We describe structure-based design and chemical synthesis of a simplified analog of bistramide A, which potently and reversibly binds monomeric actin with a K(d) of 9.0 nM, depolymerizes filamentous actin in vitro and in A549 (nonsmall cell lung cancer) cells, inhibits growth of cancer cell lines in vitro at submicromolar concentrations, and significantly suppresses proliferation of A549 cells in a nude mice tumor xenograft model in terms of both tumor growth delay and average tumor volume. This study provides a conceptual framework for the design and development of new antiproliferative compounds that target cytoskeletal organization of cancer cells in vivo by a combination of reversible G-actin binding and effective F-actin severing.

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Objective To compare the effects of dietary fat and sex on murine oral squamous cell carcinoma pathology. Materials and methods Male and female C57Bl/6 mice (36/sex) received a low‐fat (10 kcal%) or high‐fat (60 kcal%) diet. Water (control), vehicle, or 4‐nitroquinoline‐1‐oxide in vehicle (50 μg/ml) was provided for 17 weeks followed by six additional weeks of water. Oral lesion development was recorded weekly. Histopathologic changes in tongues were examined, and T cells (CD3+), macrophages (CD68+), and neutrophils (Ly6+) were quantified. Results All 4‐nitroquinoline‐1‐oxide‐treated mice developed oral tumors. High‐fat diet exacerbated pathology, demonstrated by an increased final tumor burden (10.9 ± 4.5 vs. 7.9 ± 2.5, mm/mouse, p < .05; high‐fat diet vs. low‐fat diet, respectively), and a greater histopathology score. When dietary groups were combined, 4‐nitroquinoline‐1‐oxide‐treated males displayed higher histopathology scores than females (4.2 ± 0.3 vs. 3.6 ± 0.2, respectively, p < .05). Lymphoid cell infiltration was greater in the 4‐nitroquinoline‐1‐oxide mouse tongues than controls: T cells (14.0 vs. 0.96 cells/mm2), macrophages (3.6 vs. 1.8 cells/mm2), and neutrophils (12.0 vs. 0.38 cells/mm2). Conclusion High‐fat diet and male sex increased the pathology of 4‐nitroquinoline‐1‐oxide‐induced oral cancer. Elevated lymphoid cell infiltration contributed to disease pathology.

The small intestinal microbiota has recently been implicated in contributing to metabolic disease. We previously demonstrated that diets rich in saturated milk fat have a particularly strong impact on the small bowel microbiota as opposed to more distal gastrointestinal (GI) regions. However, the impact of antibiotics and diet on the small bowel microbiota has not been clearly demonstrated. Thus, we sought to determine how diet and antibiotics interact in modulating the regional landscape of the gut microbiota. We conducted a study using male mice on a high fat (HF) or a low fat (LF) diet (n = 15/group) that received either water control (n = 5/diet), rifaximin, (nonabsorbable broad-spectrum antibiotic; n = 5/diet) or an antibiotic cocktail consisting of metronidazole, cefoperazone, vancomycin, and neomycin (Abx cocktail; n = 5/diet). 16S rRNA sequencing was performed on mucosal scrapings collected from the small intestine and cecum, as well as on stool samples. Interestingly, antibiotics had a significant effect on community composition throughout the small intestine, cecum and stool, whereas diet significantly affected only the jejunum and cecum microbiota. The antibiotic cocktail, regardless of diet, was most effective in increasing cecum size, reducing body fat percentage, and plasma lipid levels. Altogether, this study reveals a selective and divergent regional alteration of the gut microbiota by diet and antibiotics.

ObjectivesCancer is likely caused by alterations in gene structure or expression. Recently, next generation sequencing has documented mutations in 106 head and neck squamous cell cancer genomes, suggesting several new candidate genes. However, it remains difficult to determine which mutations directly contributed to cancer. Here, summarize the animal models which have already validated and may test cancer causing mutations identified by next generation sequencing approaches.Material and MethodsWe reviewed the existing literature on genetically engineered mouse models and next generation sequencing (NGS), as it relates to animal models of squamous cell cancers of the head and neck (HNSCC) in PubMed.ResultsNSG has identified an average of 19 to 130 distinct mutations per HNSCC specimen. While many mutations likely had biological significance, it remains unclear which mutations were essential to, or "drive," carcinogenesis. In contrast, "passenger" mutations also exist that provide no selection advantage. The genes identified by NGS included p53, RAS, Human Papillomavirus oncogenes, as well as novel genes such as NOTCH1, DICER and SYNE1,2. Animal models of HNSCC have already validated some of these common gene mutations identified by NGS.Conclusions The advent of next generation sequencing will provide new leads to the genetic changes occurring in squamous cell cancers of the head and neck. Animal models will enable us to validate these new leads in order to better elucidate the biology of squamous cell cancers of the head and neck.