Esophageal squamous dysplasia is believed to be the precursor lesion of esophageal squamous cell carcinoma (ESCC); however, the genetic evolution from dysplasia to ESCC remains poorly understood. Here, we applied multi-region whole-exome sequencing to samples from two cohorts, 45 ESCC patients with matched dysplasia and carcinoma samples, and 13 tumor-free patients with only dysplasia samples. Our analysis reveals that dysplasia is heavily mutated and harbors most of the driver events reported in ESCC. Moreover, dysplasia is polyclonal, and remarkable heterogeneity is often observed between tumors and their neighboring dysplasia samples. Notably, copy number alterations are prevalent in dysplasia and persist during the ESCC progression, which is distinct from the development of esophageal adenocarcinoma. The sharp contrast in the prevalence of the ‘two-hit’ event on TP53 between the two cohorts suggests that the complete inactivation of TP53 is essential in promoting the development of ESCC.

Background: Surgical closure of patent ductus arteriosus (PDA) with severe pulmonary arterial hypertension in adults carries higher risk than in children. Objectives: To investigate the application of self-expandable occluders for transcatheter closure of PDA associated with severe pulmonary arterial hypertension in adults, and the assessment of immediate and shortterm results. Methods: 29 adult patients (6 men, 23 women) underwent attempted transcatheter closure of PDA at a mean (standard deviation (SD)) age of 31.1 (11.4) years (range 18-58 years) and a mean (SD) weight of 54.1 (7.1) kg (range 42-71 kg). On the basis of haemodynamic and clinical data obtained before and after trial occlusion, the final duct occlusion was determined and carried out. Radiographs of the chest, electrocardiograms and echocardiograms were used for follow-up evaluation of the treatment within 1 day, 1 month and 3-6 months after successful closure. Results: 20 of the 29 patients had successful occlusion (group 1), and 9 patients failed (named group 2). In group 1, in which occlusion was successful, mean (SD) pulmonary arterial pressures decreased markedly after trial occlusion: 78 (19.3) mm Hg (range 50-125 mm Hg) before occlusion and 41 (13.8) mm Hg (range 23-77 mm Hg) after occlusion. Systemic arterial oxygen saturation was found to be .90% in 19 patients and ,90% in the remaining patient before inhalation of oxygen, and .95% during inhalation of oxygen or after occlusion in all 20 patients. In group 2, the occlusion was not successful, because in two patients the device was not available; another two patients showed worsening of symptoms. The other five patients showed increased pulmonary arterial pressures after trial closure; their mean (SD) pulmonary arterial pressures increased by 10.3 (6) mm Hg (4-16 mm Hg) after trial occlusion, and systemic arterial oxygen saturation was 85.5% (2.6%) (range 82.6-88%) before inhalation of oxygen and 94.7% (1.7%) (range 90.7-99.1%) during inhalation of oxygen. In group 1, the dimensions of the left atrium, left ventricle and pulmonary artery increased considerably in 3-6-months of follow-up compared with those of preocclusion. Conclusions: Transcatheter closure is an effective treatment for adults with PDA associated with reversible severe pulmonary arterial hypertension. Further research is needed for the evaluation of long-term results.

Background:Pyroptosis is the term for caspase-1-dependent cell death associated with pro-inflammatory cytokines. The role of alveolar macrophage (AM) pyroptosis in the pathogenesis of the acute lung injury and acute respiratory distress syndrome (ALI/ARDS) remains unclear.Methods:C57BL/6 wild-type mice were assigned to sham, lipopolysaccharide (LPS) + vehicle, LPS + acetyl-tyrosyl-valyl- alanyl-aspartyl-chloromethylketone (Ac-YVAD-CMK) and LPS + Z-Asp-Glu-Val-Asp-fluoromethylketone groups. Mice were given intraperitoneal (IP) injections of LPS. Drugs were IP injected 1 h before LPS administration. Mice were sacrificed 16 h after LPS administration, and AMs were isolated. Western blot analysis for active caspase-1 and cleaved caspase-3, evaluation of lung injury and a cytokine release analysis were performed. AMs were treated with LPS and adenosine triphosphate (ATP); caspase-1-dependent cell death was evaluated using flow cytometry; the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) pyroptosomes were examined by immunofluorescence.Results:The expression of activated caspase-1 in AMs was enhanced following LPS challenge compared with the sham group. In the ex vivo study, the caspase-1/propidium iodide-positive cells, caspase-1 specks and ASC pyroptosomes were up-regulated in AMs following LPS/ATP stimulation. The specific caspase-1 inhibitor Ac-YVAD-CMK inhibited the activation of caspase-1 and pyroptotic cell death. Ac-YVAD-CMK also reduced the lung injury, pulmonary edema and total protein in bronchoalveolar lavage fluid (BALF). In addition, Ac-YVAD-CMK significantly inhibited interleukin-β (IL-1β) release both in serum and BALF and reduced the levels of IL-18, tumor necrosis factor-α (TNF-α), High Mobility Group Box 1 (HMGB1) in BALF during LPS-induced ALI/ARDS.Conclusions:This study reported AM pyroptosis during LPS-induced ALI/ARDS in mice and has demonstrated that Ac-YVAD-CMK can prevent AM-induced pyroptosis and lung injury. These preliminary findings may form the basis for further studies to evaluate this pathway as a target for prevention or reduction of ALI/ARDS.

Both diagnostic criteria cause misdiagnosis, and the sensitivity did not differ significantly. The incidence of SAE was high, and 28-day and 180-day mortality rates were significantly higher than those without SAE. Sepsis-associated encephalopathy is a risk factor for poor outcome. The overall long-term prognosis of patients with sepsis was poor, and the quality of life decreased.

S100β and neuron-specific enolase (NSE) are brain injury biomarkers, mainly used in brain trauma, cerebral stroke and hypoxic ischemia encephalopathy. The aim of this study was to study the clinical significance of serum S100β and NSE in diagnosing sepsis-associated encephalopathy (SAE) and predicting its prognosis. This was a prospective and observational study. Clinical data of septic patients were collected within 24 h after ICU admission from May 2012 to April 2013. We evaluated the level of consciousness twice per day. SAE was defined as cerebral dysfunction in the presence of sepsis that fulfilled the exclusion criteria. The infection biochemical indicators, Glasgow coma scale (GCS) score, acute physiology and chronic health evaluation score II, serum NSE and S100β were newly measured or evaluated for SAE patients. Finally, hospital mortality, bacteriological categories, length of ICU stay and length of hospital stay were also recorded for all enrolled patients. The data was analyzed with the Chi square test, two-sample t test or Mann-Whitney U test between two groups. The correlation between two factors was analyzed using the Pearson or Spearman analysis. Receiver operating characteristic (ROC) curves were used to determine the ability of S100β and NSE in diagnosing SAE and predicting the hospital mortality. In addition, cut-off points were obtained from the curves to determine the highest sum of sensitivity and specificity. Of 112 enrolled patients, 48 patients were diagnosed with SAE. The serum S100β and NSE concentrations in SAE patients were both significantly higher than in non-SAE patients 0.306 (IQR 0.157-0.880) μg/L vs. 0.095 (IQR 0.066-0.177) μg/L, 24.87 (IQR 31.73-12.73) ng/mL vs. 15.49 (IQR 9.88-21.46) ng/mL, P < 0.01]. GCS scores were related more closely to S100β than NSE (-0.595 vs. -0.337). S100β levels of 0.131 μg/L diagnosed SAE with 67.2% specificity and 85.4% sensitivity in the ROC curve, the area under the curve was 0.824 (95% confidence interval 0.750-0.898). NSE levels of 24.15 ng/mL diagnosed SAE with 82.8% specificity and 54.2% sensitivity, and the area under the curve was 0.664 (95 % confidence interval 0.561-0.767). In addition, the area under the curve for S100β for predicting hospital mortality was larger than for NSE (0.730 vs. 0.590). Serum S100β concentrations in SAE patients were significantly higher than in non-SAE patients. These may be related to the severity of SAE and may predict the outcome of sepsis. The efficacy and sensitivity of serum S100β in diagnosing SAE were high, but it had a low specificity. Moreover, compared to NSE, serum S100β was better for both diagnosing SAE and predicting the outcome of sepsis.