Recent studies have shown that stromal fibroblasts have a more profound influence on the initiation and progression of carcinoma than was previously appreciated. This study aimed at investigating the reciprocal relationship between cancer cells and their associated fibroblasts at both the molecular and cellular level in oral squamous cell carcinoma (OSCC). To identify key molecular regulators expressed by carcinoma-associated fibroblasts (CAF) that promote cancer cell invasion, microarrays were performed by comparing cocultured OSCC cells and CAF with monoculture controls. Microarray and real-time PCR analysis identified marked upregulation of the chemokine (C-C motif) ligand 7 (CCL7) in cocultured CAF. ELISA showed an elevated level of CCL7 secretion from CAF stimulated by coculture with OSCC cells. CCL7 promoted the invasion and migration of OSCC cells, and the invasiveness was inhibited by treatment with CCL7 neutralizing antibody. OSCC cells were shown to express CCR1, CCR2 and CCR3, receptors for CCL7, by RT-PCR. In addition, treatment with anti-CCR1 or anti-CCR3 antibody inhibited CCL7-induced OSCC cell migration, implicating that CCL7 promotes cancer cell migration through CCR1 and CCR3 on OSCC cells. Cytokine antibody array analysis of the supernatant from OSCC cell culture revealed that interleukin-1a was an inducer of CCL7 secretion by CAF. This study confirms the reciprocal relationship of the molecular crosstalk regulating the invasion of OSCC and describes new potential targets for future therapy.Carcinomas are malignant neoplasms derived from epithelial cells and are surrounded by specialized stroma, which orchestrate with cancer cells to regulate disease progression. 1-3 Carcinoma-associated fibroblasts (CAF) have been recognized as prominent modifiers of cancer initiation and progression. 4,5 For instance, it has been previously demonstrated that human prostatic CAF induce tumor formation from initiated but nontumorigenic human prostatic epithelial cells. 6 CAF also facilitate the invasiveness of otherwise noninvasive cancer cells when coinjected into mice. 7 The putative proinvasive effects of CAF may be mediated through either direct heterotypic cellÀcell contacts 8 or diffusible molecules, such as inflammatory mediators, cytokines and chemokines. 9,10 Chemokines have been shown to play an important role in tumor biology by influencing tumor growth, invasion and metastasis. 11 Chemokines are a family of small, structurally related cytokines with chemoattractant and activation properties that are involved in inflammatory reactions. 12 They are classified mainly into the CC and CXC subfamilies, according to the location of the first 2 cysteine residues, and are produced by a range of cell types, including fibroblasts. Various types of cancer cells also express chemokines and chemokine receptors, 11,[13][14][15] and their autocrine and paracrine roles in cancer progression are receiving increasing attention. For example, the CXC chemokine, CXCL12 (stromal cell-derived factor 1), secreted by CAF, r...

Enolase is a component of the glycolysis pathway and a "moonlighting" protein, with important roles in diverse cellular processes that are not related to its function in glycolysis. However, small molecule tools to probe enolase function have been restricted to crystallography or enzymology. In this study, we report the discovery of the small molecule "ENOblock", which is the first, nonsubstrate analogue that directly binds to enolase and inhibits its activity. ENOblock was isolated by small molecule screening in a cancer cell assay to detect cytotoxic agents that function in hypoxic conditions, which has previously been shown to induce drug resistance. Further analysis revealed that ENOblock can inhibit cancer cell metastasis in vivo. Moreover, an unexpected role for enolase in glucose homeostasis was revealed by in vivo analysis. Thus, ENOblock is the first reported enolase inhibitor that is suitable for biological assays. This new chemical tool may also be suitable for further study as a cancer and diabetes drug candidate.

Xylitol dehydrogenase (XDH) is one of the key enzymes in D-xylose metabolism, catalyzing the oxidation of xylitol to D-xylulose. Two copies of the XYL2 gene encoding XDH in the diploid yeast Candida tropicalis were sequentially disrupted using the Ura-blasting method. The XYL2-disrupted mutant, BSXDH-3, did not grow on a minimal medium containing D-xylose as a sole carbon source. An enzyme assay experiment indicated that BSXDH-3 lost apparently all XDH activity. Xylitol production by BSXDH-3 was evaluated using a xylitol fermentation medium with glucose as a cosubstrate. As glucose was found to be an insufficient cosubstrate, various carbon sources were screened for efficient cofactor regeneration, and glycerol was found to be the best cosubstrate. BSXDH-3 produced xylitol with a volumetric productivity of 3.23 g liter ؊1 h ؊1 , a specific productivity of 0.76 g g ؊1 h ؊1 , and a xylitol yield of 98%. This is the first report of gene disruption of C. tropicalis for enhancing the efficiency of xylitol production.

Artificial intelligence capabilities have, recently, greatly improved. In the past few years, one of the deep learning algorithms, the recurrent neural network (RNN), has shown an outstanding ability in sequence labeling and prediction tasks for sequential data. We built a reliable visual field prediction algorithm using RNN and evaluated its performance in comparison with the conventional pointwise ordinary linear regression (OLR) method. A total of 1,408 eyes were used as a training dataset and another dataset, comprising 281 eyes, was used as a test dataset. Five consecutive visual field tests were provided to the constructed RNN as input and a 6 th visual field test was compared with the output of the RNN. The performance of the RNN was compared with that of OLR by predicting the 6 th visual field in the test dataset. The overall prediction performance of RNN was significantly better than OLR. The pointwise prediction error of the RNN was significantly smaller than that of the OLR in most areas known to be vulnerable to glaucomatous damage. The RNN was also more robust and reliable regarding worsening in the visual field examination. In clinical practice, the RNN model can therefore assist in decision-making for further treatment of glaucoma.

Molecular crosstalk between cancer cells and fibroblasts has been an emerging hot issue in understanding carcinogenesis. As oral submucous fibrosis (OSF) is an inflammatory fibrotic disease that can potentially transform into squamous cell carcinoma, OSF has been considered to be an appropriate model for studying the role of fibroblasts during early stage carcinogenesis. In this sense, this study aims at investigating whether areca nut (AN)‐exposed fibroblasts cause DNA damage of epithelial cells. For this study, immortalized hNOF (hTERT‐hNOF) was used. We found that the levels of GRO‐α, IL‐6 and IL‐8 increased in AN‐exposed fibroblasts. Cytokine secretion was reduced by antioxidants in AN‐exposed fibroblasts. Increase in DNA double strand breaks (DSB) and 8‐oxoG FITC‐conjugate was observed in immortalized human oral keratinocytes (IHOK) after the treatment of cytokines or a conditioned medium derived from AN‐exposed fibroblasts. Cytokine expression and DNA damage were also detected in OSF tissues. The DNA damage was reduced by neutralizing cytokines or antioxidant treatment. Generation of reactive oxygen species (ROS) and DNA damage response, triggered by cytokines, were abolished when NADPH oxidase (NOX) 1 and 4 were silenced in IHOK, indicating that cytokine‐triggered DNA damage was caused by ROS generation through NOX1 and NOX4. Taken together, this study provided strong evidence that blocking ROS generation might be a rewarding approach for cancer prevention and intervention in OSF.