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Akio Onishi,1 Yayoi Matsumura-Kimoto,1,2 Shinsuke Mizutani,1 Taku Tsukamoto,1 Takahiro Fujino,1 Akihiro Miyashita,1,3 Daichi Nishiyama,4 Kazuho Shimura,5 Hiroto Kaneko,5 Eri Kawata,6 Ryoichi Takahashi,7 Tsutomu Kobayashi,1,8 Hitoji Uchiyama,8 Nobuhiko Uoshima,3 Yoko Nukui,9 Yuji Shimura,1 Tohru Inaba,9 Junya Kuroda1 1Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan; 2Department of Hematology, Japan Community Health Care Organization Kyoto Kuramaguchi Medical Center, Kyoto, Japan; 3Department of Hematology, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Japan; 4Department of Hematology, Fukuchiyama City Hospital, Fukuchiyama, Japan; 5Department of Hematology, Aiseikai Yamashina Hospital, Kyoto, Japan; 6Department of Hematology, Matsushita Memorial Hospital, Moriguchi, Japan; 7Department of Hematology, Omihachiman Community Medical Center, Omihachiman, Japan; 8Department of Hematology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan; 9Division of Infection Control & Molecular Laboratory Medicine, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, JapanCorrespondence: Junya Kuroda, Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan, Tel +81-75-251-5740, Fax +81-75-251-5743, Email junkuro@koto.kpu-m.ac.jpBackground and Purpose: Anti-CD20 monoclonal antibodies (MoAbs), rituximab (RIT), and obinutuzumab (OBZ) are the central components of immunochemotherapy for B-cell lymphoma (BCL). However, these agents potentially cause B-cell depletion, resulting in the impairment of antibody (Ab) production. During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, the optimal prediction of Ab response against anti–SARS-CoV-2 vaccination is critically important in patients with BCL treated by B-cell depletion therapeutics to prevent coronavirus disease 2019 (COVID-19).Patients and Methods: We investigated the effect of using RIT and/or OBZ on the Ab response in 131 patients with various types of BCL who received the second SARS-CoV-2 mRNA vaccine either after, during, or before immunochemotherapy containing B-cell–depleting moiety between June and November 2021 at seven institutes belonging to the Kyoto Clinical Hematology Study Group. The SARS-Cov-2 neutralizing Ab (nAb) was measured from 14 to 207 days after the second vaccination dose using the iFlash3000 automatic analyzer and the iFlash-2019-nCoV Nab kit.Results: Among 86 patients who received the vaccine within 12 months after B-cell depletion therapy, 8 (9.3%) were seropositive. In 30 patients who received the vaccine after 12 months from B-cell depletion therapy, 22 (73%) were seropositive. In 15 patients who were subjected to B-cell depletion therapy after vaccination, 2 (13%) were seropositive. The multivariate analysis indicated that an interval of 12 months between B-cell depletion therapy and the subsequent vaccination was significantly associated with effective Ab production. Receiver operating characteristic curve analysis identified the optimal threshold period after anti-CD20 MoAb treatment, which determines the seropositivity against SARS-CoV-2, to be 342 days.Conclusion: The use of anti-CD20 MoAb within 12 months before vaccination is a critical risk for poor Ab response against anti–SARS-CoV-2 vaccination in patients with BCL.Keywords: COVID-19, vaccine, B-cell lymphoma, anti-CD20 monoclonal antibody

Chika Maekura,1 Ayako Muramatsu,1 Hiroaki Nagata,1 Haruya Okamoto,1 Akio Onishi,1 Daishi Kato,1 Reiko Isa,1 Takahiro Fujino,1 Taku Tsukamoto,1 Shinsuke Mizutani,1 Yuji Shimura,1,2 Tsutomu Kobayashi,1 Keita Okumura,3 Tohru Inaba,4 Yoko Nukui,4 Junya Kuroda1 1Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan; 2Department of Blood Transfusion, University Hospital, Kyoto Prefectural University of Medicine, Kyoto, Japan; 3Faculty of Clinical Laboratory, University Hospital, Kyoto Prefectural University of Medicine, Kyoto, Japan; 4Department of Infection Control & Laboratory Medicine, Kyoto Prefectural University of Medicine, Kyoto, JapanCorrespondence: Junya Kuroda, Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan, Tel +81 75 251 5740, Fax +81 75 251 5743, Email junkuro@koto.kpu-m.ac.jpAbstract: Previous studies have demonstrated that the appropriate production of serum anti-severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) neutralizing antibody (nAb) plays a critical role in the recovery from coronavirus disease 2019 (COVID-19); however, the role of nAb production in the recovery from a flare-up of chronic immune thrombocytopenia (ITP) has been unknown. We here report the first retrospectively investigated case of serum anti-SARS-Cov-2 nAb production during chronic ITP flare-up triggered by COVID-19. A 79-year-old woman with a history of corticosteroid-refractory ITP visited our hospital complaining of fever, cough, and sore throat for 4 days. Although chronic ITP was controlled by 12.5 mg of eltrombopag (EPAG) every other day, laboratory tests showed a decreased peripheral blood platelet count of 15.0 × 109/L, which indicated worsening thrombocytopenia. Meanwhile, PCR testing of a nasopharyngeal swab revealed that the patient was positive for SARS-Cov-2, and a computed tomography scan revealed bilateral pneumonia. On the basis of the flare-up of chronic ITP associated with COVID-19 pneumonia which was determined as a moderately severe status according to the WHO clinical progression scale, intravenous immunoglobulin therapy for 5 days (days 0– 4) and antiviral therapy were added on top of EPAG, which only resulted in a transient increase in the platelet count for several days. After decreasing to 8.0 × 109/L on day 13, the platelet count increased from day 16, coinciding with a positive detection for serum nAb against SARS-Cov-2. Although the increased dose up to 50 mg/day of EPAG was challenged during the clinical course, rapid dose reduction did not cause another relapse. In addition, no thrombotic or bleeding event was seen. These collectively suggest the vital role of the production of anti-SARS-Cov-2 nAb and improvement of clinical symptoms for recovery from a flare-up of chronic ITP in our case.Keywords: chronic immune thrombocytopenia, COVID-19, flare, neutralizing antibody

Yuka Kawaji-Kanayama,1 Ayako Nishimura,2 Makoto Yasuda,3 Emiko Sakiyama,1,4 Yuji Shimura,1 Taku Tsukamoto,1 Tsutomu Kobayashi,1 Shinsuke Mizutani,1 Shota Okamoto,3 Gaku Ohmura,3 Shigeru Hirano,3 Eiichi Konishi,2 Kazutoshi Shibuya,5 Junya Kuroda1 1Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan; 2Division of Surgical Pathology, Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan; 3Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan; 4Department of Hematology, Matsushita Memorial Hospital, Moriguchi, Japan; 5Department of Surgical Pathology, Toho University Graduate School of Medicine, Tokyo, JapanCorrespondence: Junya KurodaDivision of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-Cho, Kamigyo-Ku, Kyoto 602-8566, JapanTel +81 75 251 5740Fax +81 75 251 5743Email junkuro@koto.kpu-m.ac.jpAbstract: Invasive fungal rhinosinusitis (FRS) is a rare but intractable infectious disease of the sinonasal region with destructive direct infiltration into surrounding tissues, such as the bone, orbit and brain, and potential dissemination to systemic organs. Symptomatic assessments and imaging are frequently not sufficiently diagnostic, and histopathological examination is essential for definite diagnosis of FRS. We herein report a case of chronic invasive FRS (CIFRS) in a 58-year-old Japanese male with end-stage diabetic nephropathy that required maintenance dialysis after graft rejection of living kidney transplantation. His initial main clinical presentation was sinus gangrene, which gradually progressed from the paranasal sinus to the nasal septum and oral palate, but not towards the intracranial or orbital region, for two months. The patient was first strongly suspected to have extranodal natural killer/T cell lymphoma (ENKTL), nasal type, a subtype of malignant lymphoma, based on the macroscopic appearance of the gangrene, expansion pattern and high serum soluble interleukin-2 level; however, repeated biopsies and eventual resection led to diagnosis of CIFRS due to Aspergillus niger and Mucor. The disease was improved by surgical resection in combination with antifungal pharmacologic treatment with liposomal amphotericin B and voriconazole. CIFRS typically occurs in immunocompetent patients and shows intracranial progression, but this case shows that atypical CIFRS with an uncommon expansion pattern can occur in an immunodeficient patient.Keywords: chronic invasive fungal rhinosinusitis, diabetes mellitus, maintenance dialysis, extranodal natural killer/T cell lymphoma, nasal type

Emiko Sakiyama, Yoshiaki Chinen, Taku Tsukamoto, Tomoko Takimoto-Shimomura, Saeko Kuwahara-Ota, Yayoi Matsumura-Kimoto, Yuji Shimura, Tsutomu Kobayashi, Shigeo Horiike, Junya Kuroda Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, JapanCorrespondence: Junya Kuroda Email junkuro@koto.kpu-m.ac.jpAbstract: Ruxolitinib is a selective JAK1/2 inhibitor that is widely used for the treatment of myeloproliferative neoplasms (MPNs), including myelofibrosis and polycythemia vera (PV). Despite its clinical efficacy for MPNs, ruxolitinib possesses immunosuppressive properties that potentially increase the risks for opportunistic infection, such as mycobacterium tuberculosis (MTB) infection, and reactivation of occult viral infection. Herein, we report the case of a 76-year-old male with PV who developed tuberculosis peritonitis under ruxolitinib therapy for 28 weeks. While previous studies and case reports have suggested an increased risk of MTB infection of various organs during ruxolitinib treatment of MPNs, this case is apparently the first of tuberculosis peritonitis in a patient with MPN treated with ruxolitinib. A review of previous case reports suggests the need for careful observation for MTB from the relatively early phase of ruxolitinib treatment, given that the median duration from the start of ruxolitinib treatment to the emergence of MTB was 20 weeks (range: 3– 88 weeks). Clinicians should consider tuberculosis peritonitis as a differential diagnosis when patients with MPN treated with ruxolitinib develop infectious abdominal symptoms.Keywords: ruxolitinib, tuberculosis peritonitis, polycythemia vera

Shuji Suzuki,1 Mitsugi Shimoda,1 Jiro Shimazaki,1 Tsunehiko Maruyama,1 Yukio Oshiro,1 Kiyotaka Nishida,1 Jun Kuroda,1 Kenta Miyoshi,1 Nobusada Koike,2 Nobuhiko Harada21Department of Gastroenterological Surgery, Ibaraki Medical Center, Tokyo Medical University, Ibaraki 300-0395, Japan; 2Department of Surgery, Hachioji Digestive Disease Hospital, Tokyo 192-0903, JapanBackground: Early recurrence of distal cholangiocarcinoma (DCC) may result in a poorer prognosis. This study aimed to evaluate the clinicopathological factors that predict survival and recurrence in patients with DCC.Methods: Fifty-five patients with DCC who underwent pancreaticoduodenectomy between 2005 and 2015 were studied retrospectively. The following clinicopathological parameters were analyzed as predictors of disease-free survival (DFS) and overall survival (OS): sex, age, body mass index, presence of biliary tract decompression, macroscopic type, histological type, tumor size, TNM classification, lymph node metastasis ratio, number of positive lymph nodes (PLNs), lymphatic invasion, venous invasion, perineural invasion, proximal bile duct margin, dissected margin, portal system invasion, arterial system invasion, stage, and residual tumor.Results: Univariate analysis showed that contiguous extension of the primary tumor, PLN, lymphatic invasion, venous invasion, perineural invasion, and stage were significant prognostic factors for DFS and OS. Multivariate analysis revealed that PLN and lymphatic invasion were prognostic for DFS and OS (P

Saeko Kuwahara-Ota, Yoshiaki Chinen, Yoshimi Mizuno, Tomoko Takimoto-Shimomura, Yayoi Matsumura-Kimoto, Kazuna Tanba, Taku Tsukamoto, Shinsuke Mizutani, Yuji Shimura, Tsutomu Kobayashi, Shigeo Horiike, Junya Kuroda Department of Medicine, Division of Hematology and Oncology, Kyoto Prefectural University of Medicine, Kyoto, Japan Abstract: Primary infection with human herpesvirus-6 (HHV-6) commonly occurs at an early age in children, most often at 3 years of age, and is associated with childhood diseases, such as exanthema subitum, hepatitis, febrile convulsions, or encephalitis. However, the virus occasionally reactivates from its latent state in immunosuppressed adults, especially posttransplant, resulting in serious disseminated, sometimes life-threatening end-organ complications. Herein, we report a case of a 68-year-old man with relapsed follicular lymphoma who developed HHV-6 pneumonitis. Eighteen months after achieving second complete remission by salvage immunochemotherapy with rituximab, the patient was complicated by pneumonia, with chest computed tomography finding showing disseminated nodular shadows with ground-glass opacity in both lungs. While empiric antibiotic and antifungal therapies did not improve the pneumonia, polymerase chain reaction–based viral screening tests on his bronchoalveolar lavage fluid detected the presence of HHV-6 DNA, and ganciclovir treatment quickly resolved the pneumonia, indicating that he suffered from HHV-6 pneumonitis. He had no other HHV-6–related end-organ damage, such as encephalitis. This case suggests that, although extremely rare, HHV-6 reactivation should be considered as one of the candidate pathogens for pulmonary complications of uncertain etiology in patients who have been treated with intensive immunosuppressive chemotherapy, even without hematopoietic stem cell transplantation. Furthermore, polymerase chain reaction–based viral screening testing on bronchoalveolar lavage fluid is a powerful diagnostic tool for pneumonitis due to viral reactivation, including HHV-6 reactivation. Keywords: human herpesvirus-6, pneumonitis, viral reactivation, lymphoma

The 405‐kyr eccentricity cycle is a consistent orbital parameter throughout the Phanerozoic that is associated with long‐term variations in global continental weathering. However, a lack of reliable geological evidence has hampered the understanding of the relation between the 405‐kyr eccentricity cycle and continental weathering during the Cretaceous. Os isotopic ratios (187Os/188Os) of the sedimentary record reflect the balance between radiogenic Os derived from continental weathering and Os derived from unradiogenic sources (e.g., hydrothermal activity, weathering of mafic rocks, and extraterrestrial sources). This ratio is therefore considered as a good proxy for the evaluation of short‐term changes in continental weathering patterns. To trace orbital‐paced continental weathering, this study reconstructs the marine Os isotopic records in upper Hauterivian to lower Barremian (Lower Cretaceous) carbonate rocks in central Italy, where previous studies have reported that variations in clay mineral composition are paced by the 405‐kyr cycle. Our new Os isotopic record documents periodic oscillations of 187Os/188Os between 0.7 and 0.9 that correspond to the 405‐kyr Earth's eccentricity cycle. Because the sedimentary interval with radiogenic 187Os/188Os values (∼0.9) corresponds to a time interval characterized by a humid climate in areas surrounding the Tethys, variations in the 187Os/188O values likely reflect cyclic changes in continental weathering caused by eccentricity‐paced intensification of monsoonal activity at low latitudes. This variation could have been further amplified by increased input of radiogenic Os from Paleozoic shale and Precambrian crust at higher latitudes that resulted from a latitudinal shift of the intertropical convergence zone. Key Points: Hauterivian marine 187Os/188Os cyclically varied following the 405‐kyr eccentricity405‐kyr eccentricity enhanced monsoon that intensified the continental weathering187Os/188Os record does not support the massive volcanic event at the Faraoni Level [ABSTRACT FROM AUTHOR]

The study combined the Fe/polymer composites with the plated NiZn ferrite films in order to improve the quasimicrowave characteristics of the composites for application to the wave absorbers. The micro-onions contribute to (mu) to the same extent as the solid particles of the same magnetic substance, as far as the shell is not extremely thinner than the core.

The effective dielectric permittivity tensor for granular composites having multicore-shell structured nano-onions dispersed in matrixes is derived based on the Maxwell Garnett effective field approximation. It is found that the core/shell structure gives a dispersion relation in the magneto-optical effect, similar to what is found for the compositionally modulated multilayered Au/Fe films attributed to the plasma resonance of Au.

Background: Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with poor prognosis, requiring novel anticancer strategies.Methods: Mantle cell lymphoma cell lines with known p53 status were treated with GUT-70, a tricyclic coumarin derived from Calophyllum brasiliense, and the biological and biochemical consequences of GUT-70 were studied.Results: GUT-70 markedly reduced cell proliferation/viability through G(1) cell cycle arrest and increased apoptosis, with greater sensitivity in mutant (mt)-p53-expressing MCL cells than in wild-type (wt)-p53-bearing cells. Mechanistically, GUT-70 showed binding affinity to heat-shock protein 90 (Hsp90) and ubiquitin-dependent proteasomal degradation of Hsp90 client proteins, including cyclin D1, Raf-1, Akt, and mt-p53. Depletion of constitutively overexpressed cyclin D1 by GUT-70 was accompanied by p27 accumulation and decreased Rb phosphorylation. GUT-70 induced mitochondrial apoptosis with Noxa upregulation and Mcl-1 downregulation in mt-p53 cells, but Mcl-1 accumulation in wt-p53 cells. Noxa and Mcl-1 were coimmunoprecipitated, and activated BAK. Treatment with a combination of GUT-70 and bortezomib or doxorubicin had synergistic antiproliferative effects in MCL cells that were independent of p53 status.Conclusion: GUT-70 has pronounced antiproliferative effects in MCL with mt-p53, a known negative prognostic factor for MCL, through Hsp90 inhibition. These findings suggest that GUT-70 has potential utility for the treatment of MCL. [ABSTRACT FROM AUTHOR]

Background: It has been demonstrated that NK012, a novel 7-ethyl-10-hydroxycamptothecin (SN-38)-incorporating polymeric micelle, exerts significantly more potent antitumor activity against various human tumor xenografts than irinotecan (CPT-11) (a water-soluble prodrug of SN-38). Combination therapy of anticancer agents with bevacizumab (Bv), an anti-vascualr endothelial growth factor humanized monoclonal antibody, has more potently inhibited tumor growth than either agent alone. In the current study, the authors examined the antitumor effect of NK012 in combination with Bv against human lung cancer.Methods: Nude mice bearing lung adenocarcinoma (PC-14 or A549 xenografts) were administered NK012 at SN-38-equivalent doses of 5 mg/kg or 30 mg/kg in combination with or without Bv at 5 mg/kg. CPT-11 at a dose of 66.7 mg/kg was administered with or without Bv at a dose of 5 mg/kg in the same experimental model. To evaluate interaction with Bv, the pharmacokinetics and microvessel density in tumors that were treated on each regimen were analyzed.Result: In vitro, the growth-inhibitory effect of NK012 was 50-fold more potent than that of CPT-11 and was almost equivalent to that of SN-38. In vivo studies revealed that the combination of NK012 plus Bv had significantly greater antitumor activity against human lung cancer xenografts compared with NK012 alone (PC-14, P=.0261; A549, P<.001). The pharmacokinetic profile of NK012 revealed that coadministration of Bv did not interfere with the accumulation of NK012.Conclusions: In this study, significant antitumor activity was noted with NK012 in combination with Bv against lung cancer cells. The current results warrant the clinical evaluation of NK012 in lung cancer. [ABSTRACT FROM AUTHOR]

Abl tyrosine kinase inhibitors (TKIs) such as imatinib and dasatinib are ineffective against Bcr-Abl+ leukemic stem cells. Thus, the identification of novel agents that are effective in eradicating quiescent Bcr-Abl+ stem cells is needed to cure leukemias caused by Bcr-Abl+ cells. Human Bcr-Abl+ cells engrafted in the bone marrow of immunodeficient mice survive under severe hypoxia. We generated two hypoxia-adapted (HA)-Bcr-Abl+ sublines by selection in long-term hypoxic cultures (1.0% O2). Interestingly, HA-Bcr-Abl+ cells exhibited stem cell-like characteristics, including more cells in a dormant, increase of side population fraction, higher β-catenin expression, resistance to Abl TKIs, and a higher transplantation efficiency. Compared with the respective parental cells, HA-Bcr-Abl+ cells had higher levels of protein and higher enzyme activity of glyoxalase-I (Glo-I), an enzyme that detoxifies methylglyoxal, a cytotoxic by-product of glycolysis. In contrast to Abl TKIs, Glo-I inhibitors were much more effective in killing HA-Bcr-Abl+ cells both in vitro and in vivo. These findings indicate that Glo-I is a novel molecular target for treatment of Bcr-Abl+ leukemias, and, in particular, Abl TKI-resistant quiescent Bcr-Abl+ leukemic cells that have acquired stem-like characteristics in the process of adapting to a hypoxic environment. [ABSTRACT FROM AUTHOR]

Bcr-Abl tyrosine kinase (TK) inhibitors are promising therapeutic agents for Bcr-Abl-positive (Bcr-Abl+) leukemias. Although they are known to promote caspase-mediated apoptosis, it remains unclear whether caspase-independent cell death-inducing mechanisms are also triggered. Here we demonstrated that INNO-406, a second-generation Bcr-Abl TK inhibitor, induces programmed cell death (PCD) in chronic myelogenous leukemia (CML) cell lines through both caspase-mediated and caspase-independent pathways. The latter pathways include caspase-independent apoptosis (CIA) and necrosis-like cell death (CIND), and the cell lines varied regarding which mechanism was elicited upon INNO-406 treatment. We also observed that the propensity toward CIA or CIND in cells was strongly associated with cellular dependency on apoptosome-mediated caspase activity. Cells that undergo CIND have a high apoptosome activity potential whereas cells that undergo CIA tend to have a lower potential. Moreover, we found that INNO-406 promotes autophagy. When autophagy was inhibited with chloroquine or gene knockdown of beclin1 by shRNA, INNO-406-induced cell death was enhanced, which indicates that the autophagic response of the tumor cells is protective. These findings suggest new insights into the biology and therapy of Bcr-Abl+ leukemias.Cell Death and Differentiation (2008) 15, 1712–1722; doi:10.1038/cdd.2008.107; published online 11 July 2008 [ABSTRACT FROM AUTHOR]

The C242T polymorphism of p22 phox, a component of NAD(P)H oxidase, may have an impact on cardiovascular diseases; however, the association between this polymorphism and brain infarction is not fully understood. Here, we investigate the relationship between the C242T polymorphism and brain infarction in Japan. We recruited 1055 patients with brain infarction and 1055 control subjects. A chi-squared test revealed that the T-allele frequency was lower in patients with cardioembolic infarction (5.6%) than in control subjects (11.0%, P < 0.001); however, allele frequencies in patients with lacunar and atherothrombotic infarction (11.2%) were not significantly different from those in control subjects (11.0%). A multivariate-adjusted conditional logistic regression analysis also revealed no association between CT + TT genotype, and lacunar and atherothrombotic infarction (odds ratio = 0.97, 95% confidence interval: 0.72–1.32). To investigate the functional effects of the C242T polymorphism, we examined superoxide production in COS-7 cells cotransfected with Nox4 and p22 phox of each genotype. The superoxide-producing activity in those cells expressing p22 phox with the T allele was not significantly different from that in cells expressing p22 phox with the C allele. The present results suggest that the p22 phox C242T polymorphism may have a protective effect against cardioembolic infarction, but is not related to lacunar and atherothrombotic infarction in Japan. [ABSTRACT FROM AUTHOR]

Bcr-Abl is the cause of Philadelphia-positive (Ph+) leukemias and also constitutes their principal therapeutic target, as exemplified by dramatic effects of imatinib mesylate. However, mono-targeting of Bcr-Abl does not always achieve complete leukemia eradication, and additional strategies those enable complete elimination of leukemic cells are desired to develop. Here we demonstrate that INNO-406, a much more active Bcr-Abl tyrosine kinase inhibitor than imatinib, augments the activities of several proapoptotic Bcl-2 homology (BH)3-only proteins (Bim, Bad, Bmf and Bik) and induces apoptosis in Ph+ leukemia cells via Bcl-2 family-regulated intrinsic apoptosis pathway. ABT-737, an inhibitor of antiapoptotic Bcl-2 and Bcl-XL, greatly enhanced the apoptosis by INNO-406, even in INNO-406-less sensitive cells with Bcr-Abl point mutations except T315I mutation. In contrast, co-treatment with INNO-406 and other pharmacologic inducers of those BH3-only proteins, such as 17-allylaminogeldanamycin, an heat shock protein-90 inhibitor, or PS-341, a proteasome inhibitor, did not further increase the BH3-only protein levels or sensitize leukemic cells to INNO-406-induced apoptosis, suggesting a limit to how much expression levels of BH3-only proteins can be increased by anticancer agents. Thus, double-barrelled molecular targeting for Bcr-Abl-driven oncogenic signaling and the cell protection by antiapoptotic Bcl-2 family proteins may be the rational therapeutic approach for eradicating Ph+ leukemic cells.Cell Death and Differentiation (2007) 14, 1667–1677; doi:10.1038/sj.cdd.4402168; published online 18 May 2007 [ABSTRACT FROM AUTHOR]

NK105 is a micellar nanoparticle formulation designed to enhance the delivery of paclitaxel (PTX) to solid tumours. It has been reported to exert antitumour activity in vivo and to have reduced neurotoxicity as compared to that of free PTX. The purpose of this study was to investigate the radiosensitising effect of NK105 in comparison with that of PTX. Lewis lung carcinoma (LLC)-bearing mice were administered a single intravenous (i.v.) injection of PTX or NK105; 24 h after the drug administration, a proportion of the mice received radiation to the tumour site or lung fields. Then, the antitumour activity and lung toxicity were evaluated. In one subset of mice, the tumours were excised and specimens were prepared for analysis of the cell cycle distribution by flow cytometry. Combined NK105 treatment with radiation yielded significant superior antitumour activity as compared to combined PTX treatment with radiation (P=0.0277). On the other hand, a histopathological study of lung sections revealed no significant difference in histopathological changes between mice treated with PTX and radiation and those treated with NK105 and radiation. Flow-cytometric analysis showed that NK105-treated LLC tumour cells showed more severe arrest at the G2/M phase as compared to PTX-treated tumour cells. The superior radiosensitising activity of NK105 was thus considered to be attributable to the more severe cell cycle arrest at the G2/M phase induced by NK105 as compared to that induced by free PTX. The present study results suggest that further clinical trials are warranted to determine the efficacy and feasibility of combined NK105 therapy with radiation.British Journal of Cancer (2006) 95, 601–606. doi:10.1038/sj.bjc.6603311 www.bjcancer.com Published online 8 August 2006 [ABSTRACT FROM AUTHOR]

In Livello Bonarelli black shale deposited during Cretaceous Oceanic Anoxic Event 2 (OAE-2, ca. 94 Ma), nitrogen isotopic compositions of bulk sediments are in a narrow range from -2.7 to -0.7‰. We also determined molecular distribution and nitrogen isotopic compositions of geoporphyrins extracted from the black shale. The nitrogen isotopic compositions of C32 Ni deoxophylloerythroetioporphyrin (DPEP) and total Ni porphyrins are -3.5 and -3.3‰, respectively, leading us to the estimation that the mean nitrogen isotopic composition of photoautotrophic cell was around +1‰ during the formation of Bonarelli black shale. This value is suggestive of N2-fixation a dominant process for these photoautotrophs when assimilating nitrogen. Furthermore, Ni-chelated C32 DPEP, derived mainly from chlorophyll a was the highest concentration. Based on these evidence, we conclude that diazotrophic cyanobacteria were major primary producers during that time. The cyanobacteria may be key photoautotrophs during the formation of black shale type sediments intermittently observed throughout the later half of the Earth's history, and hence may have played a crucial role in the evolution of geochemical cycles. [ABSTRACT FROM AUTHOR]

Blastic natural killer cell leukemia/lymphoma (blastic NKL/L) is characterized by blastic morphology and a distinctive immunophenotype combining blastic features and cytologically resembling acute myeloid or lymphoid leukemia. The clinical, pathologic, and cytogenetic features of blastic NKL/L have not yet been systematically identified. We report herein a case of blastic NKL/L with skin lesion, adenopathy, and systemic lymphoadenopathy. The identified tumor cells were positive for CD4 and CD56, and negative for T-cell, B-cell, and myeloid markers. T-cell receptor beta, gamma, delta, and immunoglobulin heavy chain genes in the bone marrow cells showed germ-line configurations. Southern blot analysis with a terminal probe did not reveal any Epstein-Barr virus infection. Although patients diagnosed as blastic NKL/L have generally shown chemotherapy resistance and poor prognosis, our patient was treated with a combined chemotherapy, which is also used for acute lymphoblastic leukemia, and has maintained complete remission (CR) for more than 13 months. In addition to clinical investigations, we thoroughly analyzed his karyotype by using a combination of G-banding and a new technique, spectral karyotyping. The karyotype was described as 45, XY, der(1)t(1;20)(p32;q11.2), der(6) (1pter-->1p32:: 6p21.1-->6q13:: 7q11.2-->7qter), der(7) t(7;20)(q11.2;q11.2), t(13;14)(q14;q32), der(13)t(6;13) (p21.1; q14), -20. [ABSTRACT FROM AUTHOR]