Smoking and Drinking Activates NF-κB /IL-6 Axis to Promote Inflammation During Cervical Carcinogenesis

Background: High-risk strains of HPV are known to cause cervical cancer. Multiple clinical studies have emphasized that smoking and drinking are critical risk factors for cervical cancer and its high-grade precursors. In this study, we investigated the molecular mechanisms involved in the interplay of smoking and/or drinking with HPV infectivity and defined a systematic therapeutic approach for their attenuation in cervical cancer. Methods: The impact of benzo[a]pyrene (B[a]P) and/or ethanol (EtOH) exposure on cervical cancer cells was assessed by measuring changes in cell proliferation, clonogenicity, biophysical properties, cell migration, and invasion. Expression of HPV16 E6/E7, NF-κB, cytokines, cell cycle, and inflammation mediators was determined using qRT-PCR, immunoblotting, ELISA, luciferase reporter assay and confocal microscopy. Results: The exposure of cervical cancer cells to B[a]P and/or EtOH altered the expression of HPV16 E6/E7 oncogenes and EMT markers; it also enhanced cellular clonogenicity, migration, and invasion. In addition, B[a]P and/or EtOH exposure promoted inflammation pathways through TNF-α and NF-κB signaling, leading to IL-6 upregulation and activation of VEGFA. These molecular effects caused by B[a]P and/or EtOH exposure were effectively attenuated by Cur/PLGA-Cur. Conclusion: These data suggest a molecular link between smoking, drinking, and HPV infectivity in cervical carcinogenesis. However, these events were determined to be attenuated by treatment with Cur/PLGA-Cur treatment, implying its role in cervical cancer prevention/treatment

Novel nanoparticle formulation of Sabizabulin (VERU-111) for pancreatic cancer treatment

Background: Pancreatic cancer (PanCa) is one of the leading causes of cancer-related mortality in the United States due to very limited therapeutic options. Thus, developing novel therapeutic strategies will help for the management of this disease. We recently identified VERU-111, a novel synthetic molecule which showed potent anti-cancer effect against PanCa via targeting clinically important βIII and βIV tubulin isoforms. In this study, we synthesized and characterized its novel nanoformulation (MNP-VERU) and evaluated its therapeutic effects in vitro and xenograft mouse model. Methods: MNPs were prepared by chemical precipitation method and loaded with VERU-111 using diffusion method. This formulation was characterized for particle size, chemical composition, and drug loading efficiency, using various physico-chemical methods (TEM, FT-IR, DSC, TGA, and HPLC). The internalization of MNP-VERU was achieved after 6 hours incubation with MNP-VERU in PanCa cells. To determine therapeutic efficacy of MNP-VERU, we performed various in vitro (MTS, wound healing, boyden chamber real-time xCELLigence, and apoptosis assays) and in vivo (mouse tumor xenograft) studies using PanCa. Effect of MNP-VERU on various key oncogenic signaling pathways, and miRNAs was evaluated by Western blot, immunohistochemistry (IHC), confocal microscopy, qRT-PCR and in situ hybridization (ISH) analyses respectively. Results: Our novel MNP-VERU formulation provided average size of 110 nm in dynamic light scattering (DLS) and exhibited -8.23 to -11.65 mV zeta potential with an outstanding loading efficiency (94%). Cellular uptake and internalization studies demonstrate that MNP-VERU escape lysosomal degradation, providing efficient endosomal release to cytosol. MNP-VERU showed remarkable anti-cancer potential in various PanCa cells (Panc-1, AsPC-1, HPAF-II, BxPC-3, MiaPaca) and more effectively repressed βIII and βIV tubulin isoforms via restoring the expression of miR-200c. MNP-VERU more effectively suppressed AsPC-1 cells derived xenograft tumors in athymic nude mice. Conclusions: Taken together, our results suggest that MNP-VERU has more anti-cancer potential than free VERU-111 against PanCa. MNP-VERU may reduce the toxicity and improve the bioavailability of free VERU-111 and could be used for the management of PanCa and

Film tourism and its impact on residents quality of life: a multi logit analysis

Past research has confirmed film tourism emerging as a major growth sector for research in tourism and a driver of tourism development for many destinations. To date, there has been relatively substantial literature on the subject, yet this paper tries to shed some light on the quality of life perception with respect to the International Film Festival of India (IFFI). Earlier research results have shown different impacts of film tourism on the quality of life of the local community, and the perceptions and attitudes of residents towards tourism, but no research has shown neither how nor how much these perceptions and attitudes change according to a change in the demographic profile of the local community. The empirical findings show that: age, income, education and marital status have a significant impact on residents’ attitude towards film tourism. Factor analysis resulted in 4 latent factors which drive residents’ perception about quality of life, viz., Community Pride, Personal Benefits, Negative Environmental effect and Negative Social effect. The results have shown that a variation in the demographic profile of the resident community determines a variation in the attitudes towards tourism impacts. In a time of mass movement of people, man power and immigration, changes in the demographic profile of residents are very likely and this research shows that it should be taken into consideration when managing tourism destinations and planning new tourism policies