Genetic abnormalities in patients with multiple myeloma (MM) are important risk factors in terms of prognosis. In the present study, the prognostic value of several common MM genetic abnormalities was investigated. Interphase fluorescence in situ hybridization (iFISH) was used to detect genetic abnormalities, including 1q21 gain, t(4;14), t(11;14), t(14;16) and 17p13 deletion in 131 patients. A total of 46.6% patients were detected with one or more abnormalities using iFISH analysis. The 1q21 gain, t(4;14), t(11;14), t(14;16) and 17p13 deletion abnormalities were detected in 42.5, 6.9, 17.5, 0.8 and 10.7% of patients, respectively. Patients with t(4;14) commonly exhibited lower levels of albumin and hemoglobin. The progression-free survival (PFS) and overall survival times of iFISH-positive patients (particularly patients with two or more iFISH abnormalities) were significantly shorter than those of the patients without detectable abnormalities. The 1q21 gain and 17p13 deletion were also adverse prognostic factors for MM. Bortezomib-based therapies improved the PFS times in the patients with unfavorable iFISH abnormalities. These findings demonstrate that patients with two or more iFISH abnormalities, a gain of the 1q21 region or a 17p13 deletion were more likely to have a poor prognosis; however, bortezomib treatment improved the outcome for MM patients with unfavorable iFISH abnormalities.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is most commonly caused by the A3243G mutation of mitochondrial DNA. The capacity to utilize fatty acid or glucose as a fuel source and how such dynamic switches of metabolic fuel preferences and transcriptional modulation of adaptive mechanism in response to energy deficiency in MELAS syndrome have not been fully elucidated. The fibroblasts from patients with MELAS syndrome demonstrated a remarkable deficiency of electron transport chain complexes I and IV, an impaired cellular biogenesis under glucose deprivation, and a decreased ATP synthesis. In situ analysis of the bioenergetic properties of MELAS cells demonstrated an attenuated fatty acid oxidation that concomitantly occurred with impaired mitochondrial respiration, while energy production was mostly dependent on glycolysis. Furthermore, the transcriptional modulation was mediated by the AMP-activated protein kinase (AMPK) signaling pathway, which activated its downstream modulators leading to a subsequent increase in glycolytic flux through activation of pyruvate dehydrogenase. In contrast, the activities of carnitine palmitoyltransferase for fatty acid oxidation and acetyl-CoA carboxylase-1 for fatty acid synthesis were reduced and transcriptional regulation factors for biogenesis were not altered. These results provide novel information that MELAS cells lack the adaptive mechanism to switch fuel source from glucose to fatty acid, as glycolysis rates increase in response to energy deficiency. The aberrant secondary cellular responses to disrupted metabolic homeostasis mediated by AMPK signaling pathway may contribute to the development of the clinical phenotype.

Objective: To investigate the prognostic value of t(11;14) for de novo multiple myeloma (MM) patients in novel agent era. Methods: A total of 455 patients with fluorescence in situ hybridization (FISH), before treatments from three hospitals in China, were included in the study. All patients received autologous stem cell transplantation (ASCT) after induction therapy as consolidation. High risk (HR) cytogenetics were defined as t(4;14), t(14;16), and/or del 17p. Results: A total of 152 patients were in the HR group. Of patients without HR cytogenetics, 55 were in the t(11;14) group, and 248 were in the standard risk (SR) group without t(11;14). Gain in 1q21 was observed in 38.9% patients with t(11;14). There were no differences in median progression free survival (PFS) and overall survival (OS), respectively, between patients in the t(11;14) group and those in the SR group. Patients in the t(11;14) group had the longer median PFS and OS, respectively, compared with those in the HR group. Regardless of coexisting with 1q21 gain or not, patients in the t(11;14) group still had similar median PFS and OS compared to those in the SR group. Finally, multivariate analysis indicated that including 1q21 gain and bone marrow plasma cell with CD20 expression, no variables were found to predict the outcome of the t(11;14) group in our cohort. Conclusions: These results confirm that outcomes of t(11;14) MM are similar to standard risk patients when they receive novel agent induction therapy consolidated by ASCT. Gain of 1q21 coexists with t(11;14) frequently. In addition, both bone marrow plasma cell with CD20 expression and 1q21 gain have no impact on median PFS or OS for patients with t(11;14).

Bladder cancer is the most common malignant urological disease in China. Hydroxycamptothecin (HCPT) is a DNA topoisomerase I inhibitor, which has been utilized in chemotherapy for bladder cancer for nearly 40 years. Previous research has demonstrated that the isoflavone, genistein, can sensitize multiple cancer cell lines to HCPT treatment, such as prostate and cervical cancer. In this study, we investigated whether genistein could sensitize bladder cancer cell lines and bladder epithelial cell BDEC cells to HCPT treatment, and investigated the possible underlying molecular mechanisms. Genistein could significantly and dose-dependently sensitize multiple bladder cancer cell lines and BDEC cells to HCPT-induced apoptosis both in vitro and in vivo. Genistein and HCPT synergistically inhibited bladder cell growth and proliferation, and induced G2/M phase cell cycle arrest and apoptosis in TCCSUP bladder cancer cell and BDEC cell. Pretreatment with genistein sensitized BDEC and bladder cancer cell lines to HCPT-induced DNA damage by the synergistic activation of ataxia telangiectasia mutated (ATM) kinase. Genistein significantly attenuated the ability of HCPT to induce activation of the anti-apoptotic NF-κB pathway both in vitro and in vivo in a bladder cancer xenograft model, and thus counteracted the anti-apoptotic effect of the NF-κB pathway. This study indicates that genistein could act as a promising non-toxic agent to improve efficacy of HCPT bladder cancer chemotherapy.