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African-American (AA) women with breast cancer (BC) are diagnosed with more aggressive disease, have higher risk of recurrence and poorer prognosis as compared to Caucasian American (CA) women. Therefore, it is imperative to define the factors associated with such disparities to reduce the unequal burden of cancer. Emerging data suggest that inherent differences exist in the tumor microenvironment of AA and CA BC patients, however, its molecular bases and functional impact have remained poorly understood. Here, we conducted cytokine profiling in serum samples from AA and CA BC patients and identified resistin and IL-6 to be the most differentially-expressed cytokines with relative greater expression in AA patients. Resistin and IL-6 exhibited positive correlation in serum levels and treatment of BC cells with resistin led to enhanced production of IL-6. Moreover, resistin also enhanced the expression and phosphorylation of STAT3, and treatment of BC cells with IL-6-neutralizing antibody prior to resistin stimulation abolished STAT3 phosphorylation. In addition, resistin promoted growth and aggressiveness of BC cells, and these effects were mediated through STAT3 activation. Together, these findings suggest a crucial role of resistin, IL-6 and STAT3 in BC racial disparity.

Pancreatic cancer (PC) remains a highly lethal malignancy due to its unusual chemoresistance and high aggressiveness. A subpopulation of pancreatic tumor cells, known as cancer stem cells (CSCs), is considered responsible not only for tumor-maintenance, but also for its widespread metastasis and therapeutic failure. Here we investigated the role of p-21 activated kinase 4 (PAK4) in driving PC stemness properties. Our data demonstrate that triple-positive (CD24+/CD44+/EpCAM+) subpopulation of pancreatic CSCs exhibits greater level of PAK4 as compared to triple-negative (CD24−/CD44−/EpCAM−) cells. Moreover, PAK4 silencing in PC cells leads to diminished fraction of CD24, CD44, and EpCAM positive cells. Furthermore, we show that PAK4-silenced PC cells exhibit decreased sphere-forming ability and increased chemo-sensitivity to gemcitabine toxicity. PAK4 expression is also associated with enhanced levels of stemness-associated transcription factors (Oct4/Nanog/Sox2 and KLF4). Furthermore, our data show decreased nuclear accumulation and transcriptional activity of STAT3 in PAK4-silenced PC cells and restitution of its activity leads to restoration of stem cell phenotypes. Together, our findings deliver first experimental evidence for the involvement of PAK4 in PC stemness and support its clinical utility as a novel therapeutic target in PC.

The Wnt and Notch1 signaling pathways play major roles in intestinal development and tumorigenesis. Sub-cellular localization of β-catenin has been implicated in colorectal carcinogenesis. However, the β-catenin and Notch intracellular domain (NICD) interaction has to be addressed. Immunohistochemistries of β-catenin, NICD, and dual immunofluorescence of β-catenin and NICD were analyzed in colorectal tissues and HT29 cell line. Moreover, real-time PCR analysis of CyclinD1, Hes1 and MUC2 was done in HT29 cells upon N-[N-(3, 5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) treatment. Dual staining emphasized the strong interaction of β-catenin and NICD in adenoma and adenocarcinoma than in normal tissues. Hes1 transcript levels were decreased 1.5- and 7.1-fold in 12.5 and 25 µM DAPT-treated HT29 cells. CyclinD1 transcript levels decreased 1.2- and 1.6-fold, and MUC2 transcript level increased 4.3- and 7.5-fold in 12.5 and 25 µM DAPT-treated HT29 cells. The results of this study showed that the sub-cellular localization of β-catenin converges with NICD inducing proliferation through the activation of CyclinD1 and Hes1. Moreover, the inhibition of Notch1 signaling by DAPT leads to the arrest of cell proliferation and induces apoptosis leading to the upregulation of MUC2, a secretory cell lineage marker.

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ObjectiveThe study was designed to establish choline deficiency model (CDM) in broilers for evaluating efficacy of polyherbal formulation (PHF) in comparison with synthetic choline chloride (SCC).MethodsA total of 2,550 one-day-old Cobb 430 broiler chicks were randomly assigned to different groups in three experiments. In experiment 1, G1 and G2 served as normal controls and were fed a basal diet with 100% soybean meal (SBM) as a major protein source supplemented with and without SCC, respectively. In G3, G4, G5, and G6 groups, SBM was replaced at 25%, 50%, 75%, and 100% by soy protein isolate (SPI) to induce a graded level of choline deficiency. In experiment 2, PHF (500 and 1,000 g/ton) in comparison with SCC (1,000 g/ton) were evaluated. In experiment 3, dose-response of PHF (200, 400, and 500 g/ton) with SCC (400 g/ton) was determined.ResultsReplacement of SBM by SPI produced a linear decrease in body weight gain (BWG) with a poor feed conversion ratio (FCR). 25% SBM replacement by SPI yielded an optimum negative impact on BWG and FCR; hence, it is considered for further studies. In experiment 2, PHF (500 and 1,000 g/ton) and SCC (1,000 g/ton) showed a similar performance in BWG, FCR and relative liver weight. In experiment 3, PHF produced an optimum efficacy at 400 g/ton and was comparable to SCC in the restoration of serum aspartate aminotransferase activity, abdominal fat, breast muscle lipid content and liver histopathological abnormalities.ConclusionReplacement of SBM by SPI caused choline deficiency characterised by worsening of BWG, FCR, elevation in liver enzymes and histopathological changes indicating fatty liver. CDM was found valid for evaluating SCC and PHF. It is concluded that PHF has the potential to mimic biological activities of SCC through the restoration of negative effects caused by CDM.

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