1,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3); 1,25-dihydroxycholecalciferol or calcitriol] is the active form of vitamin D(3), a lipid-soluble vitamin that plays a role in calcium and bone metabolism. Recently, vitamin D(3) has been shown to function in cancer prevention, immunity and cardiovascular regulation. 1,25(OH)(2)D(3) exhibits physiological and pharmacological effects by activating the vitamin D receptor (VDR), a transcription factor of the nuclear receptor superfamily. 1,25(OH)(2)D(3) plays a role in maintaining oral health through its effects on bone and mineral metabolism and innate immunity, and several VDR gene polymorphisms have been reported to be associated with periodontal disease. VDR ligands should prove to be useful in the treatment and prevention of periodontal disease.

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Background: High-flow nasal cannula (HFNC) oxygen therapy may provide effective respiratory management of hypoxemic respiratory failure in patients with interstitial lung disease (ILD) with a do-not-intubate (DNI) order. Objectives: The aim was to assess the efficacy and tolerability of HFNC for these patients. Methods: We retrospectively reviewed the records of patients requesting a DNI order for hypoxemic respiratory failure associated with ILD, comparing treatment with HFNC and noninvasive positive pressure ventilation (NPPV). Outcomes measured were 30-day survival, in-hospital mortality, temporary interruption and discontinuation of the treatment at the patient’s request, adverse events, oral intake, and communication ability at the end of life. Results: A total of 84 patients (HFNC, n = 54; NPPV, n = 30) were analyzed. Neither 30-day survival (HFNC 31.5% vs. NPPV 30.0%; p = 0.86) nor in-hospital mortality (HFNC 79.6% vs. NPPV 83.3%; p = 0.78) differed significantly. The temporary interruption and discontinuation rates were significantly lower in the HFNC group than in the NPPV group (3.7 vs. 23.3%; p = 0.009 and 0 vs. 10%; p = 0.043, respectively), and that group had significantly fewer adverse events. Among patients who died in the hospital, those treated with HFNC had significantly better oral intake and ability to converse until just before death. Conclusion: HFNC had a survival rate equivalent to that of NPPV and was better tolerated by patients with hypoxemic respiratory failure associated with ILD who had a DNI order. HFNC allowed patients to eat and converse until just before death, suggesting that HFNC in these patients is a reasonable palliative treatment.

Benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon produced by cigarette combustion, is implicated as a causative agent in smoking-related cancer and atherosclerosis. 1,25-Dihydroxyvitamin D3 [1,25(OH)2D3], a potent ligand for the nuclear receptor vitamin D receptor (VDR), has been shown to decrease the risk of osteoporosis, some types of cancer and cardiovascular disease, suggesting an opposing effect of vitamin D3 to cigarette smoking. In this study, we investigated the effects of BaP on the vitamin D3 signaling pathway. BaP effectively enhanced the 1,25(OH)2D3-dependent induction of cytochrome P450 24A1 (CYP24A1) in human monocyte/macrophage-derived THP-1 cells and breast cancer MCF-7 cells. BaP combination was less or not effective on mRNA expression of CD14, arachidonate 5-lipoxygenase, and cathelicidin antimicrobial peptide in THP-1 cells. BaP also increased the expression of CYP24A1 induced by a non-vitamin D VDR ligand, lithocholic acid acetate. Another aryl hydrocarbon receptor (AhR) ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin, enhanced CYP24A1 expression by 1,25(OH)2D3 in THP-1 cells. Treatment of cells with an AhR antagonist and a protein synthesis inhibitor inhibited the enhancing effect of BaP on CYP24A1 induction, indicating that the effects of BaP are mediated by AhR activation and de novo protein synthesis. BaP pretreatment increased 1,25(OH)2D3-dependent recruitment of VDR and retinoid X receptor to the CYP24A1 promoter. Analysis of 1,25(OH)2D3 metabolism showed that BaP enhanced the hydroxylation of 1,25(OH)2D3 by CYP24A1 in THP-1 cells. Thus, AhR activation by BaP stimulates vitamin D3 catabolism. Modulation of vitamin D signaling by AhR may represent a mechanism underlying cigarette smoking-related diseases.

Stem cell-based therapy has been proposed as a promising strategy for regenerating tissues lost through incurable diseases. Side population (SP) cells have been identified as putative stem cells in various organs. To examine therapeutic potential of SP cells in hypofunction of exocrine glands, SP cells isolated from mouse exocrine glands, namely, lacrimal and salivary glands, were transplanted into mice with irradiation-induced hypofunction of the respective glands. The secretions from both glands in the recipient mice were restored within 2 months of transplantation, although the transplanted cells were only sparsely distributed and produced no outgrowths. Consistent with this, most SP cells were shown to be CD31-positive endothelial-like cells. In addition, we clarified that endothelial cell-derived clusterin, a secretory protein, was an essential factor for SP cell-mediated recovery of the hypofunctioning glands because SP cells isolated from salivary glands of clusterin-deficient mice had no therapeutic potential, whereas lentiviral transduction of clusterin restored the hypofunction. In vitro and in vivo studies showed that clusterin had an ability to directly inhibit oxidative stress and oxidative stress-induced cell damage. Thus, endothelial cell-derived clusterin possibly inhibit oxidative stress-induced hypofunction of these glands.

The major driver mutations of lung cancer, EGFR mutations and EML4‐ALK fusion, are mainly detected in terminal respiratory unit (TRU)‐type lung adenocarcinomas, which typically show lepidic and/or papillary patterns, but are rarely associated with a solid or invasive mucinous morphology. In order to elucidate the key genetic events in non‐TRU‐type lung cancer, we carried out whole‐exome sequencing on 43 non‐TRU‐type lung adenocarcinomas based on morphology (17 acinar, nine solid, and two enteric adenocarcinomas, and 15 adenocarcinomas with a mucinous morphology). Our analysis identified mutations in TP53 (16/43, 37.2%), KRAS (13/43, 30.2%), and NKX2‐1/TTF‐1 (7/43; 16.3%) as the top three significantly mutated genes, while the EGFR mutation was rare (1/43, 2.3%) in this cohort. Eight NKX2‐1/TTF‐1 mutations (five frameshift, two nonsense, and one missense) were identified, with one case harboring two distinct NKX2‐1/TTF‐1 mutations (one missense and one frameshift). Functional assays with the NK2 homeobox 1 (NKX2‐1)/thyroid transcription factor 1 (TTF‐1) mutants revealed that none of them retain the activity as a transcriptional factor. Histologically, invasive mucinous adenocarcinomas accounted for most of the NKX2‐1/TTF‐1 mutations (five cases), as well as one enteric and one acinar adenocarcinoma. Immunohistochemistry showed that the cohort was largely divided into TTF‐1‐postive/hepatocyte nuclear factor 4‐α (HNF4‐α)‐negative and TTF‐1‐negative/HNF4‐α‐positive groups. NKX2‐1/TTF‐1 mutations were exclusively found in the latter, in which the gastrointestinal markers, mucin 5AC and cytokeratin 20, were frequently expressed. Bisulfite sequencing revealed that the NKX2‐1/TTF‐1 gene body was highly methylated in NKX2‐1/TTF‐1‐negative cases, including those without the NKX2‐1/TTF‐1 mutations. The genetic or epigenetic inactivation of NKX2‐1/TTF‐1 may play an essential role in the development and aberrant differentiation of non‐TRU‐type lung adenocarcinomas.

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This paper deals with nonautonomous Liénard-type systems. Sufficient conditions are given for the zero solution of the systems to be globally asymptotically stable. The main result is proved by means of phase plane analysis with a Liapunov function. Examples are included to contrast our theorem with results which were presented by Hatvani and Cantarelli. Some global phase portraits are also attached.