Abstract Intestinal fibrosis induced by chronic and recurrent colitis, which is exacerbated by bowel stenosis, stricture, and obstruction, is challenging to treat. Toll-like receptor 4 (TLR4) stimulates innate and acquired immunity in response to specific microbial components, but the role of TLR4 in intestinal fibrosis is largely unknown. We investigated its role in intestinal fibrosis using not only a murine fibrosis model but also human myofibroblasts and intestinal epithelial cells. Colon fibrosis was induced in TLR4-deficient (TLR4 −/− ) mice and its wild-type counterparts with 3% dextran sulfate sodium. Absence of TLR4 gene attenuated chronic inflammation and colonic macrophages infiltration; intestinal fibrosis and collagen deposition were suppressed. Also, the production of tumor necrosis factor-α, interleukin-12p40, and transforming growth factor-β was reduced in TLR4-deficient peritoneal macrophages. TLR4 was silenced in CCD-18Co cells by small interfering RNA (siRNA), and matrix metalloproteinase-1, tissue inhibitor of metalloproteinase, and collagen α1 expression was evaluated. Role of TLR4 in epithelial-mesenchymal transition (EMT) was evaluated in HCT116 cells. Suppression of TLR4 transcription by siRNAs affected myofibroblasts activity, collagen synthesis, and EMT in the human cancer cell line. Thus, we suggest that TLR4 can be an essential mediator in intestinal chronic inflammation and fibrosis, indicating that TLR4 signaling is a potential therapeutic target for intestinal fibrosis.
A hallmark of neurodegenerative proteinopathies is the formation of misfolded protein aggregates that cause cellular toxicity and contribute to cellular proteostatic collapse. Therapeutic options are currently being explored that target different steps in the production and processing of proteins implicated in neurodegenerative disease, including synthesis, chaperone-assisted folding and trafficking, and degradation via the proteasome and autophagy pathways. Other therapies, like mTOR inhibitors and activators of the heat shock response, can rebalance the entire proteostatic network. However, there are major challenges that impact the development of novel therapies, including incomplete knowledge of druggable disease targets and their mechanism of action as well as a lack of biomarkers to monitor disease progression and therapeutic response. A notable development is the creation of collaborative ecosystems that include patients, clinicians, basic and translational researchers, foundations and regulatory agencies to promote scientific rigor and clinical data to accelerate the development of therapies that prevent, reverse or delay the progression of neurodegenerative proteinopathies.
Abstract Background:According to prior studies, the role of serum vitamin D3 has been inconsistentand clinical implications of 25-hyrdoxyvitamin D (25-OHD) have been little studiedin breast cancer patients receiving neoadjuvant chemotherapy (NCT). Objectives: The aims of study were to investigate changes in 25-OHD levels before and after NCT and to determine the association of 25-OHD and oncologic outcomes including pathological complete response (pCR) in breast cancer patients. Patients and Materials: From January 2010 to December 2013, serum 25-OHD levels at pre- and post-NCT were measured in 377 breast cancer patients. The association of serum 25-OHD levels with clinicopathological data including breast cancer subtypes, pCR and survival were retrospectively analysed. Delta 25-OHD was calculated as serum 25-OHDlevels before minus after NCT. Results: Mean ageof study population was 48.7 yearsand mean follow-up periods were 35.9months.Mean baseline serum 25-OHD concentration was 14.60 ng/mL (standard deviation, 7.44) and more than 80% of patients showed insufficient 25-OHD levels. The mean 25-OHDat post-NCT was 12.16 ng/mL (standard deviation, 6.87).There was a significant decrease in serum 25-OHD after NACT (p<0.001).The pCR rates were 25.7% among study cohort.However, 25-OHD levels at baseline and post-NCT were not related to pCR and survival outcomes. No associations were found between pCR and delta 25-OHD. According to stratification by breast cancer subtypes, however, patients with ≥ -2.67 (median value) of delta 25-OHD revealed a trend of higher achievement of pCR and better survival in luminal A subtype. No associations were found among the other subtypes. Conclusions: Many Korean breast cancer patients showed insufficient serum 25-OHD levels at diagnosis of malignancy and a significant decrease in serum vitamin D3 after NACT was observed.No significant association of 25-OHD 3 with pCR and survival was found. Therefore, correction or maintenance of appropriate serum 25-OHD levels should be focused for bone health as comprehensive management of breast cancer during NCT.In addition, possible oncological aspects of 25-OHD should further researched individually considering breast subtypes. Citation Format: Park S, Lee JS, Kim JH, Lim SM, Park HS, Kim SI. Serum 25-hydroxyvitamin D levels and oncologic outcomes of breast cancer patients receiving neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-16-25.
Trichoepithelioma (TE) is a benign neoplasm of the skin that resembles basal cell carcinoma (BCC) in its clinical and histological features. In this study, we evaluate the usefulness of elastic fiber staining and cytokeratin 15 expression pattern in terms of distinguishing TE from BCC. Eleven TE and 17 BCC were examined histochemically and immunohistochemically. It was found that BCC contain more elastic fiber than TE, and that more TE show peripheral localization than BCC in cytokeratin 15 expression patterns. The present study shows that elastic fiber staining and cytokeratin 15 expression pattern may aid the differentiation of TE from BCC.
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