Impact of chrono-radiotherapy on the prognosis and treatment-related toxicity in patients with locally advanced nasopharyngeal carcinoma: A multicenter propensity-matched study.

The timing of radiotherapy (RT) delivery has been reported to affect both cancer survival and treatment toxicity. However, the association among the timing of RT delivery, survival, and toxicity in locally advanced nasopharyngeal carcinoma (LA-NPC) has not been investigated. We retrospectively reviewed patients diagnosed with LA-NPC who received definitive RT at multiple institutions. The median RT delivery daytime was categorized as morning (DAY) and night (NIGHT). Seasonal variations were classified into the darker half of the year (WINTER) and brighter half (SUMMER) according to the sunshine duration. Cohorts were balanced according to baseline characteristics using propensity score matching (PSM). Survival and toxicity outcomes were evaluated using Cox regression models. A total of 355 patients were included, with 194/161 in DAY/NIGHT and 187/168 in WINTER/SUMMER groups. RT delivered during the daytime prolonged the 5-year overall survival (OS) (90.6% vs. 80.0%, p = 0.009). However, the significance of the trend was lost after PSM (p = 0.068). After PSM analysis, the DAY cohort derived a greater benefit in 5-year progression-free survival (PFS) (85.6% vs. 73.4%, p = 0.021) and distant metastasis-free survival (DMFS) (89.2% vs. 80.8%, p = 0.051) in comparison with the NIGHT subgroup. Moreover, multivariate analysis showed that daytime RT was an independent prognostic factor for OS, PFS, and DMFS. Furthermore, daytime RT delivery was associated with an increase in the incidence of leukopenia and radiation dermatitis. RT delivery in SUMMER influenced only the OS significantly (before PSM: p = 0.051; after PSM: p = 0.034). There was no association between toxicity and the timing of RT delivery by season. In LA-NPC, the daytime of radical RT served as an independent prognostic factor. Furthermore, RT administered in the morning resulted in more severe toxic side effects than that at night, which needs to be confirmed in a future study.

Variations of bile bacterial community alongside gallstone disease progression and key taxa involved in poor outcomes after endoscopic surgery.

Gallstone disease is a prevalent biliary disease worldwide, and bacteria play vital roles in the disease development and progression, as well as the prognosis after endoscopic surgery. However, there have been limited studies to explore the key taxa involved. In this study, bile samples from healthy controls (HCs, liver donors without hepatobiliary disease) and three diseased groups, namely patients with gallbladder stones (GBS), patients with common bile duct stones (CBDS), and patients with stricture in the common bile duct (SCBD), were collected and analyzed. Bacterial community characterization based on 16S rRNA amplicon sequencing showed that bacterial diversities did not change significantly alongside gallstone disease development and progression. The predominant phyla in each group were Proteobacteria, Firmicutes, Bacteroidota, and Fusobacteriota, representing over 80% in abundance of the biliary bacteria community. Specifically, the abundance of Proteobacteria decreased greatly while that of Firmicutes and Bacteroidota increased greatly in the diseased groups when compared to that in HCs. Moreover, linear discriminant analysis identified several genera highly represented in the diseased groups. Among them, Klebsiella, Prevotella, Pseudomonas and Veillonella are persistent in both the HCs group and the diseased groups, indicating an enrichment of local bile bacteria in the diseased bile; while Lachnoanerobaculum, Atopobium, Oribacterium, and Stomatobaculum, those aligned to oral cavity taxa, are persistent in the diseased groups but are transient in the HCs group, and their abundances sequentially increased with the disease development and progression (HCs→GBS→CBDS→SCBD), implying a translocation and colonization of the oral cavity bacteria in the diseased bile. Moreover, co-occurrence network analysis revealed that bacterial infection (e.g., Photobacterium and Plesiomonas) from the intestine was developed during endoscopic surgery with reduced bile bacteria diversity. The results of this study revealed that the bile bacterial community is relatively stable and dominated by a few persistent taxa. Moreover, we hypothesized that translocation and colonization of specific bacteria from the oral cavity happens alongside gallstone disease development and progression, and bacterial infection from the intestinal tract results in poor outcomes after endoscopic surgery.

High fat diet induces brain injury and neuronal apoptosis via down-regulating 3-ß hydroxycholesterol 24 reductase (DHCR24).

Hyperlipidemia (HLP) is one of the risk factors for memory impairment and cognitive impairment. However, its pathological molecular mechanism remained unclear. 3ß-hydroxysterol Δ24- reductase (DHCR24) is a key enzyme in cholesterol synthesis and has been reported to decrease in the affected areas in the brain of neurodegenerative disorders. In this study, hyperlipidemic mouse model was established to study the effect of high blood lipid on brain. The data obtained from HPLC analysis demonstrated that the cholesterol level in the brain of mice with hyperlipidemia was significantly elevated compared to the control group. While the pathological damages were observed in both cerebral cortex and hippocampus in the brain of hyperlipidemic mice. Furthermore, the protein level of DHCR24 was downregulated accompanied by elevated ubiquitination level in the hyperlipidemic mice brain. The mouse neuroblastoma cells N2a were exposed to the excess cholesterol loading, the cells underwent apoptosis and the mRNA and protein of DHCR24 in cholesterol-loaded N2a cells were significantly reduced. In addition, the expression level of endoplasmic reticulum stress marker protein (Bip and Chop) was markedly increased in response to the cholesterol loading. More importantly, overexpression of DHCR24 in N2a reversed neuronal apoptosis induced by the cholesterol loading. Conclusively, these findings suggested that hyperlipidemia could cause brain tissue injuries via down-regulating DHCR24, and overexpression of DHCR24 may alleviate hyperlipidemia-induced neuronal cells damage by reversing the endoplasmic reticulum stress-mediated apoptosis.

Arabidopsis OXIDATIVE STRESS 3 enhances stress tolerance in Schizosaccharomyces pombe by promoting histone subunit replacement that upregulates drug-resistant genes.

Histone replacement in chromatin-remodeling plays an important role in eukaryotic gene expression. New histone variants replacing their canonical counterparts often lead to a change in transcription, including responses to stresses caused by temperature, drought, salinity, and heavy metals. In this study, we describe a chromatin-remodeling process triggered by eviction of Rad3/Tel1-phosphorylated H2Aα, in which a heterologous plant protein AtOXS3 can subsequently bind fission yeast HA2.Z and Swc2, a component of the SWR1 complex, to facilitate replacement of H2Aα with H2A.Z. The histone replacement increases occupancy of the oxidative stress-responsive transcription factor Pap1 at the promoters of at least three drug-resistant genes, which enhances their transcription and hence primes the cell for higher stress tolerance.

Suppression of neuronal cholesterol biosynthesis impairs brain functions through insulin-like growth factor I-Akt signaling.

Some relationship between abnormal cholesterol content and impairment of insulin/insulin-like growth factor I (IGF-1) signaling has been reported in the pathogenesis of Alzheimer's disease (AD). However, the underlying mechanism of this correlation remains unclear. It is known that 3-ß hydroxycholesterol Δ 24 reductase (DHCR24) catalyzes the last step of cholesterol biosynthesis. To explore the function of cholesterol in the pathogenesis of AD, we depleted cellular cholesterol by targeting DHCR24 with siRNA (siDHCR24) or U18666A, an inhibitor of DHCR24, and studied the effect of the loss of cholesterol on the IGF-1-Akt signaling pathway in vitro and in vivo. Treatment with U18666A reduced the cellular cholesterol level and blocked the anti-apoptotic function of IGF-1 by impairing the formation of caveolae and the localization of IGF-1 receptor in caveolae of the PC12 cells. Downregulation of the DHCR24 expression induced by siRNA against DHCR24 also yielded similar results. Furthermore, the phosphorylation levels of IGF-1 receptor, insulin receptor substrate (IRS), Akt, and Bad in response to IGF-1 were all found to decrease in the U18666A-treated cells. Rats treated with U18666A via intracerebral injection also exhibited a significant decrease in the cholesterol level and impaired activities of IGF-1-related signaling proteins in the hippocampus region. A significant accumulation of amyloid ß and a decrease in the expression of neuron-specific enolase (NSE) was also observed in rats with U18666A. Finally, the Morris water maze experiment revealed that U18666A-treated rats showed a significant cognitive impairment. Our findings provide new evidence strongly supporting that a reduction in cholesterol level can result in neural apoptosis via the impairment of the IGF-1-Akt survival signaling in the brain.

Loss of HNF1α Function Contributes to Hepatocyte Proliferation and Abnormal Cholesterol Metabolism via Downregulating miR-122: A Novel Mechanism of MODY3.

PURPOSE: Mutations in hepatocyte nuclear factor 1α (HNF1α) are the cause of maturity-onset diabetes of the young type 3 (MODY3) and involved in the development of hepatocellular adenoma and abnormal lipid metabolism. Previously, we have found that the serum microRNA (miR)-122 levels in MODY3 patients were lower than those in type 2 diabetes mellitus and healthy controls. This study aimed to investigate the mechanism of decreased miR-122 levels in patients with MODY3 and whether low levels of miR-122 mediate tumorigenesis and abnormal lipid metabolism associated with HNF1α deficiency in human hepatocytes. METHODS: The expression of miR-122 was examined by real-time PCR. Dual-luciferase reporter assay was performed to confirm the transcriptional regulation of miR-122 by HNF1α. HepG2 cells were transfected with siRNA or miRNA mimic to downregulate or upregulate the expression of HNF1α or miR-122, respectively. CCK-8 and colony formation assay were used to determine cell proliferation. Lipid accumulation was examined by Oil Red O staining and intracellular triglyceride and cholesterol quantification assays. RESULTS: HNF1α regulated the expression of miR-122 by directly binding to its promoter. Knockdown of HNF1α in HepG2 cells reduced the expression of miR-122, increased proliferation and promoted intracellular cholesterol accumulation. Overexpression of miR-122 partially rescued the phenotypes associated with HNF1α deficiency in human hepatocytes. Mechanistically, HNF1α modulated cholesterol homeostasis via miR-122-dependent activation of sterol regulatory element-binding protein-2 (SREBP-2) and regulation of proprotein convertase subtilisin/kexin type 9 (PCSK9). Moreover, circulating miR-122 levels were associated with serum cholesterol levels. CONCLUSION: Loss of HNF1α function led to hepatocyte proliferation and abnormal cholesterol metabolism by downregulating miR-122. Our findings revealed a novel mechanism that low levels of miR-122 mediate tumorigenesis and abnormal lipid metabolism associated with MODY3. MiR-122 may be a potential therapeutic target for the treatment of MODY3.

Serum Albumin, but not Bilirubin, is Associated with Diabetic Chronic Vascular Complications in a Chinese Type 2 Diabetic Population.

To identify the factors associated with serum total bilirubin (STB) and determine whether STB is independently associated with diabetic retinopathy (DR) or diabetic kidney disease (DKD), 1,665 Chinese patients with type 2 diabetes (T2DM) (248 outpatients newly diagnosed with T2DM [NDM] and 1,417 inpatients previously diagnosed with T2DM [PDM]) were studied. Clinical and biochemical information was collected, and a single nucleotide polymorphism (rs6704078) of the UGT1A1 gene was genotyped in 1,059 individuals. Multiple linear regression showed that STB was associated with haemoglobin concentration, platelet count, and serum triglyceride concentration in NDM and PDM patients, and with serum albumin, duration of diabetes, and smoking in PDM patients. In patients with PDM, multiple logistic regression revealed that serum albumin was associated with DR (odds ratio [OR] = 0.92, 95% confidence interval [CI]: 0.87-0.96, p = 0.001) and DKD (OR = 0.93, 95% CI: 0.88-0.98, p = 0.005) after adjustment for STB, STB-related factors, and risk factors for DR and DKD. In addition, patients with the T allele of rs6704078 had higher STB (13.2 [10.4-17.9] µmol/L versus 11.8 (9.4-14.8) µmol/L; p < 0.001) and similar risks of DR or DKD to those without the T allele. Thus, serum albumin, but not STB, is associated with DR and DKD.

Lower Circulating miR-122 Level in Patients with HNF1A Variant-Induced Diabetes Compared with Type 2 Diabetes.

miR-122, the expression of which is regulated by several transcription factors, such as HNF1A, was recently reported to be associated with type 2 diabetes (T2DM) and hepatocellular carcinoma. HNF1A variants can cause diabetes and might be involved in the development of primary liver neoplasm. Differences in miR-122 expression among different types of diabetes have not been studied. This study aimed to investigate differences in serum miR-122 levels in Chinese patients with different forms of diabetes, including T2DM, type 1 diabetes (T1DM), HNF1A variant-induced diabetes (HNF1A-DM), glucokinase variant-induced diabetes (GCK-DM), and mitochondrial A3243G mutation-induced diabetes (MDM). In total, 12 HNF1A-DM patients, 24 gender-, age-, and body mass index-matched (1 : 2) T2DM patients and 24 healthy subjects were included in this study. In addition, 30 monogenic diabetes (11 GCK-DM and 19 MDM) and 17 T1DM patients were included. Fasted blood biochemistry and miR-122 were measured. The results showed that the HNF1A-DM patients had lower miR-122 levels [0.046 (0.023, 0.121)] than T2DM patients [0.165 (0.036, 0.939), P = 0.02] and healthy controls [0.249 (0.049, 1.234), P = 0.019]. The area under the curve of the receiver operating characteristic curve for miR-122 to discriminate HNF1A-DM and T2DM was 0.687 (95% CI: 0.52-0.86, P = 0.07). There was no difference in serum miR-122 among HNF1A-DM, GCK-DM, MDM, and T1DM patients. Lower serum miR-122 is a unique feature of HNF1A-DM patients and might partially explain the increased risk for liver neoplasm and abnormal lipid metabolism in HNF1A-DM patients.