In this study, we tested our hypothesis regarding mechanistic cross-talk between gastrointestinal inflammation and memory loss in a mouse model. Intrarectal injection of the colitis inducer ...2,4,6-trinitrobenzenesulfonic acid (TNBS) in mice caused colitis via activation of nuclear factor (NF)-κB and increase in membrane permeability. TNBS treatment increased fecal and blood levels of lipopolysaccharide (LPS) and the number of Enterobacteriaceae, particularly Escherichia coli (EC), in the gut microbiota composition, but significantly reduced the number of Lactobacillus johnsonii (LJ). Indeed, we observed that the mice treated with TNBS displayed impaired memory, as assessed using the Y-maze and passive avoidance tasks. Furthermore, treatment with EC, which was isolated from the feces of mice with TNBS-induced colitis, caused memory impairment and colitis, and increased the absorption of orally administered LPS into the blood. Treatment with TNBS or EC induced NF-κB activation and tumor necrosis factor-α expression in the hippocampus of mice, as well as suppressed brain-derived neurotrophic factor expression. However, treatment with LJ restored the disturbed gut microbiota composition, lowered gut microbiota, and blood LPS levels, and attenuated both TNBS- and EC-induced memory impairment and colitis. These results suggest that the gut microbiota disturbance by extrinsic stresses can cause gastrointestinal inflammation, resulting in memory impairment.
Capecitabine plus oxaliplatin (XELOX) has shown modest activity and tolerable toxicity in a phase II trial for biliary tract cancers (BTCs). Meanwhile, gemcitabine plus oxaliplatin (GEMOX) has been ...the reference arm in recent phase II and III trials for BTCs. We aimed to investigate the efficacy of XELOX versus GEMOX as first-line therapy for advanced BCTs.
In this open-label, randomized, phase III, noninferiority trial, we randomly selected patients with metastatic BCTs to receive GEMOX (gemcitabine 1000mg/m2 on days 1 and 8, and oxaliplatin 100mg/m2 on day 1) or XELOX (capecitabine 1000mg/m2, twice daily, on days 1–14 and oxaliplatin 130mg/m2 on day 1) as first-line treatment, given every 3weeks, totaling eight cycles. The primary end point was to prove the noninferiority of XELOX to GEMOX in terms of 6-month progression-free survival (PFS) rate.
In total, 114 patients randomly received GEMOX and 108 randomly received XELOX. The median PFS was 5.3months for the GEMOX group and 5.8months for the XELOX group. The 6-month PFS rate was 44.5% for the GEMOX group and 46.7% for the XELOX group. The 95% confidence interval of the 6-month PFS rate difference between both groups was −12% to 16%, meeting the criteria for noninferiority of XELOX to GEMOX. There was no difference in objective response (P=0.171) and median overall survival (P=0.131) between both groups. The most common grade three to four adverse events were neutropenia and thrombocytopenia. No patient died of treatment-related causes. The XELOX group had significantly lower frequencies of hospital visits than the GEMOX group (P<0.001).
XELOX showed significant noninferiority to GEMOX in terms of 6-month PFS rate. Thus, XELOX could be an alternative first-line treatment of BCTs.
This study was registered in ClinicalTrials.gov (number NCT01470443).
Human lung adenocarcinoma, the most prevalent form of lung cancer, is characterized by many molecular abnormalities. K-ras mutations are associated with the initiation of lung adenocarcinomas, but ...K-ras-independent mechanisms may also initiate lung tumors. Here, we find that the runt-related transcription factor Runx3 is essential for normal murine lung development and is a tumor suppressor that prevents lung adenocarcinoma. Runx3-/- mice, which die soon after birth, exhibit alveolar hyperplasia. Importantly, Runx3-/- bronchioli exhibit impaired differentiation, as evidenced by the accumulation of epithelial cells containing specific markers for both alveolar (that is SP-B) and bronchiolar (that is CC10) lineages. Runx3-/- epithelial cells also express Bmi1, which supports self-renewal of stem cells. Lung adenomas spontaneously develop in aging Runx3+/- mice ( approximately 18 months after birth) and invariably exhibit reduced levels of Runx3. As K-ras mutations are very rare in these adenomas, Runx3+/- mice provide an animal model for lung tumorigenesis that recapitulates the preneoplastic stage of human lung adenocarcinoma development, which is independent of K-Ras mutation. We conclude that Runx3 is essential for lung epithelial cell differentiation, and that downregulation of Runx3 is causally linked to the preneoplastic stage of lung adenocarcinoma.
Background
Classifications of intraductal papillary mucinous neoplasm (IPMN) remain ambiguous, especially for the mixed type. Factors predicting malignancy remain unclear. The aim of this study was ...to evaluate the usefulness of factors predicting malignancy in the new international consensus guidelines for resection of branch duct‐type (BD)‐IPMN and to compare them with those in the previous version.
Methods
A prospectively collected database of patients with biopsy‐proven BD‐IPMN was analysed to compare factors between the first and second consensus guidelines, particularly as predictors of malignancy.
Results
Of 350 patients with BD‐IPMN, sensitivity (0·724) and balanced accuracy (0·751) of the second guidelines were superior to those (0·639 and 0·730) in the first version at the expense of slightly reduced specificity (0·779 versus 0·822 for the first version) by random forest models. Multiple logistic regression analysis showed that main pancreatic duct dilatation greater than 5 mm (hazard ratio (HR) 4·54, 95 per cent confidence interval 2·45 to 8·41; P < 0·001), mural nodules (HR 6·27, 3·27 to 12·01; P < 0·001) and carbohydrate antigen 19–9 level above 37 units/ml (HR 4·03, 1·83 to 8·90; P = 0·001) were independent predictors of BD‐IPMN malignancy.
Conclusion
The new consensus guidelines provide better sensitivity, performance of factors predicting malignancy, and balanced accuracy in the diagnosis of BD‐IPMN malignancy. Size alone was limited in predicting malignancy. Variability in clinical significance of the individual factors associated with a risk of malignancy indicates the need for a tailored approach in the management of patients with BD‐IPMN.
Cyst size alone is not useful
Pulsar timing arrays offer a probe of the low-frequency gravitational wave spectrum (1–100 nHz), which is intimately connected to a number of markers that can uniquely trace the formation and ...evolution of the Universe. We present the dataset and the results of the timing analysis from the second data release of the European Pulsar Timing Array (EPTA). The dataset contains high-precision pulsar timing data from 25 millisecond pulsars collected with the five largest radio telescopes in Europe, as well as the Large European Array for Pulsars. The dataset forms the foundation for the search for gravitational waves by the EPTA, presented in associated papers. We describe the dataset and present the results of the frequentist and Bayesian pulsar timing analysis for individual millisecond pulsars that have been observed over the last ~25 yr. We discuss the improvements to the individual pulsar parameter estimates, as well as new measurements of the physical properties of these pulsars and their companions. This data release extends the dataset from EPTA Data Release 1 up to the beginning of 2021, with individual pulsar datasets with timespans ranging from 14 to 25 yr. These lead to improved constraints on annual parallaxes, secular variation of the orbital period, and Shapiro delay for a number of sources. Based on these results, we derived astrophysical parameters that include distances, transverse velocities, binary pulsar masses, and annual orbital parallaxes.
CoCrFeMnNi high-entropy alloy (HEA) materials were fabricated using mechanical alloying (MA) and spark plasma sintering (SPS). The MA time, SPS temperature, and contaminations strongly affected the ...final microstructure and mechanical properties. Nanocrystal face-centered cubic (FCC) solid solution was made during MA, and the FCC phase maintained as the matrix after SPS at 900 °C and 1100 °C. However, Cr carbides were transformed near the surface due to the carbon contamination. When MA time increased, phase stability of the FCC phase was improved, and the contaminant (ZrO2) from the MA balls was also increased. Ultrafine-grained microstructure was obtained at 60 min MA and 900 °C SPS. On the other hand, the higher SPS temperature and lower levels of contamination were required to achieve tensile ductility. Irregularly distributed ZrO2 particles developed bimodal microstructures.
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•CoCrFeMnNi high-entropy alloys were fabricated using powder metallurgy.•Contaminations highly affected microstructural evolution and mechanical properties.•Phase stability was improved with increasing ball milling time.•UFG microstructure was obtained under a certain condition.
ABSTRACT
We present results from the search for a stochastic gravitational-wave background (GWB) as predicted by the theory of General Relativity using six radio millisecond pulsars from the Data ...Release 2 (DR2) of the European Pulsar Timing Array (EPTA) covering a timespan up to 24 yr. A GWB manifests itself as a long-term low-frequency stochastic signal common to all pulsars, a common red signal (CRS), with the characteristic Hellings-Downs (HD) spatial correlation. Our analysis is performed with two independent pipelines, ENTERPRISE, and TEMPONEST+FORTYTWO, which produce consistent results. A search for a CRS with simultaneous estimation of its spatial correlations yields spectral properties compatible with theoretical GWB predictions, but does not result in the required measurement of the HD correlation, as required for GWB detection. Further Bayesian model comparison between different types of CRSs, including a GWB, finds the most favoured model to be the common uncorrelated red noise described by a power law with $A = 5.13_{-2.73}^{+4.20} \times 10^{-15}$ and $\gamma = 3.78_{-0.59}^{+0.69}$ (95 per cent credible regions). Fixing the spectral index to γ = 13/3 as expected from the GWB by circular, inspiralling supermassive black hole binaries results in an amplitude of $A =2.95_{-0.72}^{+0.89} \times 10^{-15}$. We implement three different models, BAYESEPHEM, LINIMOSS, and EPHEMGP, to address possible Solar system ephemeris (SSE) systematics and conclude that our results may only marginally depend on these effects. This work builds on the methods and models from the studies on the EPTA DR1. We show that under the same analysis framework the results remain consistent after the data set extension.
Summary
Escherichia coli is classified as a rod‐shaped, Gram‐negative bacterium in the family Enterobacteriaceae. The bacterium mainly inhabits the lower intestinal tract of warm‐blooded animals, ...including humans, and is often discharged into the environment through faeces or wastewater effluent. The presence of E. coli in environmental waters has long been considered as an indicator of recent faecal pollution. However, numerous recent studies have reported that some specific strains of E. coli can survive for long periods of time, and potentially reproduce, in extraintestinal environments. This indicates that E. coli can be integrated into indigenous microbial communities in the environment. This naturalization phenomenon calls into question the reliability of E. coli as a faecal indicator bacterium (FIB). Recently, many studies reported that E. coli populations in the environment are affected by ambient environmental conditions affecting their long‐term survival. Large‐scale studies of population genetics revealed the diversity and complexity of E. coli strains in various environments, which are affected by multiple environmental factors. This review examines the current knowledge on the ecology of E. coli strains in various environments with regard to its role as a FIB and as a naturalized member of indigenous microbial communities. Special emphasis is given on the growth of pathogenic E. coli in the environment, and the population genetics of environmental members of the genus Escherichia. The impact of environmental E. coli on water quality and public health is also discussed.
Background
There are concerns about the extent of impaired endocrine and exocrine pancreatic function and poor quality of life (QoL) after pancreatectomy, but there is little information from large ...prospective follow‐up studies.
Methods
Consecutive patients undergoing pancreaticoduodenectomy or distal pancreatectomy between 2007 and 2011 were included. Relative bodyweight (RBW), triceps skinfold thickness (TSFT), serum protein, albumin, transferrin, fasting blood glucose, postprandial 2‐h glucose (PP2), glycosylated haemoglobin A1c and stool elastase measurements, and European Organization for Research and Treatment of Cancer QLQ‐C30 questionnaires were collected serially for 1 year.
Results
Some 136 patients undergoing pancreatic resection completed the study. RBW and TSFT recovered to over 90 per cent of the preoperative value by 12 months, whereas transferrin, albumin and protein had returned to preoperative levels by 3 months. Diabetes mellitus, impaired fasting glucose or raised PP2 was present in 42 of 76 patients at 6 months and 36 of 76 at 12 months. Although steatorrhoea and diarrhoea had mainly resolved by 3 months, stool elastase level decreased after operation and showed no recovery. Nutritional status, pancreatic endocrine function and QoL returned to preoperative levels in 63 (46·3 per cent), 72 (52·9 per cent) and 77 (56·6 per cent) of 136 patients within 6 months of pancreatectomy. Multivariable analysis revealed that age 60 years or more, operation type, chronic pancreatitis and malignant disease had a significant impact on nutritional index, pancreatic function and QoL.
Conclusion
About half of all patients can expect recovery from pancreatectomy after 6 months, but those with risk factors need more careful follow‐up and supportive management.
Reasonable recovery takes at least 6 months
The Korea National Health and Nutrition Examination Survey (KNHANES) is a national surveillance system that has been assessing the health and nutritional status of Koreans since 1998. Based on the ...National Health Promotion Act, the surveys have been conducted by the Korea Centers for Disease Control and Prevention (KCDC). This nationally representative cross-sectional survey includes approximately 10 000 individuals each year as a survey sample and collects information on socioeconomic status, health-related behaviours, quality of life, healthcare utilization, anthropometric measures, biochemical and clinical profiles for non-communicable diseases and dietary intakes with three component surveys: health interview, health examination and nutrition survey. The health interview and health examination are conducted by trained staff members, including physicians, medical technicians and health interviewers, at a mobile examination centre, and dieticians' visits to the homes of the study participants are followed up. KNHANES provides statistics for health-related policies in Korea, which also serve as the research infrastructure for studies on risk factors and diseases by supporting over 500 publications. KCDC has also supported researchers in Korea by providing annual workshops for data users. KCDC has published the Korea Health Statistics each year, and microdata are publicly available through the KNHANES website (http://knhanes.cdc.go.kr).
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