppp6c deficiency predisposes mice to skin carcinogenesis initiated by DMBA. This is the first report showing that such deficiency promotes tumor formation in mice. [ABSTRACT FROM AUTHOR]

A stable packaging cell line (Vero/BC-F) constitutively expressing fusion (F) protein of the human parainfluenza virus type 2 (hPIV2) was established for production of the F-defective and single round-infectious hPIV2 vector in a strategy for recombinant vaccine development. The F gene expression has not evoked cytostatic or cytotoxic effects on the Vero/BC-F cells and the F protein was physiologically active to induce syncytial formation with giant polykaryocytes when transfected with a plasmid expressing hPIV2 hemagglutinin-neuraminidase (HN). Transduction of the F-defective replicon RNA into the Vero/BC-F cells led to the release of the infectious particles that packaged the replicon RNA (named as hPIV2ΔF) without detectable mutations, limiting the infectivity to a single round. The maximal titer of the hPIV2ΔF was 6.0 × 108 median tissue culture infections dose per ml. The influenza A virus M2 gene was inserted into hPIV2ΔF, and the M2 protein was found to be highly expressed in a human lung cancer cell line after transduction. Furthermore, in vivo airway infection experiments revealed that the hPIV2ΔF was capable of delivering transgenes to hamster tracheal cells. Thus, non-transmissible or single round-infectious hPIV2 vector will be potentially applicable to human gene therapy or recombinant vaccine development. [ABSTRACT FROM AUTHOR]

Background:This dose-finding study evaluated lenvatinib, an oral multitargeted receptor tyrosine kinase inhibitor, in combination with carboplatin/paclitaxel in chemotherapy-naïve non-small-cell lung cancer (NSCLC) patients.Patients and Methods:Patients received lenvatinib twice daily (BID) with carboplatin (area under the curve 6 mg ml−1 min−1, day 1)/paclitaxel (200 mg m−2, day 1) every 3 weeks. The initial dose of lenvatinib was 6 mg BID. The primary end point was maximum tolerated dose (MTD) of lenvatinib. At the MTD, the cohort was expanded by 16 patients. Safety, pharmacokinetics, pharmacodynamics, and antitumor effects were evaluated.Results:Twenty-eight patients were treated. At 6 mg BID, dose-limiting toxicities (DLTs) included febrile neutropenia/gingival infection (n=2). No DLTs occurred with 4 mg BID, the recommended MTD for the expansion. Common grade 3/4 toxicities included neutropenia, leukopenia, hypertension, and thrombocytopenia. The combination had no significant impact on individual drug pharmacokinetics. Response rate and median progression-free survival were 68% and 9.0 months, respectively, with 4 mg BID. In the plasma biomarker analysis, stromal cell-derived factor 1α, stem cell factor, and granulocyte colony-stimulating factor correlated with antitumor activity.Conclusion:The MTD for lenvatinib with carboplatin/paclitaxel is 4 mg BID in advanced NSCLC patients. This regimen demonstrated manageable tolerability and encouraging antitumor activity. [ABSTRACT FROM AUTHOR]

A letter to the editor commenting on a study related to expansion of natural killer (NK) cells from cord blood with antileukemic activity using GMP-compliant substances without feeder cells is presented.

As the safety of folinic acid administration and its efficacy for reducing the toxicity of MTX remain controversial, we assessed the effect of folinic acid administration after MTX treatment for GVHD prophylaxis on the incidence of oral mucositis and acute GVHD. We retrospectively analyzed data for 118 patients who had undergone allogeneic hematopoietic SCT and had received MTX for GVHD prophylaxis. Multivariate analysis showed that systemic folinic acid administration significantly reduced the incidence of severe oral mucositis (odds ratio (OR)=0.13, 95% confidence interval (CI) 0.04-0.73, P=0.014). There was also a tendency for a lower incidence of severe oral mucositis in patients who received folinic acid mouthwash (OR=0.39, 95%CI 0.15-1.00, P=0.051). No significant difference was observed in the incidence of acute GVHD between patients who received systemic folinic acid administration and those who did not (P=0.88). Systemic folinic acid administration and mouthwash appear to be useful for reducing the incidence of severe oral mucositis in patients who have received allogeneic hematopoietic SCT using MTX as GVHD prophylaxis. [ABSTRACT FROM AUTHOR]

Background: Currently, no effective treatments exist for non-small cell lung cancer (NSCLC) after failure of gefitinib therapy. Pre-clinical studies have demonstrated that gefitinib-resistant NSCLC cells are more sensitive to irinotecan than parental cells, and that combined administration of irinotecan and gefitinib has a synergistic additive effect. We conducted a phase I study to evaluate the combination of irinotecan and gefitinib as a therapeutic option for NSCLC patients with progressive disease (PD) after initial gefitinib treatment.Methods: Eligibility criteria included histologically confirmed NSCLC, age range of 20-74 years, refractory to or relapsed after gefitinib treatment, one or more previous chemotherapy regimens, Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and informed consent. Patients were treated with irinotecan on days 1 and 15, and treated daily with gefitinib from day 2 every 4 weeks. The treatment was continued until disease progression. The gefitinib dose was fixed at 250 mg. Irinotecan dosing started at 50 mg m(-2) and was escalated in patients by 25 mg m(-2) increments up to a maximum dose of 150 mg m(-2).Results: Twenty-seven patients were enrolled: male/female=14/13; median age=60 (45-75); histology, adenocarcinoma/non-adenocarcinoma=25/2; performance status 0-1/2=19/8; previous response to gefitinib, partial response/stable disease/PD=21/2/4. Dose-limiting toxicities were observed in 2 patients at level 3. Maximum tolerated dose was not determined, and the full dose of irinotecan could be combined with the full dose of gefitinib. The disease control rate (DCR) and response rate (RR) were 69.2 and 26.9%, respectively. For 12 patients at level 5 (the recommended phase II dose), the DCR and RR were 75.0% and 41.7%, respectively. The median treatment cycles were 4; median time to treatment failure, 57 days (95% confidence interval (CI), 32-82 days); median overall survival, 244 days (95% CI, 185-303 days); and 1-year survival rate, 32.6%.Conclusion: The combination of irinotecan and gefitinib was well tolerated and potentially beneficial for NSCLC patients failing initial gefitinib monotherapy. [ABSTRACT FROM AUTHOR]

Background: To assess the efficacy and safety of S-1 and cisplatin with concurrent thoracic radiation for unresectable stage III non-small-cell lung cancer (NSCLC).Methods: Eligible patients were 20-74 years old and had histologically or cytologically confirmed NSCLC, a performance status of 0-1, and no prior chemotherapy. Patients were treated with cisplatin (60 mg m(-2) on day 1) and S-1 (orally at 40 mg m(-2) per dose, b.i.d., on days 1-14), with the treatment repeated every 4 weeks for four cycles. Beginning on day 2, a 60-Gy thoracic radiation dose was delivered in 30 fractions.Results: Of 50 patients, 48 were eligible. Partial response was observed in 42 patients (87.5%; 95% CI: 79.1-96.9%). This regimen was well tolerated. Common toxicities included grade 3/4 neutropenia (32%), grade 3/4 leukopenia (32%), grade 3/4 thrombocytopenia (4%), grade 3 febrile neutropenia (6%), grade 3 oesophagitis (10%), and grade 3 pneumonitis (5%). Median progression-free survival was 12.0 months and median overall survival was 33.1 months. The 1- and 2-year survival rates were 89.5 and 56%, respectively.Conclusion: This chemotherapy regimen with concomitant radiotherapy is a promising treatment for locally advanced NSCLC because of its high response rates, good survival rates, and mild toxicities. [ABSTRACT FROM AUTHOR]

Safety and efficacy of intrapericardial (i.p.c.) instillation of bleomycin (BLM) following pericardial drainage in patients with malignant pericardial effusion (MPE) remain unclear. Patients with pathologically documented lung cancer, who had undergone pericardial drainage for MPE within 72 h of enrolment, were randomised to either arm A (observation alone after drainage) or arm B (i.p.c. BLM at 15 mg, followed by additional i.p.c. BLM 10 mg every 48 h). The drainage tube was removed when daily drainage was 20 ml or less. The primary end point was survival with MPE control (effusion failure-free survival, EFFS) at 2 months. Eighty patients were enrolled, and 79 were eligible. Effusion failure-free survival at 2 months was 29% in arm A and 46% in arm B (one-sided P=0.086 by Fisher's exact test). Arm B tended to favour EFFS, with a hazard ratio of 0.64 (95% confidence interval: 0.40-1.03, one-sided P=0.030 by log-rank test). No significant differences in the acute toxicities or complications were observed. The median survival was 79 days and 119 days in arm A and arm B, respectively. This medium-sized trial failed to show statistical significance in the primary end point. Although ipc BLM appeared safe and effective in the management of MPE, the therapeutic advantage seems modest. [ABSTRACT FROM AUTHOR]

Gefitinib, an inhibitor of the epidermal growth factor receptor (EGFR, HER1/ErbB1) tyrosine kinase, has been shown to have clinical activity against non-small-cell lung cancers (NSCLCs), especially in women nonsmokers with adenocarcinomas. The aim of the present study was to clarify the relationship between androgen levels and gefitinib treatment in patients with advanced NSCLCs. Sera from 67 cases (36 men and 31 women) were obtained pretreatment and during treatment with gefitinib monotherapy (days 14-18) for examination of testosterone, dehydroepiandrosterone sulphate (DHEA), and dehydroepiandrosterone sulphate (DHEAS) levels. Testosterone and DHEA during treatment were significantly lower than the pretreatment values in both women and men, and the DHEAS levels during treatment were also significantly lowered in women. Gefitinib treatment significantly suppressed androgen levels, especially in women who had no smoking history. In addition, hormone levels in women responding to gefitinib were significantly lower during the treatment than in women who did not respond. Gefitinib-associated decrease in serum androgen levels may play a role in its clinical efficacy.British Journal of Cancer (2005) 92, 1877-1880. doi:10.1038/sj.bjc.6602585 www.bjcancer.com Published online 3 May 2005 [ABSTRACT FROM AUTHOR]

Summary:We mobilized peripheral blood stem cells (PBSC) following CHOP plus rituximab (CHOP-R) therapy, and compared with the findings following CHOP therapy without rituximab. All patients were given G-CSF starting from day 11 after CHOP therapy. Patients in the CHOP-R group (n=8) were given rituximab on day 12. Target CD34+ cells number was collected in a single leukapheresis on day 14, from all the eight patients in the CHOP-R group. PBSC mobilization kinetics, CD34+ cells yield and colony-forming ability in the graft collection, toxicity during mobilization, and engraftment after transplantation of CHOP-R group were not significantly different from those in the CHOP group (n=8). In all patients given CHOP-R therapy, CD20+ cells and immunoglobulin heavy chain (IgH) rearrangement in the graft collection were undetectable by flow-cytometric analysis and Southern blot analysis, respectively, but with PCR analysis two of eight grafts were positive for IgH rearrangement. While further studies are needed to evaluate the efficacy of purging and the outcome of patients undergoing autologous transplantation, CHOP-R therapy can be safely and effectively used in the mobilization phase of PBSC collection, without excess clinical toxicity or deleterious effect on PBSC mobilization kinetics or engraftment time.Bone Marrow Transplantation (2004) 33, 703-707. doi:10.1038/sj.bmt.1704413 Published online 26 January 2004 [ABSTRACT FROM AUTHOR]

The optical technology based on Mach-Zehnder interferometry was successfully applied to a high-pressure liquid CO[sub 2] and water system to measure CO[sub 2] solution density. Experiments were carried out at a pressure range of from 5.0 to 12.5 MPa, temperatures from 273.25 to 284.15 K, and CO[sub 2] mass fraction in solution up to 0.061. CO[sub 2] solution density data were obtained from two sets of experiments. These data were calculated through the fringe shifts induced by density changes inside of the high-pressure vessel, which were directly recorded during the experiments, and a modified version of Lorentz-Lorenz formulation. The experimental results indicated that the density ratio of CO[sub 2] solution to that of pure water at the same pressure and temperature is monotonically linear with the CO[sub 2] concentration in the solution. The slope of this linear function, calculated by the experimental data fitting, is 0.275. [ABSTRACT FROM AUTHOR]

Marangoni convection, driven by interracial instability due to a surface tension gradient, presents a significant problem in the crystal growth process. To achieve better materials processing, it is necessary to suppress and control this convection, especially in crystal growth using Liquid Encapsulated Czochralski techniques in which the melt is encapsulated in an immiscible medium. Marangoni convection can occur at the liquid-liquid interface and at the gas-liquid free surface. Buoyancy driven convection can also affect and complicate the flow. The present report studied Marangoni convection in a two-liquid layer system in an open and enclosed cavity. Flow in the cavity was subjected to a horizontal temperature gradient. Interactive flow near the liquid-liquid interface was measured by the Particle Image Velocimetry (PIV) technique. The measured flow field is in good agreement with numerical predictions. [ABSTRACT FROM AUTHOR]

The inner structure of a two-phase plume, driven by air bubble buoyancy and formed in a stratification ambient fluid in a rectangular tank, is numerically simulated by means of two-phase flow theory and Large-eddy simulation technology. Focusing on the discrete nature of the buoyant dispersed phase and on the role of momentum exchange between two phases during plume formation, we investigated the phenomena of mass "entraining-in" and "peeling-out" that occurs inside the stratified ambient plume. These phenomena are thought to result from an intricate interplay among phase interaction, static stability of the stratification ambient fluid itself, and dynamic stability due to turbulence. Numerical simulations show that there exists an inner-out structure of the stratified ambient plume, while at the same time predicting that the re-entraining-in mass flux is on the same order of magnitude as that of the inner peeling-out mass flux within the annular region centered around the plume. This further explains the mechanism underlying the formation of multi-scale eddies at the edge of the air bubble plume, which also constitutes the boundary between the inner and outer zones of this inner-out stratified fluid plume. Within the inner part of the plume, the mass entraining-in and peeling-out appeared as a spatial discontinuity. The numerically visualized three-dimensional density fields are consistent with the two-phase plume characteristics. [ABSTRACT FROM AUTHOR]

Examines the visualization of flow structure pattern using particle tracers. Expansion and entrainment of the annual air flow; Details on the melting of solid paraffin conducted in a melting cavity; Application of ultrasonic vibrations for thermal oscillation.

Hepatitis B virus (HBV) reactivation, a well-known complication in immunosuppressed patients, can give rise to acute hepatitis and even fatal fulminant hepatitis. Three Japanese males with non-Hodgkin’s lymphoma (NHL) who were carriers of HBV received high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (PBSCT). To prevent HBV reactivation, all received oral lamivudine (150 mg/day), a nucleoside analogue, at the start of chemotherapy. All were treated at full-dose intensity, including corticosteroids, without modification of treatment regimens. All three patients completed the total course of chemotherapy and PBSCT, with no signs of HBV reactivation. Peripheral blood stem cell (PBSC) harvests and hematological recoveries after transplantation were not affected by lamivudine, which was continued for at least 16 weeks after transplantation. HBV-DNA and DNA polymerase levels remained negative/normal after discontinuation of lamivudine. Lamivudine effectively inhibits HBV replication and has few serious adverse effects, particularly those related to hematopoiesis. Thus, prophylactic use of lamivudine from initiation of chemotherapy deserves consideration in the treatment of HBV carriers who require immunosuppressive chemotherapy, and may prevent HBV reactivation. Bone Marrow Transplantation (2001) 27, 433–436. [ABSTRACT FROM AUTHOR]

Isolation of large numbers of human peripberal blood CD34[sup+] cells could lead to therapeutic applications, including purging of malignant cells from blood cell transplantations, purging of T cells from allogeneic bone marrow, and even blood cell transplantation. This procedure has limitations if there are not sufficient numbers of progenitor cells in the leukapheresis concentrates available for selection after detection of tumor cells in apheresis products. Use of frozen/thawed peripheral blood mononuclear cell (PBMC) samples would make feasible pooling of two or even more stem cell harvests collected at different time points and the total number of CD34[sup+] progenitor cells available would increase. We established an efficient method for purification of CD34[sup+] cells from cryopreserved apheresis products, using a nylon-fiber syringe system and immunomagnetic microspheres. We compared purity, recovery rate and clonogenicity of CD34[sup+] cells purified from fresh (n = 22) and cryopreserved apheresis products (n=14), using a nylon-fiber syringe system and immunomagnetic microspheres. The purity of CD34[sup+] cells from cryopreserved products was less than that from fresh products (85.9 ± 14.4% vs 94.6 ± 10.0%), but the recovery rate of CD34[sup+] cells and colony-forming cells was comparable between fresh and cryopreserved products. One patient underwent grafting with peripheral blood CD34[sup-] cells selected after freezing, with good success. Therefore, these cells are capable of rapidly reconstituting hematopoiesis after high-dose chemotherapy. [ABSTRACT FROM AUTHOR]

Localized cutaneous nontender nodules appeared on the back of a 52-year-old Japanese woman. Skin biopsy revealed atypical large T-lymphocytes infiltrating the dermis. CD30 staining was negative in tumor cells. The diagnosis was CD30-negative cutaneous large T cell lymphoma. There was no evidence of peripheral lymphadenopathy or bone marrow involvement. Six cycles of induction chemotherapy were administered and a complete clinical remission (CCR) was attained. Local irradiation was not given. As the clinical course of CD30-negative cutaneous large T cell lymphoma is recurrent and often incurable with conventional chemoradiotherapy, she received high-dose chemotherapy without total body irradiation (TBI) followed by unpurged autologous peripheral blood stem cell transplantation (APBSCT). A relapse in the skin followed 40 days after APBSCT, but tumor cells transformed into a CD30-positive anaplastic large cell lymphoma (ALCL). We question the need for TBI in conditioning and for purged stem cells for APBSCT in patients with high risk cutaneous lymphomas. [ABSTRACT FROM AUTHOR]

We studied the relationship between portal pressure and colorectal mucosal vascular lesions in cirrhotics and the effectiveness of drug therapy in treating these lesions. Colonoscopy and hepatic venous pressure gradient (HVPG) studies were performed in 21 cirrhotics. Oral spironolactone plus transdermal nitroglycerin were given to patients who had diffuse mucosal cherry-red spots and/or rectal varices. The colonoscopy and HVPG determinations were repeated after four weeks. Colonoscopic findings included vascular ectasias in 13 patients (62%), diffuse cherry-red spots in the rectum in five patients (24%), and rectal varices in eight patients (38%). Overall, colorectal mucosal vascular lesions were found in 16 cirrhotics (76%). These findings were not found in 21 age- and sex-matched noncirrhotic controls. Vascular ectasias appeared without relationship to the HVPG. Patients with diffuse cherry-red spots (N = 5, 22.4+/-3.4 mm Hg) had a significantly higher HVPG than those without (N = 16, 16.6+/-3.3 mm Hg, P < 0.01). However, no significant difference was found in HVPG between patients with rectal varices (N = 8, 19.4+/-4.6 mm Hg) and patients without rectal varices (N = 13, 17.2+/-3.8 mm Hg). After four weeks of drug therapy, diffuse cherry-red spots became less obvious when the HVPG decreased more than 20%. Rectal varices did not change their appearance with HVPG reduction. We found that colorectal vascular lesions are common in cirrhotics. Diffuse cherry-red spots are probably dependent on elevated portal pressure, but vascular ectasias and rectal varices are not related to the degree of portal pressure. Chronic drug therapy with reduction of portal pressure improves colonoscopic findings such as diffuse cherry-red spots. [ABSTRACT FROM AUTHOR]

The article discusses the presence of aluminum in various canned and bottled beverages which researchers considered as neurotoxins. With numerous researches conducted in animals and humans, researchers had associated aluminum with neurocognitive dysfunction and which in worst cases would lead to death. Although, evidences linking aluminum intake and Alzheimer's Disease are still unclear, still some experts imposed strict warning on the exposure of human to aluminum. The common sources of aluminum include air, antacids, antiperspirants, cosmetics and dental preparations, food additives and more. Another source of aluminum is canned drinks which are positive in their aluminum content.

We studied the hemodynamic changes following a four-week administration of either low-dose transdermal nitroglycerin (a constant release of 5 mg of nitroglycerin/day) (N = 10) or low-dose transdermal nitroglycerin plus spironolactone (100 mg/day) (N = 9) in patients with cirrhosis and portal hypertension. Two patients in the latter group did not undergo repeat measurements after dropping out because of severe headaches or developing ascites during the study. Transdermal nitroglycerin induced a significant reduction in the hepatic venous pressure gradient (HVPG) (-11.7 +/- 14.9%, P < 0.05), which was associated with a significant reduction of cardiac output (-10.5 +/- 7.3%). Nitroglycerin plus spironolactone induced a significant reduction in the HVPG (-18.3 +/- 16.0%, P < 0.05) associated with a significant reduction of cardiac output (-13.8 +/- 5.6%), right atrial pressure (-35.0 +/- 30.0%), mean arterial pressure (-7.5 +/- 6.8%), and plasma volume (-10.2 +/- 7.0%). The difference of the mean HVPG reduction between the groups was insignificant. A decrease in the HVPG greater than 10% was observed in six of 10 patients (60%) and in five of seven patients (71.4%), defined as "responders," at four weeks. The difference in percentage of responders between the groups was insignificant. We found that in some cirrhotic patients, low-dose transdermal nitroglycerin is potentially useful in the treatment of portal hypertension. Spironolactone as an adjunct to low dose transdermal nitroglycerin did not demonstrate therapeutic advantages in the treatment of portal hypertension in cirrhotics. That there were nonresponders indicates that there are variable responses in splanchnic hemodynamics to these drugs. [ABSTRACT FROM AUTHOR]

Cachexia frequently occurs in the late stages of cancer, and is difficult to manage. We previously reported that interleukin-6 (IL-6) cDNA transfection into Lewis lung carcinoma (LLC-IL6) induced cachexia-like symptoms in C57BL/6 mice. This was thought to be a useful experimental model of cancer cachexia. We have examined the effects of two eicosanoids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), in order to evaluate whether they could relieve cachexia. LLC-IL6-bearing animals were divided into three treatment groups receiving DHA, EPA or water as the control; 80-μl samples of these compounds (purity>95%) were administered orally by catheter daily starting 7 days after tumor transplantation. Tumor growth curves were similar in the three groups. There were no differences in water or food intake in the three groups. However, body weight, a marker of cachexia, was significantly higher in treated mice than in the control group. Sixteen days after tumor transplantation, the mean body weight was 17.45 g ( P<0.05), 17.2 g and 16.41 g in the groups receiving DHA, EPA and water respectively. The eicosanoids did not affect serum levels of IL-6. Ubiquitination of muscle protein, a marker of proteolysis coupled to cachexia, was compared in LLC-IL6-and LLC-transplanted mice. The eicosanoids prevented the ubiquitination of approximately 180 kDa protein. These results suggest that eicosanoids may prevent the cachexia mediated by IL-6. [ABSTRACT FROM AUTHOR]

The early phases of three flares, observed by the Nobeyama Radio Heliograph, are studied. Nonthermal and thermal radio sources are identified by comparison with soft X-ray images taken by the Soft X-ray Telescope onboard the Yohkoh satellite. Two of the flares are mainly of nonthermal origin and their location coincides with one of the footpoints of soft X-ray loops. Another flare has both thermal and nonthermal components which start to brighten simultaneously. This suggests that particle acceleration and plasma compression develop simultaneously. [ABSTRACT FROM AUTHOR]

The Yohkoh solar X-ray observatory carries two telescopes that require coalignment at a level better than the minimum pixel size of 2_45″. This coalignment is needed both internally within Yohkoh and for many scientific applications involving data from ground-based radio and optical observatories. We describe the methods successfully developed for this purpose and now incorporated in the Yohkoh software. Soft X-ray observations of the 1993 transit of Mercury across the solar disk provided key information for the calibration of the coalignment procedures. [ABSTRACT FROM AUTHOR]

The nucleotide sequences of the NP and M genes of human parainfluenza type 1 virus (HPIV-1) were determined. The NP gene was 1677 nucleotides long excluding polyadenylic acid. The NP gene contained a single large open reading frame (ORF), which encoded a polypeptide of 524 amino acids with a calculated molecular weight of 57,736. The M gene 1173 nucleotides long excluding the poly(A) tract and the sequence also contained a single large ORF which encoded a polypeptide of 348 amino acid with a molecular weight of 38,445, which was inconsistent with 28 kDa previously determined by SDS-PAGE. We aligned the deduced HPIV-1 NP and M protein sequences with 12 and 13 other paramyxoviruses, respectively, suggesting that a common tertiary structure was found in the NPs or Ms of HPIV-1, Sendai virus (SV), HPIV-3 and BPIV-3 and that other common structure was also maintained in these proteins of HPIV-2, SV 41 and 5, MuV, HPIV-4. Phylogenetic trees were constructed for the NP and M proteins of all the paramyxoviruses of which nucleotide sequences had been previously reported. Paramyxoviruses could be subdivided into two groups, i.e., PIV-1 group and PIV-2 group; the former group is composed of HPIV-1, SV, HPIV-3 and BPIV-3, and the latter group consists of HPIV-2, SV 41, SV 5, MuV, HPIV-4 A and HPIV-4 B. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented concerning the role of vascular endothelial growth factor in the pathophysiology of POEMS syndrome.

A 30-year-old Japanese woman who underwent nonmyeloablative stem cell transplantation from her HLA-matched sister developed autoimmune hemolytic anemia (AIHA). There was proliferation of EBV-DNA in her peripheral blood and monoclonal gammopathy, both predictive factors of post-transplant lymphoproliferative disorder (PTLD). As conventional immunosuppressive therapy for AIHA could lead to overt PTLD, we decided to give her rituximab 375 mg/m2 once weekly for a total of four doses. After this therapy, both her AIHA and monoclonal gammopathy were resolved and EBV-DNA became undetectable. Rituximab therapy deserves consideration for treatment of post-allogeneic stem cell transplant patients with AIHA, especially for patients who cannot be given immunosuppressive therapy. [ABSTRACT FROM AUTHOR]

A 30-year-old Japanese woman weighing 35 kg with severe hemochromatosis due to multiple transfusions was referred to our clinic for treatment of severe aplastic anemia (SAA). The patient had heart failure with an ejection fraction of 36% requiring diuretics and a severe liver dysfunction with an indocyanine green clearance rate of 18%, as well as other transfusion-related complications such as chronic hepatitis due to hepatitis C virus and diabetes mellitus. She was treated with a non-myeloablative preparative regimen that included fludarabine monophosphate (Flu, 120 mg/m2), cyclophosphamide (CY, 1200 mg/m2) and antithymocyte globulin (ATG, 15 mg/kg) followed by allogeneic peripheral blood stem cell transplantation (PBSCT) from her HLA-matched sister. The regimen was well tolerated, and engraftment rapidly occurred without any therapy-related complications. Chimerism analysis on day 14 after transplant showed reconstitution with 100% donor cells. She no longer needed transfusion after day 23 and has been well in 90% Karnofsky status at 4 months post transplant. The clinical course of this patient indicates that this preparative regimen enables SAA patients with severe organ failure to safely undergo allogeneic stem cell transplantation. Bone Marrow Transplantation (2001) 28, 783–785. [ABSTRACT FROM AUTHOR]

Generalized multiple cutaneous tumors developed in a 60-year-old Japanese man. Skin biopsy revealed atypical large T lymphocytes infiltrating the dermis. CD30 staining was negative in the tumor cells. The diagnosis of CD30-negative cutaneous large T cell lymphoma was made. Axial and inguinal lymphadenopathy was present, but there was no evidence of bone marrow involvement. Seven cycles of chemotherapy and local electron beam irradiation were administered and complete remission (CR) was attained. As CD30-negative cutaneous large T cell lymphoma has a poor prognosis despite intensive chemotherapy, high-dose chemotherapy followed by CD34+-selected autologous peripheral blood stem cell transplantation (CD34+-APBSCT) was prescribed. The clinical course after CD34+-selected APBSCT was complicated with CMV infection occurring twice but administration of ganciclovir resolved the symptoms. He has remained in CR for 16 months after CD34+-APBSCT. This appears to be the first case report of CD34+-APBSCT in a patient with CD30-negative cutaneous large T cell lymphoma. Bone Marrow Transplantation (2000) 25, 1315–1317. [ABSTRACT FROM AUTHOR]

Describes the clinical features in a young man with subcutaneous panniculitic T cell lymphoma (SPTCL) originating on the right cheek, which transformed into leukemia at the time of the first relapse. Treatment given; Findings from physical and blood examinations; Conclusion concerning the therapy for patients with SPTCL.

A 20-year-old Japanese man developed generalized, subcutaneous, painless nodules, fever, abnormal liver function, serosal effusions, hepatosplenomegaly, lymphadenopathy and anemia. Skin biopsies revealed lobular panniculitis with a morphologically benign histiocytic infiltration and prominent phagocytosis. Atypical T lymphocytes were also present in the skin and liver. The diagnosis given was aggressive cytophagic histiocytic panniculitis (CHP) or aggressive subcutaneous panniculitic T cell lymphoma (SPTCL). He received cyclophosphamide, doxorubicin, and vincristine on day 1, prednisolone on days 1–5, and etoposide on days 1, 3 and 5 (CHOP-E), with the support of granulocyte colony-stimulating factor. This regimen was repeated every 2 weeks and complete clinical remission (CCR) was attained after three cycles of CHOP-E. As the clinical course of aggressive CHP is recurrent and often fatal, he was given high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (APBSCT), after five cycles of CHOP-E. He has remained in CCR for 12 months after APBSCT. High-dose chemotherapy followed by APBSCT is considered to be one of the most beneficial therapies for patients with aggressive CHP and aggressive phase SPTCL. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor referencing an article about reversal of HIV-associated motor neuron syndrome after highly active antiretroviral therapy.

Brigatinib-based therapy was effective against osimertinib-resistant EGFR C797S mutants and is undergoing clinical studies. However, tumor relapse suggests additional resistance mutations might emerge. Here, we first demonstrated the binding mode of brigatinib to the EGFR-T790M/C797S mutant by crystal structure analysis and predicted brigatinib-resistant mutations through a cell-based assay including N-ethyl-N-nitrosourea (ENU) mutagenesis. We found that clinically reported L718 and G796 compound mutations appeared, consistent with their proximity to the binding site of brigatinib, and brigatinib-resistant quadruple mutants such as EGFR-activating mutation/T790M/C797S/L718M were resistant to all the clinically available EGFR-TKIs. BI-4020, a fourth-generation EGFR inhibitor with a macrocyclic structure, overcomes the quadruple and major EGFR-activating mutants but not the minor mutants, such as L747P or S768I. Molecular dynamics simulation revealed the binding mode and affinity between BI-4020 and EGFR mutants. This study identified potential therapeutic strategies using the new-generation macrocyclic EGFR inhibitor to overcome the emerging ultimate resistance mutants., (© 2024. The Author(s).)

Anaplastic lymphoma kinase (ALK) fusion is found in ~3%-5% of patients with non-small-cell lung cancers (NSCLCs). Although the third-generation ALK tyrosine kinase inhibitor (TKI) lorlatinib shows high clinical efficacy in ALK-positive NSCLC, most of the patients eventually relapse with acquired resistance. Recently, drug-tolerant persister (DTP) cells have been considered an important seed of acquired resistance cells. In this study, we established lorlatinib intermediate resistant cells from a patient-derived cell model. Glycogen synthase kinase 3 (GSK3) inhibitions significantly suppressed lorlatinib intermediate resistant cell growth. GSK3 inhibition also sensitized acquired resistance cells derived from alectinib-treated patients with or without secondary mutations to lorlatinib. Therefore, GSK3 plays a crucial role in developing acquired resistance against lorlatinib in ALK-positive NSCLC mediated by lorlatinib intermediate resistant cells and could be a potential molecular target to prevent acquired lorlatinib resistance and overcome ALK-TKI resistance., (© 2022. The Author(s).)

Approximately 15-30% of patients with lung cancer harbor mutations in the EGFR gene. Major EGFR mutations (>90% of EGFR-mutated lung cancer) are highly sensitive to EGFR tyrosine kinase inhibitors (TKIs). Many uncommon EGFR mutations have been identified, but little is known regarding their characteristics, activation, and sensitivity to various EGFR-TKIs, including allosteric inhibitors. We encountered a case harboring an EGFR-L747P mutation, originally misdiagnosed with EGFR-del19 mutation using a routine diagnostic EGFR mutation test, which was resistant to EGFR-TKI gefitinib. Using this minor mutation and common EGFR-activating mutations, we performed the binding free energy calculations and microsecond-timescale molecular dynamic (MD) simulations, revealing that the L747P mutation considerably stabilizes the active conformation through a salt-bridge formation between K745 and E762. We further revealed why several EGFR inhibitors, including the allosteric inhibitor, were ineffective. Our computational structural analysis strategy would be beneficial for future drug development targeting the EGFR minor mutations.

The recapitulation of bone formation via the in vitro generation of bone-like nodules is frequently used to understand bone development. However, current bone-induction techniques are slow and difficult to reproduce. Here, we report the formation of bone-like nodules within ten days, via the use of retinoic acid (RA) to induce the osteogenic differentiation of human induced pluripotent stem cells (hiPSCs) into osteoblast-like and osteocyte-like cells that create human bone tissue when implanted in calvarial defects in mice. We also show that the induction of bone formation depends on cell signalling through the RA receptors RARα and RARβ, which simultaneously activate the BMP (bone morphogenetic protein) and Wnt signalling pathways. Moreover, by using patient-derived hiPSCs, the bone-like nodules recapitulated the osteogenesis-imperfecta phenotype, which was rescued via the correction of disease-causing mutations and partially by an mTOR (mechanistic target of rapamycin) inhibitor. The method of inducing bone nodules may serve as a fast and reproducible model for the study of the formation of both healthy and pathological bone.