IMPORTANCE: Case series suggest favorable results of peroral endoscopic myotomy (POEM) for treatment of patients with achalasia. Data comparing POEM with pneumatic dilation, the standard treatment ...for patients with achalasia, are lacking. OBJECTIVE: To compare the effects of POEM vs pneumatic dilation as initial treatment of treatment-naive patients with achalasia. DESIGN, SETTING, AND PARTICIPANTS: This randomized multicenter clinical trial was conducted at 6 hospitals in the Netherlands, Germany, Italy, Hong Kong, and the United States. Adult patients with newly diagnosed achalasia and an Eckardt score greater than 3 who had not undergone previous treatment were included. The study was conducted between September 2012 and July 2015, the duration of follow-up was 2 years after the initial treatment, and the final date of follow-up was November 22, 2017. INTERVENTIONS: Randomization to receive POEM (n = 67) or pneumatic dilation with a 30-mm and a 35-mm balloon (n = 66), with stratification according to hospital. MAIN OUTCOMES AND MEASURES: The primary outcome was treatment success (defined as an Eckardt score ≤3 and the absence of severe complications or re-treatment) at the 2-year follow-up. A total of 14 secondary end points were examined among patients without treatment failure, including integrated relaxation pressure of the lower esophageal sphincter via high-resolution manometry, barium column height on timed barium esophagogram, and presence of reflux esophagitis. RESULTS: Of the 133 randomized patients, 130 (mean age, 48.6 years; 73 56% men) underwent treatment (64 in the POEM group and 66 in the pneumatic dilation group) and 126 (95%) completed the study. The primary outcome of treatment success occurred in 58 of 63 patients (92%) in the POEM group vs 34 of 63 (54%) in the pneumatic dilation group, a difference of 38% (95% CI, 22%-52%; P < .001). Of the 14 prespecified secondary end points, no significant difference between groups was demonstrated in 10 end points. There was no significant between-group difference in median integrated relaxation pressure (9.9 mm Hg in the POEM group vs 12.6 mm Hg in the pneumatic dilation group; difference, 2.7 mm Hg 95% CI, −2.1 to 7.5; P = .07) or median barium column height (2.3 cm in the POEM group vs 0 cm in the pneumatic dilation group; difference, 2.3 cm 95% CI, 1.0-3.6; P = .05). Reflux esophagitis occurred more often in the POEM group than in the pneumatic dilation group (22 of 54 41% vs 2 of 29 7%; difference, 34% 95% CI, 12%-49%; P = .002). Two serious adverse events, including 1 perforation, occurred after pneumatic dilation, while no serious adverse events occurred after POEM. CONCLUSIONS AND RELEVANCE: Among treatment-naive patients with achalasia, treatment with POEM compared with pneumatic dilation resulted in a significantly higher treatment success rate at 2 years. These findings support consideration of POEM as an initial treatment option for patients with achalasia. TRIAL REGISTRATION: Netherlands Trial Register number: NTR3593
Glioblastoma (GBM) is a common and malignant tumor with a poor prognosis. Glioblastoma stem cells (GSCs) have been reported to be involved in tumorigenesis, tumor maintenance and therapeutic ...resistance. Thus, to discover novel candidate therapeutic drugs for anti-GBM and anti-GSCs is an urgent need. We hypothesized that if treatment with a drug could reverse, at least in part, the gene expression signature of GBM and GSCs, this drug may have the potential to inhibit pathways essential in the formation of GBM and thereby treat GBM. Here, we collected 356 GBM gene signatures from public databases and queried the Connectivity Map. We systematically evaluated the in vitro antitumor effects of 79 drugs in GBM cell lines. Of the drugs screened, thioridazine was selected for further characterization because it has potent anti-GBM and anti-GSCs properties. When investigating the mechanisms underlying the cytocidal effects of thioridazine, we found that thioridazine induces autophagy in GBM cell lines, and upregulates AMPK activity. Moreover, LC3-II was upregulated in U87MG sphere cells treated with thioridazine. In addition, thioridazine suppressed GBM tumorigenesis and induced autophagy in vivo. We not only repurposed the antipsychotic drug thioridazine as a potent anti-GBM and anti-GSCs agent, but also provided a new strategy to search for drugs with anticancer and anticancer stem cell properties.
Summary
In Taiwan, an outbreak of acute hepatitis A (AHA) infection has been identified since June 2015. Approximately half of the cases occurred in HIV‐infected men who have sex with men (MSM). We ...used the Taiwan Centers for Disease Control (TCDC)‐operated National Disease Surveillance Systems (NDSS) to identify the incidence of AHA during 2011‐2016. Between June 2015 and December 2016, a total of 1268 AHA cases were documented, and 601 cases (47.4%) were co‐infected with HIV; the majority of whom were MSM (98.4%). Each AHA case was matched to two HIV‐infected controls without AHA reported in the NDSS on age (± 5 years), risk factor of HIV infection, HIV diagnosis date (± 30 days) and county/city of residence at HIV diagnosis. Three hundred forty‐three HIV/AHA cases were matched to 686 controls. In multivariable conditional logistic regression analysis, a previous gonorrhoea (adjusted OR=1.77, 95% CI 1.16‐2.70) and recent (aOR=6.77, 95% CI 4.34‐10.55) or remote syphilis report (aOR=3.56, 95% CI 2.48‐5.13) were independently associated with AHA. The epidemic persisted till December 2016, and the cases with a new diagnosis of HIV infection after AHA (28/301, 9.3%) increased after July 2016 (P = .001). HIV/AHA cases were centralized in northern and central metropolitan areas and HIV‐infected MSM with a recent history of sexually transmitted diseases in Taiwan. We recommend surveillance of associated behavioural and virologic characteristics and HAV counselling and testing for HIV‐infected men.
MicroRNAs (miRNAs) play important roles in tumorigenesis by regulating oncogenes and tumor-suppressor genes. In this study, miR-187 and miR-200a were found to be expressed at higher levels in ovarian ...cancers than in benign tumors. In patients with ovarian cancer, however, higher levels of miR-187 and miR-200a expression were paradoxically associated with better OS and recurrence-free survival. Further, multivariate analysis showed that miR-187 served as an independent prognostic factor for patients with ovarian cancer (n=176). Computational prediction and microarray results indicated that miR-187 directly targeted Disabled homolog-2 (Dab2), and luciferase reporter assays confirmed that the target site of miR-187 was located at the 3'-UTR of the Dab2 gene. Generally considered as a tumor-suppressor gene, Dab2 may actually promote tumor progression in advanced cancers through epithelial-to-mesenchymal transition (EMT). Ectopic expression of miR-187 in cancer cells promoted cell proliferation, but continued overexpression of miR-187 suppressed Dab2 and inhibited migration. Suppression of miR-187 upregulated Dab2, which, by inhibiting E-cadherin levels while stimulating vimentin and phospho-FAK levels, promoted EMT. Reduced ovarian cancer Dab2 histoscores correlated with high miR-187 levels and improved outcomes of patients. Collectively, these results demonstrate distinct dual roles of Dab2 in cell proliferation and tumor progression. In the initial steps of tumorigenesis, upregulated miR-187 suppresses Dab2, promoting cell proliferation. During the later stages, however, continued increased levels of miR-187 inhibits the Dab2-dependent EMT that is associated with tumor invasiveness, which is presumed to be the reason why cancers with high miR-187 levels were associated with better survivals.
Nanometer-thick passive films on metals usually impart remarkable resistance to general corrosion but are susceptible to localized attack in certain aggressive media, leading to material failure with ...pronounced adverse economic and safety consequences. Over the past decades, several classic theories have been proposed and accepted, based on hypotheses and theoretical models, and oftentimes, not sufficiently nor directly corroborated by experimental evidence. Here we show experimental results on the structure of the passive film formed on a FeCr
Ni
single crystal in chloride-free and chloride-containing media. We use aberration-corrected transmission electron microscopy to directly capture the chloride ion accumulation at the metal/film interface, lattice expansion on the metal side, undulations at the interface, and structural inhomogeneity on the film side, most of which had previously been rejected by existing models. This work unmasks, at the atomic scale, the mechanism of chloride-induced passivity breakdown that is known to occur in various metallic materials.
► A two-model system composing a watershed model and a water quality model was developed. ► The system was developed to simulate the impact of non-point source pollution on water quality. ► The ...system is useful in developing appropriate watershed management strategies.
In this study, an integrated two-model system composed of a multimedia watershed model and a river water quality model was developed to effectively simulate the impacts of non-point source (NPS) pollution on river water quality. NPS pollution loadings from Kaoping River Basin were calculated using the Integrated Watershed Management Model (IWMM). Results from the IWMM modeling were used as the input data for the Kaoping River water quality evaluation using the Water Quality Analysis Simulation Program (WASP) modeling. The land use patterns classified using SPOT images and Digital Elevation Model techniques with the aid of Erdas Imagine® process and ArcView® geographical information system were applied to assist the NPS pollution simulation. Results indicate that land use patterns of orchard farms and farmland areas were the major causes of the NPS pollution, and they should be effectively controlled. Results show that higher flow rates (>200
m
3/s) were observed in the wet seasons, which would cause the increase in NPS pollution loadings. Results demonstrate that the integral approach could develop a direct linkage between upstream land use changes and downstream water quality. Using water quality modeling alone would underestimate the impact of NPS pollution on river water quality. The introduction of the integrated two-model system shows a significant advance in estimating the water quality.
Colorectal cancer (CRC) development has been associated with increased proportions of Bacteroides fragilis and certain Streptococcus, Fusobacterium, and Peptostreptococcus species in the intestinal ...microbiota. We investigated associations between bacteremia from specific intestinal microbes and occurrence of CRC.
We performed a retrospective study after collecting data on 13,096 adult patients (exposed group) in Hong Kong hospitalized with bacteremia (identified by blood culture test) without a previous diagnosis of cancer from January 1, 2006 through December 31, 2015. We collected data on intestinal microbes previously associated with CRC (genera Bacteroides, Clostridium, Filifactor, Fusobacterium, Gemella, Granulicatella, Parvimonas, Peptostreptococcus, Prevotella, Solobacterium, and Streptococcus). Clinical information, including patient demographics, comorbid medical conditions, date of bacteremia, and bacterial species identified, were collected. The incidence of biopsy-proved CRC was compared between the exposed and unexposed (patients without bacteremia matched for age, sex, and comorbidities) groups.
The risk of CRC was increased in patients with bacteremia from B fragilis (hazard ratio HR = 3.85, 95% CI = 2.62–5.64, P = 5.5 × 10−12) or Streptococcus gallolyticus (HR = 5.73, 95% CI = 2.18–15.1, P = 4.1 × 10−4) compared with the unexposed group. In addition, the risk of CRC was increased in patients with bacteremia from Fusobacterium nucleatum (HR = 6.89, 95% CI = 1.70–27.9, P = .007), Peptostreptococcus species (HR = 3.06, 95% CI = 1.47–6.35, P = .003), Clostridium septicum (HR = 17.1, 95% CI = 1.82–160, P = .013), Clostridium perfringens (HR = 2.29, 95% CI = 1.16–4.52, P = .017), or Gemella morbillorum (HR = 15.2, 95% CI = 1.54–150, P = .020). We observed no increased risk in patients with bacteremia caused by microbes not previously associated with colorectal neoplasms.
In a retrospective analysis of patients hospitalized for bacteremia, we associated later diagnosis of CRC with B fragilis and S gallolyticus and other intestinal microbes. These bacteria might have entered the bloodstream from intestinal dysbiosis and perturbed barrier function. These findings support a model in which specific members of the intestinal microbiota promote colorectal carcinogenesis. Clinicians should evaluate patients with bacteremia from these species for neoplastic lesions in the colorectum.
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Abstract
Increasing the carrier density in a Mott insulator by chemical doping gives rise to a generic superconducting dome in high temperature superconductors. An intriguing question is whether a ...second superconducting dome may exist at higher dopings. Here we heavily overdope La
2-
x
Sr
x
CuO
4
(0.45 ≤
x
≤ 1.0) and discover an unprecedented reentrance of interface superconductivity in La
2-
x
Sr
x
CuO
4
/La
2
CuO
4
heterostructures. As
x
increases, the superconductivity is weakened and completely fades away at
x
= 0.8; but it revives at higher doping and fully recovers at
x
= 1.0. This is shown to be correlated with the suppression of the interfacial charge transfer around
x
= 0.8 and the weak-to-strong localization crossover in the La
2-
x
Sr
x
CuO
4
layer. We further construct a theoretical model to account for the sophisticated relation between charge localization and interfacial charge transfer. Our work advances both the search for and control of new superconducting heterostructures.
Two new heteroleptic ruthenium‐based dyes, SJW‐E1 and CYC‐B3 (see figure), with very high photon‐to‐current conversion efficiency are reported and their application in dye‐sensitized solar cells ...(DSCs) described. The higher performance of SJW‐E1 in DSCs is suggested to arise from successful molecular‐engineering of the ancillary ligand, that is, two‐dimensional conjugation enhancement and functional group substitution.
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