BackgroundAn adult zebrafish heart possesses a high capacity of regeneration. However, it has been unclear whether and how myocyte hyperplasia contributes to cardiac remodeling in response to biomechanical stress and whether myocyte hypertrophy exists in the zebrafish. To address these questions, we characterized the zebrafish mutant tr265/tr265, whose Band 3 mutation disrupts erythrocyte formation and results in anemia. Although Band 3 does not express and function in the heart, the chronic anemia imposes a sequential biomechanical stress towards the heart.Methodology/Principal FindingsHearts of the tr265/tr265 Danio rerio mutant become larger than those of the sibling by week 4 post fertilization and gradually exhibit characteristics of human cardiomyopathy, such as muscular disarray, re-activated fetal gene expression, and severe arrhythmia. At the cellular level, we found both increased individual cardiomyocyte size and increased myocyte proliferation can be detected in week 4 to week 12 tr265/tr265 fish. Interestingly, all tr265/tr265 fish that survive after week-12 have many more cardiomyocytes of smaller size than those in the sibling, suggesting that myocyte hyperplasia allows the long-term survival of these fish. We also show the cardiac hypertrophy process can be recapitulated in wild-type fish using the anemia-inducing drug phenylhydrazine (PHZ).Conclusions/SignificanceThe anemia-induced cardiac hypertrophy models reported here are the first adult zebrafish cardiac hypertrophy models characterized. Unlike mammalian models, both cardiomyocyte hypertrophy and hyperplasia contribute to the cardiac remodeling process in these models, thus allowing the effects of cardiomyocyte hyperplasia on cardiac remodeling to be studied. However, since anemia can induce effects on the heart other than biomechanical, non-anemic zebrafish cardiac hypertrophy models shall be generated and characterized.

The majority of acute myeloid leukemia (AML) patients will respond to standard chemotherapy, however, resistance is a prevalent problem contributing to incomplete responses, refractory disease, and ultimately patient death. Therefore, choosing more sensitive and effective chemotherapy regimens is of key clinical importance. In order to explore this issue, we investigated and optimized PharmaFlow, an automated flow cytometry method for evaluating the sensitivity of leukemia cells to multiple chemotherapeutic drugs ex vivo. We examined bone marrow samples from 38 Chinese AML patients and incubated them for 48 or 72 h with a panel of 7 single drugs and 6 combinations with cytarabine at different concentrations. Leukemic cell depletion was assessed by PharmaFlow and drug response parameter, called PharmaFlow score, was estimated using population pharmacodynamic models. We identified that most chemotherapeutic drugs and combinations could effectively eliminate pathological cells ex vivo. Estimated drug activities strongly correlated with the patients' duration to achieve clinical remission and PharmaFlow chemosensitivity measured ex vivo was highly predictive of the clinical outcome after chemotherapy. Applying a classification model, we determined a PharmaFlow score of 89.4 as the threshold to predict response to chemotherapy. Using this threshold, we found that in 84.2% of cases patient's cell response ex vivo predicted the observed clinical response and performed similarly or better than prognostic subgroups determined by cytogenetic characteristics. PharmaFlow has the potential to predict chemosensitivity for de novo, secondary and relapsed AML patients prior to treatment and may guide clinicians to tailor treatments and improve patient outcome. K E Y W O R D Sacute myeloid leukemia, chemosensitivity, PharmaFlow

Abstract. t(8;22)(p11;q11) is a rare but recurrent genetic alteration in various hematological disorders. Patients with t(8;22)(p11;q11) may be misdiagnosed with chronic myelogenous leukemia (CML), due to the similar clinical features. Thus, the current study presents a patient with t(8;22) (p11;q11) who was previously misdiagnosed with CML in the chronic phase. The current patient was a 26-year-old woman who was 4-weeks pregnant and in whom an increased white blood cell count (4.0x10 10 /l) was found upon physical examination. The patient had no history of hematological disease. Although cytogenetics showed a normal karyotype and no breakpoint cluster region/Abelson murine leukemia viral oncogene homolog 1 (BCR/ABL) fusion gene was detected by reverse transcription-polymerase chain reaction, a diagnosis of chronic myelogenous leukemia (CML) was initially made according to the clinical and morphological features. Another 6 weeks later, t(8;22)(p11;q11) rearrangement was present in 9 out of 10 analyzed metaphases. Fluorescence in situ hybridization and reverse transcription-polymerase chain reaction indicated a negative result for the BCR/ABL fusion, but gave a positive result for the BCR-fibroblast growth factor receptor 1 fusion. A hematological diagnosis of atypical CML was again formed. IntroductionChronic myelogenous leukemia (CML) is characterized by the presence of the Philadelphia chromosome, which is generated by the reciprocal translocation, t(9;22) (1). This abnormality is found in >90% of CML cases, in 15-20% of acute lymphoblastic leukemia cases, and a small number of acute myeloid leukemia cases (1). Recently, certain studies have reported that patients with t(8;22) exhibit similar morphological and clinical features to those observed in CML patients (2-4). Since the first case reported by Fioretos in 2001 (5), to the best of our knowledge, t(8;22)(p11;q11) has been reported in only 17 cases with hematological malignancies (2-17). Of these, 6 cases presented with atypical CML (2-4,6,7), 3 with myeloproliferative neoplasms (5,8,9), 3 with B-cell acute lymphoblastic leukemia (10-12) and 5 with other types of hematological neoplasms (13-17). t(8;22) results in an in-frame fusion of FGFR1 on 8p11 and BCR on 22q11, and causes constitutive activation of the tyrosine kinase of the breakpoint cluster region/fibroblast growth factor receptor 1 (BCR/FGFR1) chimera protein, similar to Abelson murine leukemia viral oncogene homolog 1 (ABL) kinase activity in the BCR/ABL chimera (2,18).The present study reports the 18th case of a CML-like hematological tumor bearing t(8;22)(p11;q11) with no other cell lineages involved. Case reportOn February 23, 2013, a 26-year-old woman who was 4-weeks pregnant, with no history of hematological disease, was found to exhibit an increased white blood cell (WBC) count (4.0x10 10 /l; normal range, 0.37-0.92x10 10 /l) upon physical examination. Cytogenetic study on the patient's bone marrow (BM) cells showed a normal female karyotype in all metaphases. Tests for the BCR/ABL fusion ...

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