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- PP4 Is Essential for Germinal Center Formation and Class Switch Recombination in Mice. [JOURNAL ARTICLE]
- PLoS One 2014; 9(9):e107505.
PP4 is a serine/threonine phosphatase required for immunoglobulin (Ig) VDJ recombination and pro-B/pre-B cell development in mice. To elucidate the role of PP4 in mature B cells, we ablated the catalytic subunit of murine PP4 in vivo utilizing the CD23 promoter and cre-loxP recombination and generated CD23crePP4F/F mice. The development of follicular and marginal zone B cells was unaffected in these mutants, but the proliferation of mature PP4-deficient B cells stimulated by in vitro treatment with either anti-IgM antibody (Ab) or LPS was partially impaired. Interestingly, the induction of CD80 and CD86 expression on these stimulated B cells was normal. Basal levels of serum Igs of all isotypes were strongly reduced in CD23crePP4F/F mice, and their B cells showed a reduced efficiency of class switch recombination (CSR) in vitro upon stimulation by LPS or LPS plus IL-4. When CD23crePP4F/F mice were challenged with either the T cell-dependent antigen TNP-KLH or the T cell-independent antigen TNP-Ficoll, or by H1N1 virus infection, the mutant animals failed to form germinal centers (GCs) in the spleen and the draining mediastinal lymph nodes, and did not efficiently mount antigen-specific humoral responses. In the resting state, PP4-deficient B cells exhibited pre-existing DNA fragmentation. Upon stimulation by DNA-damaging drug etoposide in vitro, mutant B cells showed increased cleavage of caspase 3. In addition, the mutant B cells displayed impaired CD40-mediated MAPK activation, abnormal IgM-mediated NF-κB activation, and reduced S phase entry upon IgM/CD40-stimulation. Taken together, our results establish a novel role for PP4 in CSR, and reveal crucial functions for PP4 in the maintenance of genomic stability, GC formation, and B cell-mediated immune responses.
- Treatment outcome of elderly patients with aggressive adult T cell leukemia-lymphoma: Nagasaki University Hospital experience. [JOURNAL ARTICLE]
- Int J Hematol 2014 Sep 11.
VCAP (vincristine, cyclophosphamide, doxorubicin, and prednisone)-AMP (doxorubicin, ranimustine, and prednisone)-VECP (vindesine, etoposide, carboplatin, and prednisone) is a standard regimen for aggressive adult T cell leukemia-lymphoma (ATL). However, the efficacy of this regimen has not been fully elucidated for patients aged 70 years or older. Here, we retrospectively analyzed elderly patients with aggressive ATL at Nagasaki University Hospital between 1994 and 2010 to assess treatment outcomes. Of 148 evaluable patients, 54 were aged 70 years or older at diagnosis. The median survival time (MST) and overall survival (OS) at 2 years in elderly patients were 10.6 months and 22.1 %, respectively. Thirty-four patients received VCAP-AMP-VECP as the initial treatment, although the doses were reduced for most patients. In these patients, MST and OS at 2 years were 13.4 months and 26.6 %, respectively. Eleven of 34 patients (32 %) received maintenance oral chemotherapy after two or three cycles of VCAP-AMP-VECP, and MST and OS at 2 years were 16.7 months and 32.7 %, respectively. Our results suggest that the VCAP-AMP-VECP regimen may be effective and that maintenance oral chemotherapy may be considered as a therapeutic option for elderly patients with aggressive ATL.
- Digital holographic microscopy for non-invasive monitoring of cell cycle arrest in l929 cells. [Journal Article]
- PLoS One 2014; 9(9):e106546.
Digital holographic microscopy (DHM) has emerged as a powerful non-invasive tool for cell analysis. It has the capacity to analyse multiple parameters simultaneously, such as cell- number, confluence and phase volume. This is done while cells are still adhered and growing in their culture flask. The aim of this study was to investigate whether DHM was able to monitor drug-induced cell cycle arrest in cultured cells and thus provide a non-disruptive alternative to flow cytometry. DHM parameters from G1 and G2/M cell cycle arrested L929 mouse fibroblast cells were collected. Cell cycle arrest was verified with flow cytometry. This study shows that DHM is able to monitor phase volume changes corresponding to either a G1 or G2/M cell cycle arrest. G1-phase arrest with staurosporine correlated with a decrease in the average cell phase volume and G2/M-phase arrest with colcemid and etoposide correlated with an increase in the average cell phase volume. Importantly, DHM analysis of average cell phase volume was of comparable accuracy to flow cytometric measurement of cell cycle phase distribution as recorded following dose-dependent treatment with etoposide. Average cell phase volume changes in response to treatment with cell cycle arresting compounds could therefore be used as a DHM marker for monitoring cell cycle arrest in cultured mammalian cells.
- Primary central nervous system extranodal NK/T cell lymphoma, nasal type, with antecedent hemophagocytic syndrome in a child. [JOURNAL ARTICLE]
- Pediatr Dev Pathol 2014 Sep 10.
Abstract Primary central nervous system (CNS) NK/T cell lymphoma, nasal type (NKTCL) is an exceedingly uncommon entity. Here, we present a case of CNS NKTCL which manifested firstly as hemophagocytic syndrome four months earlier in a 13-year-old girl. Histological examination revealed the cerebellum mass was composed of large-sized and atypical tumor cells, with angiocentric and angiodestructive growth pattern and prominent necrosis. The tumor cells exhibited marked pleomorphism with conspicuous nucleoli and prominent mitotic activity. Immunohistochemical staining showed the tumor cells were positive for CD45, CD2, CD3ε, CD30, CD43, CD56 and granzyme B. Epstein-Barr virus-encoded RNAs was expressed in almost all the nuclei of lymphoma cells. The T-cell receptor γ chain gene rearrangement study showed no evidence of a clonal rearrangement. The patient was treated with etoposide and dexamethasone, and died a few days after the operation. As far as we know, this case is the first pediatric and female patient of primary CNS NKTCL with antecedent hemophagocytic syndrome, which highlights the clinical data and is helpful for the diagnosis of this tumor.
- Two cases of neuroendocrine carcinoma of the gallbladder. [Journal Article]
- World J Gastroenterol 2014 Sep 7; 20(33):11916-20.
Neuroendocrine carcinoma (NEC) of the gallbladder is a rare subtype of gallbladder tumor. Here, we report two cases of NEC in two patients initially suspected to have gallbladder carcinoma. No specific symptoms or abnormal blood test results were observed preoperatively. Abdominal computed tomography scans indicated intraluminal masses in the gallbladder and lymph node enlargement in the hepatic hilum. Radical cholecystectomy and regional lymphadenectomy were performed. The first patient also presented with liver invasion and therefore underwent resection of liver segment IV. A diagnosis of NEC was made upon postoperative pathological examination and immunohistochemical staining according to the WHO Classification of Tumors of the Digestive System (2010). One tumor was identified as poorly differentiated NEC and the other as poorly differentiated mixed adenoneuroendocrine carcinoma. Immunohistochemical staining data from both tumors showed positivity for chromogranin A and synaptophysin. The first patient received 4 cycles of chemotherapy consisting of cisplatin and etoposide. No metastases or recurrence were observed 12 mo following surgery. The second patient refused chemotherapy and presented with tumor recurrence 4 mo after surgery. In conclusion, NEC of the gallbladder is an aggressive tumor and the identification of a standardized optimal treatment still requires further research. Our experience together with published studies suggests that radical surgery and adjuvant chemotherapy may improve the prognosis.
- Esthesioneuroblastoma metastasis to the breast: A case report and review of the literature. [JOURNAL ARTICLE]
- Oncol Lett 2014 Oct; 8(4):1505-1508.
Metastasis to the breast from an extramammary malignant neoplasm, including esthesioneuroblastoma, is uncommon. The present study describes a rare case of sinonasal esthesioneuroblastoma, Hyams' histologic grade 2, Kadish's stage C, T4N0M0, in a 30-year-old female. The patient underwent a radical ethmoidectomy with external beam radiotherapy, followed by chemotherapy including five cycles of cisplatin and etoposide. One year after the initial diagnosis, the patient presented to the hospital with the chief complaint of a rapidly enlarging lump in the right breast. A fine needle aspiration was performed and immunocytochemistry revealed a metastatic esthesioneuroblastoma. The patient received palliative chemotherapy and radiotherapy; however, the patient developed a local recurrence with systemic metastasis and succumbed to the disease seven months later.
- Synthesis and Anti-Cancer Activity Evaluation of New Dimethoxylated Chalcone and Flavanone Analogs. [JOURNAL ARTICLE]
- Arch Pharm (Weinheim) 2014 Sep 8.
A novel series of chalcones and flavanones discriminated by the presence of a 3,4-dimethoxyphenyl moiety in their structures were synthesized as anti-cancer agents. The cytotoxicity evaluation of the analogs against the MCF-7, MDA-MB-231 (human breast cancer), and SK-N-MC (human neuroblastoma) cell lines demonstrated that the introduction of a halogen on the 3,4-dimethoxyphenyl part of both series and the attachment of a pyrrolidinylethoxy group on the C-7 position of the flavanone derivatives increased their activity. Indeed, 3-halogenated chalcones (1c and 1d) were more potent than the standard drug etoposide against all tested cell lines. Fluorescence microscopy and flow cytometry analyses confirmed that the anti-cancer effect of the most potent compounds 1c and 1d occurs via apoptosis induction.
- Tumor lysis syndrome in a nonsmall cell lung cancer. [Journal Article]
- Conn Med 2014 Aug; 78(7):421-3.
Tumor lysis syndrome (TLS) is an oncologic emergency caused by intense tumor cell destruction resulting in profound electrolyte abnormalities. It is generally recognized as a consequence of cytotoxic therapy in particularly chemotherapy-sensitive tumors such as hematologic cancers. Despite having been primarily recognized in hematologic malignancies, TLS has been reported in solid tumors as well. We present a case of a 72-year-old female who developed TLS after receiving etoposide and carboplatin for a poorly-differentiated carcinoma with areas of small-cell differentiation metastatic to her liver. She had previously undergone a thoracotomy and resection for a poorly differentiated squamous cell cancer of the lung.
- Continuous low-dose oral chemotherapy in recurrent and persistent carcinoma of cervix following chemoradiation: a comparative study between prolonged oral cyclophosphamide and oral Etoposide. [Journal Article]
- Indian J Palliat Care 2014 Sep; 20(3):208-11.
To compare the efficacy and toxicities of low-dose oral cyclophosphamide and oral etoposide in patients with persistent and recurrent cervical cancer with gross pelvic disease following full course of chemoradiation therapy.30 patients with recurrent and persistent cervical cancer with gross pelvic disease were enrolled in this trial. The patients were randomly divided into two groups of 15 patients each with one group receiving low dose oral cyclophosphamide (100 mg/day) and the other group receiving low-dose oral etoposide (50 mg/day). Results were statistically analysed by IBM SPSS Statistics 19.Oral etoposide was not well tolerated with grade 2 neutropenia occurring in 33.3% and grade 3 neutropenia in 6.6% and thrombocytopenia occurring in 13.3%. Oral cyclophosphamide group on the other hand was better tolerated with none of the patients having thrombocytopenia and 6.6% patients having grade 2 neutropenia. There were two complete response (15.38%) and one partial response at the end of study (7.6%) in the cyclophosphamide group whereas there was no complete response and two partial response (16.6%) in the oral etoposide group.Long-term, low-dose oral etoposide was found to be less tolerated without any significant effect with patients with persistent and recurrent cervical cancer with gross pelvic disease following full course of chemoradiation therapy in contrast to oral cyclophosphamide which was found to be effective and well-tolerated by the patients.
- Significance of serine threonine tyrosine kinase 1 as a drug resistance factor and therapeutic predictor in acute leukemia. [JOURNAL ARTICLE]
- Int J Oncol 2014 Sep 3.
Alterations in the mRNA expression or the mutation of previously reported tyrosine kinases have been detected only in a limited number of patients with acute leukemia. In this study, we examined whether the widely expressed serine threonine tyrosine kinase 1 (STYK1)/novel oncogene with kinase domain (NOK) acts as a drug resistance factor in acute leukemia. The transfection of leukemic HL-60 cells with an STYK1 expression vector resulted in the resistance to doxorubicin and etoposide and decreased drug-induced caspase-3/7 activity and sub-G1 population. To investigate the mechanism of STYK1-induced drug resistance, microarray analysis was performed using HL-60 cells transfected with control or STYK1 expression vectors. Three tyrosine kinases (EphA4, FLT4 and STK31), two NF-κB inducers (MAPK4 and TNF-RSF11A), and two genes essential for stem cell replication (SALL4 and NOV) were identified as novel STYK1-induced genes. In addition to the data using cell line, a comparison of the leukemic patients who did and did not respond to therapy revealed that STYK1 expression before therapy was significantly higher in the non-responder group compared with the group that responded completely. These results suggest that STYK1 is a novel drug resistance factor and could be a predictor of the therapeutic response in acute leukemia.