Citations

Abstract1q21 gain is a common cytogenetic abnormality featuring high‐risk multiple myeloma (HRMM). However, the molecular mechanism underlying the adverse prognostic effect of 1q21 gain remains largely unclear. Here, we report that ARNT/HIF‐1β, a 1q21 gene, is highly expressed in HRMM and induced by microenvironmental hypoxia, which confers drug resistance and correlates with inferior outcome. Analysis of the gene expression profile database revealed that ARNT expression was upregulated in MM and increased with disease progression or in HRMM subtypes (particularly 1q21 gain), while correlated to shorter overall survival. In a cohort of 40 MM patients, qPCR further validated that ARNT expression was higher in MM patients than normal donors. MM cells carrying 1q21 gain or acquired drug resistance displayed a robust increase in HIF‐1β protein level. Hypoxia induced HIF‐1β expression via a NF‐κB‐dependent process. Notably, HIF‐1β overexpression impaired bortezomib sensitivity, whereas shRNA knockdown of ARNT reversed hypoxia‐mediated drug resistance. Together, these findings suggest that ARNT/HIF‐1β might represent a novel biomarker for risk stratification and prognosis of HRMM patients, as well as a potential therapeutic target for overcoming 1q21 gain‐ or microenvironment‐mediated and acquired drug resistance in MM.

Background and Purpose— White matter (WM) ischemic injury, a major neuropathological feature of cerebral small vessel diseases, is an important cause of vascular cognitive impairment in later life. The pathogenesis of demyelination after WM ischemic damage are often accompanied by microglial activation. Fingolimod (FTY720) was approved for the treatment of multiple sclerosis for its immunosuppression property. In this study, we evaluated the neuroprotective potential of FTY720 in a WM ischemia model. Methods— Chronic WM ischemic injury model was induced by bilateral carotid artery stenosis. Cognitive function, WM integrity, microglial activation, and potential pathway involved in microglial polarization were assessed after bilateral carotid artery stenosis. Results— Disruption of WM integrity was characterized by demyelination in the corpus callosum and disorganization of Ranvier nodes using Luxol fast blue staining, immunofluorescence staining, and electron microscopy. In addition, radial maze test demonstrated that working memory performance was decreased at 1-month post–bilateral carotid artery stenosis–induced injury. Interestingly, FTY720 could reduce cognitive decline and ameliorate the disruption of WM integrity. Mechanistically, cerebral hypoperfusion induced microglial activation, production of associated proinflammatory cytokines, and priming of microglial polarization toward the M1 phenotype, whereas FTY720 attenuated microglia-mediated neuroinflammation after WM ischemia and promoted oligodendrocytogenesis by shifting microglia toward M2 polarization. FTY720’s effect on microglial M2 polarization was largely suppressed by selective signal transducer and activator of transcription 3 (STAT3) blockade in vitro, revealing that FTY720-enabled shift of microglia from M1 to M2 polarization state was possibly mediated by STAT3 signaling. Conclusions— Our study suggested that FTY720 might be a potential therapeutic drug targeting brain inflammation by skewing microglia toward M2 polarization after chronic cerebral hypoperfusion.

Purpose According to the lung cancer staging project, T1a (≤ 2 cm) non–small-cell lung cancer (NSCLC) should be additionally classified into ≤ 1 cm and > 1 to 2 cm groups. This study aimed to investigate the surgical procedure for NSCLC ≤ 1 cm and > 1 to 2 cm. Methods We identified 15,760 patients with T1aN0M0 NSCLC after surgery from the Surveillance, Epidemiology, and End Results database. Overall survival (OS) and lung cancer–specific survival (LCSS) were compared among patients after lobectomy, segmentectomy, or wedge resection. The proportional hazards model was applied to evaluate multiple prognostic factors. Results OS and LCSS favored lobectomy compared with segmentectomy or wedge resection in patients with NSCLC ≤ 1 cm and > 1 to 2 cm. Multivariable analysis showed that segmentectomy and wedge resection were independently associated with poorer OS and LCSS than lobectomy for NSCLC ≤ 1 cm and > 1 to 2 cm. With sublobar resection, lower OS and LCSS emerged for NSCLC > 1 to 2 cm after wedge resection, whereas similar survivals were observed for NSCLC ≤ 1 cm. Multivariable analyses showed that wedge resection is an independent risk factor of survival for NSCLC > 1 to 2 cm but not for NSCLC ≤ 1 cm. Conclusion Lobectomy showed better survival than sublobar resection for patients with NSCLC ≤ 1 cm and > 1 to 2 cm. For patients in whom lobectomy is unsuitable, segmentectomy should be recommended for NSCLC > 1 to 2 cm, whereas surgeons could rely on surgical skills and the patient profile to decide between segmentectomy and wedge resection for NSCLC ≤ 1 cm.

AbstractTumor necrosis factor‐α (TNF‐α) contributes to myocardial infarction (MI) injury. Polymorphism of TNF‐α gene promoter region and secretion and release of TNF‐α and its transformation by a series of signaling pathways are all changed at different points of pathophysiological process in MI. Researches also investigated TNF‐α antagonists and their potential therapeutic role in the setting of MI and heart failure at both molecular and clinical level. This article briefly reviews TNF‐α and its mechanism as a mediator in MI.

Abstract Genetically modified mice with spontaneous development of mammary carcinoma provide a powerful tool to study the efficacy of tumor vaccines, since they mimic breast cancer development in humans. We used a transgenic murine model expressing polyomavirus middle T oncogene and mucin 1 tumor-associated Ag to determine the preventive effect of a dendritic/tumor fusion cell vaccine. The MMT (a transgenic murine model) mice developed mammary carcinoma between the ages of 65–108 days with 100% penetrance. No spontaneous CTL were detected. However, prophylactic vaccination of MMT mice with dendritic/tumor fusion cells induced polyclonal CTL activity against spontaneous mammary carcinoma cells and rendered 57–61% of the mice free of the disease at the end of experiment (180 days). Furthermore, the level of CTL activity was maintained with multiple vaccinations. The antitumor immunity induced by vaccination with dendritic/tumor fusion cells reacted differently to injected tumor cells and autochthonous tumor. Whereas the injected tumor cells were rejected, the autochthonous tumor evaded the attack and was allowed to grow. Collectively these results indicate that prophylactic vaccination with dendritic/tumor fusion cells confers sufficient antitumor immunity to counter the tumorigenesis of potent oncogenic products. The findings in the present study are highly relevant to cancers in humans.

Abstract Rationale: Given recent success in delivering interferon-beta (IFNβ) using replication incompetent adenovirus in patients with malignant pleural effusions, we hypothesized that vectors that could replicate (inducing oncolysis) and express IFNβ at high level would be more effective. Both vaccinia virus (VV) and vesicular stomatitis (VSV) expressing mouse IFNβ have been constructed in a manner to improve their safety and efficacy as oncolytic vectors. In this study, we evaluated these two oncolytic vectors in different murine thoracic cancer models for clinical translation. Experimental procedures: We compared the efficacy of VVIFNβ and VSVIFNβ to kill 3 mouse lung cancer and 4 mouse mesothelioma lines in vitro over a 5 day-period assessing cell viability by MTT assay. The amount of IFNβ produced by these two vectors were measured with ELISA. The viral replication in infected mice was assessed by measuring viral titers in both immunocompetent and immunodeficient mice bearing an IFN-non-responsive AB12 tumor, following intratumoral injection of either vector at 108 pfu/mouse. To assess their anti-tumor activity, the two vectors were also given at 108 pfu/mouse intratumorally in mice bearing two lung cancer tumors on their flanks. Results: The replication of VSVIFNβ and its killing ability was limited in some of the tumor lines. This appeared to be due to an intact IFN response pathway. In contrast, VVIFNβ was able to kill all of the tumor lines. In culture, VSV replicates faster than VV, which resulted in faster cell killing (in susceptible cell lines), but with less IFNβ production. The amount of IFNβ production by VVIFNβ was comparable with AdIFNβ over a 5 day period. VVIFNβ-infected immunodeficient mice showed minimal or no toxicity when given virus intravenously, while all 5 mice infected with VSVIFNβ developed neurotoxicity within a week. In the TC-1 lung cancer model, VVIFNβ caused tumor regression, while VSVIFNβ and AdIFNβ were completely ineffective. In a second model using LKRM2, all 3 viral vectors were equivalent. The anti-tumor effect of VVIFNβ was shown to be mainly CD8 dependant, as depletion of CD8 with antibody dampened the tumor growth inhibition from 48% to 20%. Conclusions: Overall, VVIFNβ appears to be a better oncolytic vector than VSVIFNβ for a number of reasons: 1) it is safer, 2) it is able to replicate in vitro and in vivo in almost every cell line tested, 3) it induces longer and larger IFNβ production, and 4) it can potentially be given intravenously. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1513.