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Background: To understand the molecular mechanisms involved in regulation of DNA methyltransferases (DNMTs) by metformin in non-small cell lung cancer (NSCLC) cells., Methods: Expression levels of DNMTs in response to metformin were analyzed in NSCLC cells. MicroRNAs regulating expression of DNMTs at the post-transcriptional level were searched using miRNA-target databases (miRDB and miRTarBase), TCGA RNASeqV2 lung cancer data, and miRNA-seq., Results: Metformin dose-dependently downregulated expression of DNMT1 and DNMT3a at the post-transcriptional level and expression of DNMT3b at the transcriptional level in A549 lung cancer cells. Activity of DNMTs was reduced by about 2.6-fold in A549 cells treated with 10 mM metformin for 72 h. miR-148/-152 family members (miR-148a, miR-148b, and miR-152) targeting the 3'UTR of DNMTs were associated with post-transcriptional regulation of DNMTs by metformin. Metformin upregulated expression of miR-148a, miR-148b, and miR-152 in A549 and H1650 cells. Transfection with an miR-148b plasmid or a mimic suppressed expression of DNMT1 and DNMT3b in A549 cells. Transfection with the miR-148a mimic in A549 and H1650 cells decreased the luciferase activity of DNMT1 3'UTR. A combination of metformin and cisplatin synergistically increased expression levels of miR-148/-152 family members but decreased expression of DNMTs in A549 cells. Low expression of miR-148b was associated with poor overall survival (HR = 2.56, 95% CI 1.09-6.47; P = 0.04) but not with recurrence-free survival., Conclusions: The present study suggests that metformin inhibits expression of DNMTs by upregulating miR-148/-152 family members in NSCLC cells., (© 2023. The Author(s).)

Background: People with a spinal cord injury (SCI) have a high rate of bowel-related morbidity, even compared with people with other neurological disorders. These complications lower quality of life and place a financial burden on the health system. A noninvasive intervention that improves the bowel function of people with an SCI should reduce morbidity, improve quality of life, and lead to cost savings for health care providers., Objectives: To investigate the effectiveness of noninvasive abdominal functional electrical stimulation (FES) for improving bowel function in people with a chronic SCI., Methods: A prospective, double-blinded, 1:1 randomized, placebo-controlled intervention trial will be conducted with 80 adults with chronic SCI (>12 months since injury) above T8 single neurological level. The intervention will be a 45-minute abdominal FES (or placebo) session, 3 days per week, for 6 weeks., Main Study Parameters/endpoints: Primary endpoint is whole gut transit time before and after 6 weeks of abdominal FES. Secondary endpoints measured before and after 6 weeks of abdominal FES are (1) colonic transit time; (2) quality of life (EQ-5D-5L); (3) participant-reported bowel function (International SCI Bowel Function Basic Data Set Questionnaire and visual analogue scale); (4) respiratory function (forced vital capacity, forced expiratory volume in 1 second, peak expiratory flow, maximal inspiratory pressure, and maximal expiratory pressure); (5) bladder symptoms (Neurogenic Bladder Symptom Score); (6) daily bowel management diary; and (7) unplanned hospital visits., Conclusion: Safety data will be collected, and a cost utility analysis using quality of life scores will be performed., Trial Registration: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12621000386831., Competing Interests: Conflicts of Interest The authors declare no conflicts of interest., (© 2022 American Spinal Injury Association.)

The magnocellular (MC) pathway in the primate has much higher achromatic contrast sensitivity than the parvocellular (PC) pathway, and is implicated in luminance contrast detection. But MC pathway responses tend to saturate at lower achromatic contrast than do PC pathway responses. It has been proposed that the PC pathway plays a major role in discriminating suprathreshold achromatic contrast, because the MC pathway is in saturation. This has been termed the pulsed-pedestal protocol. To test this hypothesis, responses of MC and PC pathway ganglion cells have been examined under suprathreshold conditions with stimulus configurations similar to those in psychophysical tests. For MC cells, response saturation was much less for flashed or moving edges than for sinusoidal modulation, and MC cell thresholds predicted for these stimuli were similar to psychophysical discrimination (and detection) data. Results suggest the protocol is not effective in segregating MC and PC function.

Study Design: An international multi-centred, double-blinded, randomised sham-controlled trial (eWALK)., Objective: To determine the effect of 12 weeks of transcutaneous spinal stimulation (TSS) combined with locomotor training on walking ability in people with spinal cord injury (SCI)., Setting: Dedicated SCI research centres in Australia, Spain, USA and Scotland., Methods: Fifty community-dwelling individuals with chronic SCI will be recruited. Participants will be eligible if they have bilateral motor levels between T1 and T11, a reproducible lower limb muscle contraction in at least one muscle group, and a Walking Index for SCI II (WISCI II) between 1 and 6. Eligible participants will be randomised to one of two groups, either the active stimulation group or the sham stimulation group. Participants allocated to the stimulation group will receive TSS combined with locomotor training for three 30-min sessions a week for 12 weeks. The locomotor sessions will include walking on a treadmill and overground. Participants allocated to the sham stimulation group will receive the same locomotor training combined with sham stimulation. The primary outcome will be walking ability with stimulation using the WISCI II. Secondary outcomes will record sensation, strength, spasticity, bowel function and quality of life., Trial Registration: ANZCTR.org.au identifier ACTRN12620001241921., (© 2021. The Author(s), under exclusive licence to International Spinal Cord Society.)

Background: Obesity is a serious health problem with an incidence that is increasing rapidly. Enlisted men are a distinctive group characterised by 24-hour community-living and are likely to experience changes in body weight as a result of regular diet and exercise during enlistment., Methods: This study reviewed data from the Second Military Health Survey. Changes in body mass index (BMI) before and during military service were analysed using paired t-test. We calculated OR and 95% CI for factors affecting weight improvement during military service through logistic regression., Results: The mean BMI in the underweight group increased by 5.87 kg/m 2 during service, while that in the normal weight group increased by 1.18 kg/m 2 . In contrast, the mean BMI in the overweight group decreased by 5.47 kg/m 2 during service. The OR for an improved BMI in the subjective good health group compared with the subjective poor health group was statistically significant (OR=1.71, 95% CI 1.02 to 2.87). The OR for an improved BMI was significantly higher in the group with three or more times per week of strength training than in the group with one to two times per week of strength training, and was higher among the marines compared with the Army soldiers (OR=1.48, 95% CI 1.03 to 2.12 and OR=2.15, 95% CI 1.07 to 4.32, respectively)., Conclusions: Strength training showed a statistically significant increase in BMI during military service. Furthermore, the BMI of men who were underweight before their service increased, while it decreased among those who were overweight., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The AKT kinases have emerged as promising therapeutic targets in oncology and both allosteric and ATP-competitive AKT inhibitors have entered clinical investigation. However, long-term efficacy of such inhibitors will likely be challenged by the development of resistance. We have established prostate cancer models of acquired resistance to the allosteric inhibitor MK-2206 or the ATP-competitive inhibitor ipatasertib following prolonged exposure. While alterations in AKT are associated with acquired resistance to MK-2206, ipatasertib resistance is driven by rewired compensatory activity of parallel signaling pathways. Importantly, MK-2206 resistance can be overcome by treatment with ipatasertib, while ipatasertib resistance can be reversed by co-treatment with inhibitors of pathways including PIM signaling. These findings demonstrate that distinct resistance mechanisms arise to the two classes of AKT inhibitors and that combination approaches may reverse resistance to ATP-competitive inhibition., (© 2022. The Author(s).)

Aims: Our understanding of the pathological interactions between amyloidosis and tauopathy in Alzheimer's disease is incomplete. We sought to determine if the relative timing of the amyloidosis and tauopathy is critical for amyloid-enhanced tauopathy., Methods: We crossed an inducible tauopathy model with two β-amyloid models utilising the doxycycline-repressible transgenic system to modulate timing and duration of human tau expression in the context of amyloidosis and then assessed tauopathy, amyloidosis and gliosis., Results: We combined inducible rTg4510 tau with APPswe/PS1dE9 [Line 85 (L85)] mice to examine the interactions between Aβ and tauopathy at different stages of amyloidosis. When we initially suppressed mutant human tau expression for 14-15 months and subsequently induced tau expression for 6 months, severe amyloidosis with robust tauopathy resulted in rTg4510/L85 but not rTg4510 mice. When we suppressed mutant tau for 7 months before inducing expression for a subsequent 6 months in another cohort of rTg4510/L85 and rTg4510 mice, only rTg4510/L85 mice displayed robust tauopathy. Lastly, we crossed rTg4510 mice to tet-regulated APPswe/ind [Line 107 (L107)] mice, using doxycycline to initially suppress both transgenes for 1 month before inducing expression for 5 months to model early amyloidosis. In contrast to rTg4510, rTg4510/L107 mice rapidly developed amyloidosis, accompanied by robust tauopathy., Conclusions: These data suggest that tau misfolding is exacerbated by both newly forming Aβ deposits in younger brain and mature deposits in older brains. Refined use and repurposing of these models provide new tools to explore the intersection of ageing, amyloid and tauopathy and to test interventions to disrupt the amyloid cascade., (© 2022 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

This study aimed to understand aberrant methylation of SLITs genes as a biomarker for the early detection and prognosis prediction of non-small cell lung cancer (NSCLC). Methylation levels of SLITs were determined using the Infinium HumanMethylation450 BeadChip or pyrosequencing. Five CpGs at the CpG island of SLIT1 , SLIT2 or SLIT3 genes were significantly (Bonferroni corrected p < 0.05) hypermethylated in tumor tissues obtained from 42 NSCLC patients than in matched normal tissues. Methylation levels of these CpGs did not differ significantly between bronchial washings obtained from 76 NSCLC patients and 60 cancer-free patients. However, methylation levels of SLIT2 gene were significantly higher in plasma cell-free DNA of 72 NSCLC patients than in that of 61 cancer-free patients ( p = 0.001, Wilcoxon rank sum test). Prediction of NSCLC using SLIT2 methylation was achieved with a sensitivity of 73.7% and a specificity of 61.9% in a plasma test dataset ( N = 40). A Cox proportional hazards model showed that SLIT2 hypermethylation in plasma cell-free DNA was significantly associated with poor recurrence-free survival (hazards ratio = 2.19, 95% confidence interval = 1.21-4.36, p = 0.01). The present study suggests that aberrant methylation of SLIT2 in plasma cell-free DNA is a valuable biomarker for the early detection of NSCLC and prediction of recurrence-free survival. However, further research is needed with larger sample size to confirm results.

Transient receptor potential vanilloid member 1 (TRPV1) is activated in response to capsaicin, protons, temperature, and free reactive oxygen species (ROS) released from inflammatory molecules after exposure to harmful stimuli. The expression level of TRPV1 is elevated in the dorsal root ganglion, and its activation through capsaicin and ROS mediates neuropathic pain in mice. Its expression is high in peripheral and central nervous systems. Although pain is a response evolved for survival, many studies have been conducted to develop analgesics, but no clear results have been reported. Here, we found that naringin selectively inhibited capsaicin-stimulated inward currents in Xenopus oocytes using a two-electrode voltage clamp. The results of this study showed that naringin has an IC 50 value of 33.3 μM on TRPV1. The amino acid residues D471 and N628 of TRPV1 were involved in its binding to naringin. Our study bridged the gap between the pain suppression effect of TRPV1 and the preventive effect of naringin on neuropathic pain and oxidation. Naringin had the same characteristics as a model selective antagonist, which is claimed to be ideal for the development of analgesics targeting TRPV1. Thus, this study suggests the applicability of naringin as a novel analgesic candidate through antioxidative and analgesic effects of naringin.

During RNA polymerase II (RNA Pol II) transcription, the chromatin structure undergoes dynamic changes, including opening and closing of the nucleosome to enhance transcription elongation and fidelity. These changes are mediated by transcription elongation factors, including Spt6, the FACT complex, and the Set2-Rpd3S HDAC pathway. These factors not only contribute to RNA Pol II elongation, reset the repressive chromatin structures after RNA Pol II has passed, thereby inhibiting aberrant transcription initiation from the internal cryptic promoters within gene bodies. Notably, the internal cryptic promoters of infrequently transcribed genes are sensitive to such chromatin-based regulation but those of hyperactive genes are not. To determine why, the weak core promoters of genes that generate cryptic transcripts in cells lacking transcription elongation factors (e.g. STE11) were replaced with those from more active genes. Interestingly, as core promoter activity increased, activation of internal cryptic promoter dropped. This associated with loss of active histone modifications at the internal cryptic promoter. Moreover, environmental changes and transcription elongation factor mutations that downregulated the core promoters of highly active genes concomitantly increased their cryptic transcription. We therefore propose that the chromatin-based regulation of internal cryptic promoters is mediated by core promoter strength as well as transcription elongation factors., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Key Points: Responses to natural scenes are the business of the retina. We find primate ganglion cell responses to such scenes consistent with those to simpler stimuli. A biophysical model confirmed this and predicted ganglion cell responses with close to retinal reliability. Primate ganglion cell responses to natural scenes were driven by temporal variations in colour and luminance over the receptive field centre caused by eye movements, and little influenced by interaction of centre and surround with structure in the scene. We discuss implications in the context of efficient coding of the visual environment. Much information in a higher spatiotemporal frequency band is concentrated in the magnocellular pathway., Abstract: Responses of visual neurons to natural scenes provide a link between classical descriptions of receptive field structure and visual perception of the natural environment. A natural scene video with a movement pattern resembling that of primate eye movements was used to evoke responses from macaque ganglion cells. Cell responses were well described through known properties of cell receptive fields. Different analyses converge to show that responses primarily derive from the temporal pattern of stimulation derived from eye movements, rather than spatial receptive field structure beyond centre size and position. This was confirmed using a model that predicted ganglion cell responses close to retinal reliability, with only a small contribution of the surround relative to the centre. We also found that the spatiotemporal spectrum of the stimulus is modified in ganglion cell responses, and this can reduce redundancy in the retinal signal. This is more pronounced in the magnocellular pathway, which is much better suited to transmit the detailed structure of natural scenes than the parvocellular pathway. Whitening is less important for chromatic channels. Taken together, this shows how a complex interplay across space, time and spectral content sculpts ganglion cell responses., (© 2021 The Authors. The Journal of Physiology © 2021 The Physiological Society.)

This study aimed at understanding the effect of metformin on histone H3 methylation, DNA methylation, and chromatin accessibility in lung cancer cells. Metformin significantly reduced H3K4me3 level at the promoters of positive cell cycle regulatory genes such as CCNB2, CDK1, CDK6, and E2F8. Eighty-eight genes involved in cell cycle showed reduced H3K4me3 levels in response to metformin, and 27% of them showed mRNA downregulation. Metformin suppressed the expression of H3K4 methyltransferases MLL1, MLL2, and WDR82. The siRNA-mediated knockdown of MLL2 significantly downregulated global H3K4me3 level and inhibited lung cancer cell proliferation. MLL2 overexpression was found in 14 (33%) of 42 NSCLC patients, and a Cox proportional hazards analysis showed that recurrence-free survival of lung adenocarcinoma patients with MLL2 overexpression was approximately 1.32 (95% CI = 1.08-4.72; p = 0.02) times poorer than in those without it. Metformin showed little effect on DNA methylation and chromatin accessibility at the promoter regions of cell cycle regulatory genes. The present study suggests that metformin reduces H3K4me3 levels at the promoters of positive cell cycle regulatory genes through MLL2 downregulation in lung cancer cells. Additionally, MLL2 may be a potential therapeutic target for reducing the recurrence of lung adenocarcinoma.

Background: Intraoral defects after tumor resection are often reconstructed with free tissue transfer. However, in patients who are not good candidates for free tissue transfer, regional flaps based on the superficial temporal artery can be utilized. The authors present our technique to reconstruct intraoral defects with the superficial temporal artery perforator (STAP) flap and early outcomes., Methods: Five patients underwent STAP flaps for defects including the hard palate, buccal sulcus, floor of mouth, and retromolar trigone between 2017 and 2019. The mean defect size was 5.6 × 3.4 cm 2 (3 × 3 cm 2 - 7 × 4 cm 2 ). The mean age was 74 (57-88) and all patients had recurrent cancer. External Doppler, indocyanine green laser angiography, and FLIR thermal imaging were used intra-operatively to identify the best perforators and plan for flap design., Results: The mean flap size was 7.6 × 3.5 cm 2 (6 × 3 cm 2 - 10 × 5 cm 2 ). Four flaps were based off of the posterior branch of the STA, while the fifth was based off of the anterior branch. Two donor sites were closed primarily, and three required skin grafts. One patient experienced partial flap necrosis. There were no complete flap losses and no donor site complications. Average follow up was 14.6 months (9-20 months). All patients maintained preoperative level of speech, mastication, and oral continence., Conclusions: The STAP flap can be based on the anterior or posterior branch of the superficial temporal artery and is a useful regional flap for intraoral defects after tumor resection., (© 2020 Wiley Periodicals LLC.)

This research focused on physiochemical and nutritional properties and functional characterization of three cultivars of yuzu-Native, Tadanishiki yuzu, and Namhae1-during different seasons. According to the cultivar and harvest time, yuzu cultivars were analyzed for free sugar, dietary fiber, hesperidin, naringin, and flavonoid content as well as antioxidant and antihypertensive activity. During November, Namhae1 exhibited the highest fruit weight, °Brix/acidity ratio, and total dietary fiber content. Tadanishiki contained the highest fructose and sucrose levels, pectin and cellulose contents, and soluble dietary fiber. Tadanishiki also had the highest hesperidin content in October, while the naringin content and antioxidant activity were the greatest in November. Antihypertensive activity was also the strongest for Tadanishiki, which was picked in October and November. These results indicated that Tadanishiki in October or November was the best for consumption or favorable processing because of its excellent product quality and high levels of nutritional and functional compounds., Competing Interests: Conflict of interestNone of the authors of this study has any financial interest or conflict with industries or parties., (© The Korean Society of Food Science and Technology 2021.)

In yeast, NuA3 histone acetyltransferase (NuA3 HAT) promotes acetylation of histone H3 lysine 14 (H3K14) and transcription of a subset of genes through interaction between the Yng1 plant homeodomain (PHD) finger and H3K4me3. Although NuA3 HAT has multiple chromatin binding modules with distinct specificities, their interdependence and combinatorial actions in chromatin binding and transcription remain unknown. Modified peptide pulldown assays reveal that the Yng1 N-terminal region is important for the integrity of NuA3 HAT by mediating the interaction between core subunits and two methyl-binding proteins, Yng1 and Pdp3. We further uncover that NuA3 HAT contributes to the regulation of mRNA and lncRNA expression dynamics by antagonizing the histone deacetylases (HDACs) Rpd3S and Rpd3L. The Yng1 N-terminal region, the Nto1 PHD finger and Pdp3 are important for optimal induction of mRNA and lncRNA transcription repressed by the Set2-Rpd3S HDAC pathway, whereas the Yng1 PHD finger-H3K4me3 interaction affects transcriptional repression memory regulated by Rpd3L HDAC. These findings suggest that NuA3 HAT uses distinct chromatin readers to compete with two Rpd3-containing HDACs to optimize mRNA and lncRNA expression dynamics., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)

This study aimed to understand whether the effect of non-metastatic cells 1 (NME1) on recurrence-free survival (RFS) in early stage non-small cell lung cancer (NSCLC) can be modified by β-catenin overexpression and cisplatin-based adjuvant chemotherapy. Expression levels of NME1 and β-catenin were analyzed using immunohistochemistry in formalin-fixed paraffin-embedded tissues from 425 early stage NSCLC patients. Reduced NME1 expression was found in 39% of samples. The median duration of follow-up was 56 months, and recurrence was found in 186 (44%) of 425 patients. The negative effect of reduced NME1 expression on RFS was worsened by cisplatin-based adjuvant chemotherapy (adjusted hazard ratio = 3.26, 95% CI = 1.16-9.17, p = 0.03). β-catenin overexpression exacerbated the effect of reduced NME1 expression on RFS and the negative effect was greater when receiving cisplatin-based adjuvant chemotherapy: among patients treated with cisplatin-based adjuvant chemotherapy, hazard ratios of patients with reduced NME1 expression increased from 5.59 (95% confidence interval (CI) = 0.62-50.91, p = 0.13) to 15.52 (95% CI = 2.94-82.38, p = 0.001) by β-catenin overexpression, after adjusting for confounding factors. In conclusion, the present study suggests that cisplatin-based adjuvant chemotherapy needs to be carefully applied to early stage NSCLC patients with overexpressed β-catenin in combination with reduced NME1 expression.

Purpose: Intermittent catheterization (IC) is a proven effective long-term bladder management strategy for individuals who have lower urinary tract dysfunction. This study provides clinical evidence about multiple-reuse versus single-use catheterization techniques and if catheter choice can have an impact on health-related quality of life (HRQoL)., Method: A prospective, multi-center, clinical trial studied patients who currently practiced catheter reuse, and who agreed to prospectively evaluate single-use hydrophilic-coated (HC) (i.e. LoFric) catheters for 4 weeks. A validated Intermittent Self-Catheterization Questionnaire (ISC-Q) was used to obtain HRQoL. Reused catheters were collected and studied with regard to microbial and debris contamination., Results: The study included 39 patients who had practiced IC for a mean of 10 years, 6 times daily. At inclusion, all patients reused catheters for a mean of 21 days (SD = 48) per catheter. 36 patients completed the prospective test period and the mean ISC-Q score increased from 58.0 (SD = 22.6) to 67.2 (SD = 17.7) when patients switched to the single-use HC catheters (p = 0.0101). At the end of the study, 83% (95% CI [67-94%]) preferred to continue using single-use HC catheters. All collected reused catheters (100%) were contaminated by debris and 74% (95% CI [58-87%]) were contaminated by microorganisms, some with biofilm., Conclusion: Single-use HC catheters improved HRQoL and were preferred over catheter reuse among people practicing IC. Catheter multiple-reuse may pose a potential safety concern due to colonization by microorganisms as well as having reduced acceptance compared to single use., Trial Registry Number: ClinicalTrials.gov NCT02129738.

Study Design: Randomised double-blind placebo-controlled trial., Objectives: Multi-resistant organism (MRO) colonisation is common in people with SCI. We aimed to determine whether Lactobacillus reuteri RC-14 + Lactobacillus GR-1 (RC14-GR1) and/or Lactobacillus rhamnosus GG + Bifidobacterium BB-12 (LGG-BB12) are effective in preventing or clearing MRO colonisation., Setting: New South Wales, Australia., Methods: The 207 SCI participants were randomised to one of four arms: (i) RC14-GR1 + LGG-BB12, (ii) RC14-GR1 + placebo, (iii) LGG-BB12 + placebo or (iv) double placebos for 6 months. Microbiological samples of nose, groin, urine and bowel were taken at baseline, 3 and 6 months. Analysis was conducted for the presence of methicillin-resistant Staphylococcus aureus (MRSA), multi-resistant gram-negative organisms (MRGNs) and vancomycin-resistant enterococcus (VRE). The outcomes were clearance of, or new colonisation with MRSA, MRGN, VRE or MROs and whether participants remained free of MRSA, MRGN, VRE or MROs throughout the study. Risk factors associated with an outcome were adjusted for using nominal or binary logistic regression., Results: There was a significant reduction in new MRGN colonisation compared with placebo for participants treated with RC14-GR1 (OR 0.10, 95% CI, 0.01-0.88, P = 0.04), after allowing that inpatients were more likely to be newly colonised (OR 21.41, 95% CI, 3.98-115.13, P < 0.0001). Participants who intermittent self-catheterised (IMC) were more likely to remain MRO-free than those utilising SPC or IDCs (OR 2.80, 95% CI, 1.41-5.54, P = 0.009)., Conclusions: Probiotics are ineffective at clearing MROs in people with SCI. However, RC14-GR1 is effective at preventing new colonisation with MRGNs. The use of IMC significantly improves the chance of remaining MRO-free.

This study aimed to understand the clinicopathological significance of runt-related transcription factor 1 ( RUNX1 ) in non-small cell lung cancer (NSCLC). The methylation and mRNA levels of RUNX1 in NSCLC were determined using the Infinium HumanMethylation450 BeadChip and the HumanHT-12 expression BeadChip. RUNX1 protein levels were analyzed using immunohistochemistry of formalin-fixed paraffin-embedded tissues from 409 NSCLC patients. Three CpGs (cg04228935, cg11498607, and cg05000748) in the CpG island of RUNX1 showed significantly different methylation levels (Bonferroni corrected p < 0.05) between tumor and matched normal tissues obtained from 42 NSCLC patients. Methylation levels of the CpGs in the tumor tissues were inversely related to mRNA levels of RUNX1 . A logistic regression model based on cg04228935 showed the best performance in predicting NSCLCs in a test dataset (N = 28) with the area under the receiver operating characteristic (ROC) curve (AUC) of 0.96 (95% confidence interval (CI) = 0.81-0.99). The expression of RUNX1 was reduced in 125 (31%) of 409 patients. Adenocarcinoma patients with reduced RUNX1 expression showed 1.97-fold (95% confidence interval = 1.16-3.44, p = 0.01) higher hazard ratio for death than those without. In conclusion, the present study suggests that abnormal methylation of RUNX1 may be a valuable biomarker for detection of NSCLC regardless of race. And, reduced RUNX1 expression may be a prognostic indicator of poor overall survival in lung adenocarcinoma.

Background: Respiratory complications remain a leading cause of morbidity and mortality in people with acute and chronic tetraplegia. Respiratory muscle weakness following spinal cord injury-induced tetraplegia impairs lung function and the ability to cough. In particular, inspiratory muscle strength has been identified as the best predictor of the likelihood of developing pneumonia in individuals with tetraplegia. We hypothesised that 6 weeks of progressive respiratory muscle training (RMT) increases respiratory muscle strength with improvements in lung function, quality of life and respiratory health., Methods: Sixty-two adults with tetraplegia participated in a double-blind randomised controlled trial. Active or sham RMT was performed twice daily for 6 weeks. Inspiratory muscle strength, measured as maximal inspiratory pressure (PImax) was the primary outcome. Secondary outcomes included lung function, quality of life and respiratory health. Between-group comparisons were obtained with linear models adjusting for baseline values of the outcomes., Results: After 6 weeks, there was a greater improvement in PImax in the active group than in the sham group (mean difference 11.5 cmH 2 O (95% CI 5.6 to 17.4), p<0.001) and respiratory symptoms were reduced (St George Respiratory Questionnaire mean difference 10.3 points (0.01-20.65), p=0.046). Significant improvements were observed in quality of life (EuroQol-Five Dimensional Visual Analogue Scale 14.9 points (1.9-27.9), p=0.023) and perceived breathlessness (Borg score 0.64 (0.11-1.17), p=0.021). There were no significant improvements in other measures of respiratory function (p=0.126-0.979)., Conclusions: Progressive RMT increases inspiratory muscle strength in people with tetraplegia, by a magnitude which is likely to be clinically significant. Measurement of baseline PImax and provision of RMT to at-risk individuals may reduce respiratory complications after tetraplegia., Trial Registration Number: Australian New Zealand Clinical Trials Registry (ACTRN 12612000929808)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: EUS-guided fine-needle aspiration (FNA) has long been the main method for sampling pancreatic lesions. Recently, the method of fine-needle biopsy (FNB) was introduced in practice, allowing for the acquisition of tissue cores while aspirating the lesion. We hereby report our experience with a new FNB needle compared with the standard FNA needle., Methods: Retrospective data from our department were collected on patients who underwent FNB using the Acquire EUS-FNB needle (Boston Scientific, Massachusetts) and FNA using the EchoTip Ultra EUS-FNA Needle (Cook Medical, Indiana) between January 2017 and February 2018. The cases were reviewed independently by two cytopathologists and evaluated for the presence of cell block or core tissue material, adequacy for potential ancillary testing, and number of passes., Results: The number of passes ranged from 1 to 16, with a mean of 5.52 ± 3.74 in the FNA group, and from 1 to 6, with a mean of 2.74 ± 1.11 passes in the FNB group (P < .0001). Tissue cores were present in 87.23% of the FNB needle samples. A cell block was adequate in 36.36% of cases using the FNA needle. The diagnostic yield as well as the adequacy for ancillary testing were significantly different between the two groups (P = .0001). The tumor size, location and patients' demographics were not statistically significant between the two groups., Conclusion: Compared with the conventional needle, the new FNB needle was associated with a lower number of passes and a better yield for histological material., (© 2019 Wiley Periodicals, Inc.)

In yeast, Hda1 histone deacetylase complex (Hda1C) preferentially deacetylates histones H3 and H2B, and functionally interacts with Tup1 to repress transcription. However, previous studies identified global increases in histone H4 acetylation in cells lacking Hda1, a component of Hda1C. Here, we find that Hda1C binds to hyperactive genes, likely via the interaction between the Arb2 domain of Hda1 and RNA polymerase II. Additionally, we report that Hda1C specifically deacetylates H4, but not H3, at hyperactive genes to partially inhibit elongation. This role is contrast to that of the Set2-Rpd3S pathway deacetylating histones at infrequently transcribed genes. We also find that Hda1C deacetylates H3 at inactive genes to delay the kinetics of gene induction. Therefore, in addition to fine-tuning of transcriptional response via H3-specific deacetylation, Hda1C may modulate elongation by specifically deacetylating H4 at highly transcribed regions.

Study Design: Randomised double-blind factorial-design placebo-controlled trial., Objective: Urinary tract infections (UTIs) are common in people with spinal cord injury (SCI). UTIs are increasingly difficult to treat due to emergence of multi-resistant organisms. Probiotics are efficacious in preventing UTIs in post-menopausal women. We aimed to determine whether probiotic therapy with Lactobacillus reuteri RC-14+Lactobacillus GR-1 (RC14-GR1) and/or Lactobacillus rhamnosus GG+Bifidobacterium BB-12 (LGG-BB12) are effective in preventing UTI in people with SCI., Setting: Spinal units in New South Wales, Australia with their rural affiliations., Methods: We recruited 207 eligible participants with SCI and stable neurogenic bladder management. They were randomised to one of four arms: RC14-GR1+LGG-BB12, RC14-GR1+placebo, LGG-BB12+ placebo or double placebos for 6 months. Randomisation was stratified by bladder management type and inpatient or outpatient status. The primary outcome was time to occurrence of symptomatic UTI., Results: Analysis was based on intention to treat. Participants randomised to RC14-GR1 had a similar risk of UTI as those not on RC14-GR1 (HR 0.67; 95% CI: 0.39-1.18; P = 0.17) after allowing for pre-specified covariates. Participants randomised to LGG-BB12 also had a similar risk of UTI as those not on LGG-BB12 (HR 1.29; 95% CI: 0.74-2.25; P = 0.37). Multivariable post hoc survival analysis for RC14-GR1 only vs. the other three groups showed a potential protective effect (HR 0.46; 95% CI: 0.21-0.99; P = 0.03), but this result would need to be confirmed before clinical application., Conclusion: In this RCT, there was no effect of RC14-GR1 or LGG-BB12 in preventing UTI in people with SCI.

Sirtuin 1 (SIRT1) is known to play a role in a variety of tumorigenesis processes by deacetylating histone and non-histone proteins; however, antitumour effects by suppressing SIRT1 activity in non-small cell lung cancer (NSCLC) remain unclear. This study was designed to scrutinize clinicopathological significance of SIRT1 in NSCLC and investigate effects of metformin on SIRT1 inhibition. This study also evaluated new possibilities of drug combination using a SIRT1 inhibitor, tenovin-6, in NSCLC cell lines. It was found that SIRT1 was overexpressed in 300 (62%) of 485 formalin-fixed paraffin-embedded NSCLC tissues. Its overexpression was significantly associated with reduced overall survival and poor recurrence-free survival after adjusted for histology and pathologic stage. Thus, suppression of SIRT1 expression may be a reasonable therapeutic strategy for NSCLC. Metformin in combination with tenovin-6 was found to be more effective in inhibiting cell growth than either agent alone in NSCLC cell lines with different liver kinase B1 (LKB1) status. In addition, metformin and tenovin-6 synergistically suppressed SIRT1 expression in NSCLC cells regardless of LKB1 status. The marked reduction in SIRT1 expression by combination of metformin and tenovin-6 increased acetylation of p53 at lysine 382 and enhanced p53 stability in LKB1-deficient A549 cells. The combination suppressed SIRT1 promoter activity more effectively than either agent alone by up-regulating hypermethylation in cancer 1 (HIC1) binding at SIRT1 promoter. Also, suppressed SIRT1 expression by the combination synergistically induced caspase-3-dependent apoptosis. The study concluded that metformin with tenovin-6 may enhance antitumour effects through LKB1-independent SIRT1 down-regulation in NSCLC cells., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Introduction: Vascular anomalies encompass an extremely heterogeneous group of congenital abnormalities of the vascular system. They include vascular tumors and malformations and have a prevalence of 4.5%. Vascular anomalies are frequently sporadic and associated with somatic mutations and/or a double-hit mechanism and are characterized by considerable phenotypic and genetic heterogeneity. The aim of this review was to provide a genetic description of vascular anomalies, the sequencing technologies used for their diagnosis and the drugs that may potentially be used for their treatment., Evidence Acquisition: PubMed, OMIM, Orphanet, Genetic Testing Registry and ClinicalTrials.gov were searched for monogenic vascular anomalies in order to evaluate the genetic tests (based on sequencing) currently used for their diagnosis, and for any drugs that could be useful to treat them., Evidence Synthesis: From the search of the clinical synopsis section of OMIM and PubMed for vascular anomalies we selected 19 disorders with a known molecular etiology. From the search for pharmacological trials and therapies in the ClinicalTrials.gov and PubMed databases we selected 87 drugs., Conclusions: Most genetic tests with validated clinical utility are based on a next generation sequencing (NGS) approach. Targeted NGS is indeed the best approach for the analysis of disorders with complex phenotypes and genetics and involvement of somatic mutations. Genetic diagnosis provides data for determine genotype-phenotype correlations, segregation and recurrence risk in families, and new targets for gene- or mutation-specific pharmacological therapies. Improvement of diagnostic techniques is needed to offer patients appropriate care, more focused follow-up, and hopefully drugs to treat their disorders.

Study Design: Literature review., Objectives: Globally map key paediatric spinal cord damage epidemiological measures and provide a framework for an ongoing repository of data., Setting: Worldwide, initiative of ISCoS Prevention Committee., Methods: Literature search of Medline (1946-March 2017) and Embase (1974-March 2017). Relevant articles in any language regarding children with spinal cord damage included. Stratification of data quality into Green/Yellow /Red 'zones' facilitated comparison between countries., Results: A total of 862 abstracts were reviewed and data from 25 articles were included from 14 countries in 6 of the 21 Global Regions. Fourteen studies involved paediatric traumatic spinal cord injury (SCI) and seven were regarding non-traumatic spinal cord dysfunction (SCDys). An additional four articles provided both paediatric SCI and SCDys data. The median SCI incidence rates in Global Regions were: Asia, East 5.4/million population/year; Australasia 9.9/million population/year; Western Europe 3.3/million population/year and North America, High Income 13.2 million population/year. The median SCDys incidence rates in Global Regions were: Australasia 6.5/million population/year; Western Europe 6.2/million population/year and North America, High Income 2.1/million population/year. SCI was mostly due to land transport (46-74%), falls (12-35%) and sport/recreation (10-25%) and SCDys was mostly caused by tumours (30-63%) and inflammatory/autoimmune causes (28-35%)., Conclusions: There is a scarcity of quality epidemiology studies of paediatric SCD regarding incidence, prevalence, aetiology and survival. Recent ISCoS frameworks provide guidance for researchers to use established classification of SCDys and age group cut-off levels in future studies, thereby improving the ability to compare and combine data.

Background: Functional electrical stimulation (FES) is the application of electrical pulses to a nerve to achieve a functional muscle contraction. Surface electrical stimulation of the nerves that innervate the abdominal muscles, termed abdominal FES, can cause the abdominal muscles to contract, even when paralysed after spinal cord injury. As the abdominal muscles are the major expiratory muscles, and commonly partially or completely paralysed in tetraplegia, abdominal FES offers a promising method of improving respiratory function for this patient group. Objective: The aim of the article is to provide readers with a better understanding of how abdominal FES can be used to improve the health of the spinal cord-injured population. Methods: A narrative review of the abdominal FES literature was performed. Results: Abdominal FES can achieve an immediate effective cough in patients with tetraplegia, while the repeated application over 6 weeks of abdominal FES can improve unassisted respiratory function. Ventilator duration and tracheostomy cannulation time can also be reduced with repeated abdominal FES. Conclusion: Abdominal FES is a noninvasive method to achieve functional improvements in cough and respiratory function in acute and chronically injured people with tetraplegia. Potential practical outcomes of this include reduced ventilation duration, assisted tracheostomy decannulation, and a reduction in respiratory complications. All of these outcomes can contribute to reduced morbidity and mortality, improved quality of life, and significant potential cost savings for local health care providers., Competing Interests: Conflicts of Interest Dr. McCaughey reports grants and personal fees from Liberate Medical LLC, outside the submitted work. Dr. Butler reports grants from National Health and Medical Research Council during the conduct of the study and grants from National Health and Medical Research Council and Wings for Life outside the submitted work. Dr. Hudson reports grants from the Lung Foundation Australia, grants from Boehringer Ingelheim, during the conduct of the study and grants from Rebecca L. Cooper Foundation, the Lung Foundation Australia, Boehringer Ingelheim, National Health and Medical Research Council (Australia), and University of New South Wales outside the submitted work. The other authors report no conflicts of interest.

The receptive field structure of long (L) to middle (M) wavelength (L/M) cone-opponent ganglion cells of the parafoveal macaque retina was investigated using drifting gratings. Gratings were luminance, chromatic or selective for the L- or M-cones. Based on these spatial tuning curves, receptive field profiles for the individual cones were derived. Receptive field profiles were coarse compared to single cones, and often could not be described by a simple Gaussian, having shallower flanks. There was a continuum of spatial properties, which blurred any systematic distinction between Type I and Type II receptive fields. Opponent center-surround organization within a single cone was rare. Usually, responses to all four grating types could be described based on the cone receptive field profiles. An exception was a few cells that showed irregularities of amplitude and phase at high spatial frequencies for one or other of the cone isolating conditions. The data are related to standard models of M/L opponent receptive fields and implications for central processing are considered., (Copyright © 2017. Published by Elsevier Ltd.)

Transcriptional memory is critical for the faster reactivation of necessary genes upon environmental changes and requires that the genes were previously in an active state. However, whether transcriptional repression also displays 'memory' of the prior transcriptionally inactive state remains unknown. In this study, we show that transcriptional repression of ∼540 genes in yeast occurs much more rapidly if the genes have been previously repressed during carbon source shifts. This novel transcriptional response has been termed transcriptional repression memory (TREM). Interestingly, Rpd3L histone deacetylase (HDAC), targeted to active promoters induces TREM. Mutants for Rpd3L exhibit increased acetylation at active promoters and delay TREM significantly. Surprisingly, the interaction between H3K4me3 and Rpd3L via the Pho23 PHD finger is critical to promote histone deacetylation and TREM by Rpd3L. Therefore, we propose that an active mark, H3K4me3 enriched at active promoters, instructs Rpd3L HDAC to induce histone deacetylation and TREM.

Background: The objective of this study was to discover DNA methylation biomarkers for detecting non-small lung cancer (NSCLC) in bronchial washings and understanding the association between DNA methylation and smoking cessation., Methods: DNA methylation was analyzed in bronchial washing samples from 70 NSCLCs and 53 hospital-based controls using Illumina HumanMethylation450K BeadChip. Methylation levels in these bronchial washings were compared to those in 897 primary lung tissues of The Cancer Genome Atlas (TCGA) data., Results: Twenty-four CpGs ( p  < 1.03E-07) were significantly methylated in bronchial washings from 70 NSCLC patients compared to those from 53 controls. The CpGs also had significant methylation in the TCGA cohort. The 123 participants were divided into a training set ( N  = 82) and a test set ( N  = 41) to build a classification model. Logistic regression model showed the best performance for classification of lung cancer in bronchial washing samples: the sensitivity and specificity of a marker panel consisting of seven CpGs in TFAP2A , TBX15 , PHF11 , TOX2 , PRR15 , PDGFRA , and HOXA11 genes were 87.0 and 83.3% in the test set, respectively. The area under the curve (AUC) was equal to 0.87 (95% confidence interval = 0.73-0.96, p  < 0.001). Methylation levels of two CpGs in RUNX3 and MIR196A1 genes were inversely associated with duration of smoking cessation in the controls, but not in NSCLCs, after adjusting for pack-years of smoking., Conclusions: The present study suggests that NSCLC may be detected by analyzing methylation changes of seven CpGs in bronchial washings. Furthermore, smoking cessation may lead to decreased DNA methylation in nonmalignant bronchial epithelial cells in a gene-specific manner., Competing Interests: All patient samples were obtained after receiving written informed consent from all participants. This study was approved by the Institutional Review Board of Samsung Medical Center (IRB #: 2010-07-204).The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Objectives: The aim was to assess more accurately the net flow of the lower limb perforating veins (PVs)., Material and Methods: This was an observational prospective study. Two hundred and twenty one limbs with chronic venous disease (C1-6EpAs,pPr) of 193 patients underwent a duplex ultrasound (DUS). All identified PVs were scanned also by means of quality Doppler profile (QDP) multigate analysis in order to determine their net inward and outward flow direction. A comparison between the traditional pulsed wave Doppler analysis and QDP was performed to detect potential discrepancy between the traditional definition of PV incompetence and a net outward flow., Results: The DUS investigation identified 774 PVs. Only 7.7% of the PVs showed an outward flow lasting more than 500 ms. Among the PVs showing a longer than 500 ms outward flow, QDP assessment revealed net outward flow in only 84% of the PVs along the thigh and in 28.6% along the lower leg. Among the PVs showing a shorter than 500 ms outward flow, QDP assessment reported a net outward flow in 2.4% of the PVs along the thigh and in 47.3% of those along the lower leg. The sensitivity of an outward flow lasting more than 500 ms in detecting an actual net outward flow was 13.9% (9-20.1%). The specificity of an outward flow lasting less than 500 ms in detecting a net inward flow was 96.4% (93.2-98.3%)., Conclusions: A lack of overlap exists between the finding of a PV outward flow lasting more than 500 ms and the net outward flow of the same vessel. The traditional definition of PV incompetence is challenged by the reported data and further investigations are required to identify a gold standard assessment., (Copyright © 2018 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Study Objective: To evaluate if copious irrigation and suctioning after electromechanical power morcellation will reduce myoma cell dissemination and if there is a difference between sterile water and normal saline., Design: Prospective single-center cohort pilot study (Canadian Task Force classification II-2)., Setting: Academic tertiary referral center., Patients: Sixteen women undergoing laparoscopic myomectomy with 1 surgeon between January 1, 2017 and August 31, 2017., Interventions: Peritoneal washings were collected 3 specific times during surgery: after dissection of myoma(s) and hysterotomy repair but before morcellation, after morcellation, and after irrigation with 3 L normal saline or sterile water. The primary outcome was the detection of benign spindle cells (BSCs) in peritoneal washings., Measurements and Main Results: Sixteen patients were enrolled in the study. Eight were randomized to the normal saline group and 8 to the sterile water group. In the normal saline group BSCs were detected in 3 of 8 patients (37.5%) after closure of the hysterotomy but before morcellation, in 3 of 8 (37.5%) after morcellation, and in 0 of 8 (0%) after irrigation and suctioning of the peritoneal cavity with 3 L normal saline. In the sterile water group BSCs were detected in 3 of 8 patients (37.5%) after closure of the hysterotomy but before morcellation, 2 of 8 (25%) after morcellation, and in 0 of 8 (0%) after irrigation and suctioning with 3 L sterile water. Thus, no differences were found between the normal saline and sterile water groups., Conclusion: In this pilot study myoma cells were disseminated before electromechanical morcellation. Irrigation and suctioning with 3 L normal saline or sterile water after morcellation may reduce myoma cell dissemination., (Copyright © 2018 American Association of Gynecologic Laparoscopists. Published by Elsevier Inc. All rights reserved.)

Objective: This experiment was conducted to determine the effects of dietary β-mannanase on the additivity of true metabolizable energy (TME) and nitrogen-corrected true metabolizable energy (TME n ) for broiler diets., Methods: A total of 144 21-day-old broilers were randomly allotted to 12 dietary treatments with 6 replicates. Five treatments consisted of 5 ingredients of corn, wheat, soybean meal, corn distillers dried grains with solubles, or corn gluten meal. One mixed diet containing 200 g/kg of those 5 ingredients also was prepared. Additional 6 treatments were prepared by mixing 0.5 g/kg dietary β-mannanase with those 5 ingredients and the mixed diet. Based on a precision-fed chicken assay, TME and TME n values for 5 ingredients and the mixed diet as affected by dietary β-mannanase were determined., Results: Results indicated that when β-mannanase was not added to the diet, measured TME and TME n values for the diet did not differ from the predicted values for the diet, which validated the additivity. However, for the diet containing β-mannanase, measured TME n value was greater (p<0.05) than predicted TME n value, indicating that the additivity was not validated., Conclusion: In conclusion, the additivity of energy values for the mixed diet may not be guaranteed if the diet contains β-mannanase.

Syndromes with lymphatic malformations show phenotypic variability within the same entity, clinical features that overlap between different conditions and allelic as well as locus heterogeneity. The aim of this review is to provide a comprehensive clinical genetic description of lymphatic malformations and the techniques used for their diagnosis, and to propose a flowchart for genetic testing. Literature and database searches were performed to find conditions characterised by lymphatic malformations or the predisposition to lymphedema after surgery, to identify the associated genes and to find the guidelines and genetic tests currently used for the molecular diagnosis of these disorders. This search allowed us to identify several syndromes with lymphatic malformations that are characterised by a great heterogeneity of phenotypes, alleles and loci , and a high frequency of sporadic cases, which may be associated with somatic mutations. For these disorders, we found many diagnostic tests, an absence of harmonic guidelines for molecular diagnosis and well-established clinical guidelines. Targeted sequencing is the preferred method for the molecular diagnosis of lymphatic malformations. These techniques are easy to implement and have a good diagnostic success rates. In addition, they are relatively inexpensive and permit parallel analysis of all known disease-associated genes. The targeted sequencing approach has improved the diagnostic process, giving patients access to better treatment and, potentially, to therapy personalised to their genetic profiles. These new techniques will also facilitate the prenatal and early postnatal diagnosis of congenital lymphatic conditions and the possibility of early intervention., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: This study was aimed at understanding whether bronchial biopsy specimen can be used as a surrogate for DNA methylation analysis in surgically resected lung cancer., Methods: A genome-wide methylation was analyzed in 42 surgically resected tumor tissues, 136 bronchial washing, 12 sputum, and 8 bronchial biopsy specimens using the Infinium HumanMethylation450 BeadChip, and models for prediction of lung cancer were evaluated using TCGA lung cancer data., Results: Four thousand seven hundred and twenty-six CpGs ( P  < 1.0E-07) that were highly methylated in tumor tissues were identified from 42 lung cancer patients. Ten CpGs were selected for prediction of lung cancer. Genes including the 10 CpGs were classified into three categories: (i) transcription ( HOXA9 , SOX17 , ZNF154 , HOXD13 ); (ii) cell signaling ( HBP1 , SFRP1 , VIPR2 ); and (iii) adhesion ( PCDH17 , ITGA5 , CD34 ). Three logistic regression models based on the 10 CpGs classified 897 TCGA primary lung tissues with a sensitivity of 95.0~97.8% and a specificity of 97.4~98.7%. However, the classification performance of the models was very poor in bronchial washing samples: the area under the curve (AUC) was equal to 0.72~0.78. The methylation levels of the 10 CpGs in bronchial biopsy were not significantly different from those in surgically resected tumor tissues ( P  > 0.05, Wilcoxon rank-sum test). However, their methylation levels were significantly different between paired bronchial biopsy and washing ( P  < 0.05, Wilcoxon signed-rank test)., Conclusions: The present study suggests that bronchial biopsy specimen may be used as a surrogate for DNA methylation analysis in patient with inoperable lung cancer., Competing Interests: All samples were obtained with written informed consent from all participants. This study was approved by our Institutional Review Board (IRB #: 2010-07-204) at the Samsung Medical Center.Not applicable.The authors declare that they have no competing interest.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This corrects the article DOI: 10.1038/ncomms13534.

A target molecule responsible for cell cycle arrest by metformin was discovered using a gene chip array in lung cancer cells and the effect of metformin on E2F8 was assessed. The siRNA-mediated knockdown of E2F8 significantly suppressed G1-S progression while ectopic expression of E2F8 relieved metformin-induced G1 arrest. The mRNA levels of p21 were found to be inversely related to those of E2F8 in lung cancer cells while siRNA-mediated knockdown of p21 partly rescued siE2F8-induced arrest of the cell cycle. Metformin had no effect on degradation of E2F8 mRNA. Activation and inhibition of AMPK by AICAR and Dorsomorphin, respectively, did not affect E2F8 suppression by metformin. The clinical significance of E2F8 was analyzed in The Cancer Genome Atlas (TCGA) data. One hundred six (13%) of 848 TCGA lung cancers overexpressed E2F8 mRNA. The overexpression of E2F8 was associated with poor overall survival (adjusted hazard ratio = 1.58, 95% confidence interval = 1.13-2.22; P = 0.008). The present study suggests that metformin may induce cell cycle arrest at the G1 phase by suppressing E2F8 expression in lung cancer cells. In addition, E2F8 may be associated with poor overall survival in lung cancer patients irrespective of histology., Competing Interests: CONFLICTS OF INTEREST The authors have no conflicts of interest to disclose.

Background and Purpose: The development of syringomyelia has been associated with changes in CSF flow dynamics in the spinal subarachnoid space. However, differences in CSF flow velocity between patients with posttraumatic syringomyelia and healthy participants remains unclear. The aim of this work was to define differences in CSF flow above and below a syrinx in participants with posttraumatic syringomyelia and compare the CSF flow with that in healthy controls., Materials and Methods: Six participants with posttraumatic syringomyelia were recruited for this study. Phase-contrast MR imaging was used to measure CSF flow velocity at the base of the skull and above and below the syrinx. Velocity magnitudes and temporal features of the CSF velocity profile were compared with those in healthy controls., Results: CSF flow velocity in the spinal subarachnoid space of participants with syringomyelia was similar at different locations despite differences in syrinx size and locations. Peak cranial and caudal velocities above and below the syrinx were not significantly different (peak cranial velocity, P = .9; peak caudal velocity, P = 1.0), but the peak velocities were significantly lower ( P < .001, P = .007) in the participants with syringomyelia compared with matched controls. Most notably, the duration of caudal flow was significantly shorter ( P = .003) in the participants with syringomyelia., Conclusions: CSF flow within the posttraumatic syringomyelia group was relatively uniform along the spinal canal, but there are differences in the timing of CSF flow compared with that in matched healthy controls. This finding supports the hypothesis that syrinx development may be associated with temporal changes in spinal CSF flow., (© 2017 by American Journal of Neuroradiology.)

The use of long-term catheterisation to manage insensate bladders, often associated with spinal cord injury (SCI), increases the risk of microbial colonisation and infection of the urinary tract. Urinary tract infection (UTI) is typically diagnosed and treated based on the culturing of organisms from the urine, although this approach overlooks low titer, slow growing and non-traditional pathogens. Here, we present an investigation of the urinary tract microbiome in catheterised SCI individuals, using T-RFLP and metagenomic sequencing of the microbial community. We monitored three neurogenic patients over a period of 12 months, who were part of a larger study investigating the efficacy of probiotics in controlling UTIs, to determine how their urinary tract microbial community composition changed over time and in relation to probiotic treatment regimens. Bacterial biofilms adherent to urinary catheters were examined as a proxy for bladder microbes. The microbial community composition of the urinary tract differed significantly between individuals. Probiotic therapy resulted in a significant change in the microbial community associated with the catheters. The community also changed as a consequence of UTI and this shift in community composition preceded the clinical diagnosis of infection. Changes in the microbiota due to probiotic treatment or infection were transient, resolving to microbial communities similar to their pre-treatment communities, suggesting that the native community was highly resilient. Based on these results, we propose that monitoring a patient's microbial community can be used to track the health of chronically catheterized patients and thus, can be used as part of a health-status monitoring program.

Hepatic vena cava syndrome, also known as membranous obstruction of inferior vena cava (IVC), was considered a rare congenital disease and classified under Budd-Chiari syndrome. It is now recognized as a bacterial infection-induced disease related to poor hygiene. Localized thrombophlebitis of the IVC at the site close to hepatic vein outlets is the initial lesion which converts on resolution into stenosis or complete obstruction, the circulatory equilibrium being maintained by development of cavo-caval collateral anastomosis. These changes persist for the rest of the patient's life. The patient remains asymptomatic for a variable period until acute exacerbations occur, precipitated by bacterial infection, resulting in deposition of thrombi at the site of the lesion and endophlebitis in intrahepatic veins. Large thrombus close to hepatic vein outlets results in ascites from hepatic venous outflow obstruction, which is followed by development of venocentric cirrhosis. Endophlebitis of intrahepatic veins results in ischemic liver damage and development of segmental stenosis or membrane. Acute exacerbations are recognized clinically as intermittent jaundice and/or elevation of aminotransferase or ascites associated with neutrophil leukocytosis and elevation of C-reactive protein; sonologically, they are recognized as the presence of thrombi of different ages in IVC and thrombosis of intrahepatic veins. Development of liver cirrhosis and hepatocellular carcinoma is related to severity or frequency of acute exacerbations and not to duration or type of caval obstruction. Hepatic vena cava syndrome is a common co-morbid condition with other liver diseases in developing countries and it should be considered in differential diagnosis in patient with intermittent elevation serum bilirubin and or aminotransferase or development of ascites and cirrhosis., (© 2017 The Japan Society of Hepatology.)

Study Design: Prospective cohort study., Objectives: For acute traumatic spinal cord injury (ATSCI), this study aimed to determine differences in outcomes between patient groups stratified by admission time (⩽24 vs >24 h) to the Spinal Injury Unit (SIU) and by the nature of the admission (direct admission to the SIU vs indirect admission via another hospital). We also aimed to measure the effect on time to admission of a 'non-refusal' policy that triggered immediate acceptance of ATSCI cases to the SIU., Setting: New South Wales, Australia., Methods: Study population was all adult SCI patients admitted to the Prince of Wales SIU from 1 January 2001 to 31 December 2012. Patients admitted with chronic-stage SCI or with incomplete data for the duration of their stay were excluded. Comparison of outcomes was made between groups according to the setting of admission. Time to admission before and after initiation (2009) of the 'non-refusal' policy was compared. The prevalence of complications, lengths of stay (LOSs) and time to admission were compared by Mann-Whitney non-parametric methods. Count modelling was used to control for confounders of age and gender., Results: A total of 460 cases were identified and 76 were excluded. The early group had fewer pressure areas (41.8% vs 63.2%; P<0.001) and shorter LOS (136 vs 172 days; P<0.001) than the late group. The direct group had fewer pressure areas (35.2% vs 54.9%, P<0.001), deep vein thrombosis (9.9% vs 24.6%, P=0.003) and shorter LOS (124 vs 158 days, P=0.007) than those admitted indirectly. Time to admission was reduced after introduction of the 'non-refusal' policy (1.53 vs 0.63 days; P=0.001)., Conclusions: Early and direct admission to SIU reduced complication rates and LOS. A non-refusal policy reduced time to admission.

RNA polymerase II-interacting the Set2 methyltransferase co-transcriptionally methylates histone H3 at lysine 36 within the body of genes. This modification facilitates histone deacetylation by Rpd3S HDAC in 3' transcribed regions to suppress cryptic initiation and slow elongation. Although this pathway is important for global deacetylation, no strong effects have been seen on genome-wide transcription under optimized laboratory conditions. In contrast, this pathway slows the kinetics of mRNA induction when target genes are induced upon environmental changes. Interestingly, a majority of Set2-repressed genes are overlapped by a lncRNA transcription that targets H3K36 methylation and deacetylation by Rpd3S HDAC to mRNA promoters. Furthermore, this pathway delays the induction of many cryptic transcripts upon environmental changes. Therefore, the Set2-Rpd3S HDAC pathway functions to fine-tune expression dynamics of mRNAs and ncRNAs. [BMB Reports 2017; 50(4): 162-163].