Morphology of immune-mediated hepatitis: A comparison between immune checkpoint inhibitor therapy and combined immune checkpoint inhibitor/anti-angiogenic therapy.

BACKGROUND: The combination of immune checkpoint inhibitors (ICIs) with anti-angiogenic drugs has shown promising anticancer effects. However, ICIs can trigger immune-mediated hepatitis (IMH). We aimed to clarify whether the combined use of anti-angiogenic drugs and ICIs would increase the severity of IMH. METHODS: One hundred IMH patients (ICI monotherapy vs. ICI plus anti-angiogenic therapy 30 vs. 70) were retrospectively enrolled. Clinicopathological parameters were compared between the two groups. RESULTS: IMH mainly showed variable degrees of panlobular hepatitis (84 %), while some cases presented mixed cholangio-hepatitic (14 %) or cholangitic (2 %) pattern. The incidence of moderate-severe injury was not significantly different between the two groups (combination vs. monotherapy 38.6 % vs. 20.0 %, p = 0.109). Specifically, the rates of marked lobular injury and portal inflammation were higher in the combination group than in the monotherapy cohort (p < 0.005), while the frequencies of interface hepatitis, bile duct injury, histiocytosis aggregates, and endothelialitis were comparable between the two groups (p > 0.05). Compared to mild IMH cases, severe IMH cases showed higher immunostaining expression levels of PD-L1 (60.7 % vs. 19.4 %, p < 0.0001). Treatments and outcomes of IMH were not significantly different between the two groups (p > 0.05). CONCLUSIONS: Compared to ICI monotherapy, the administration of anti-angiogenic drugs in combination with ICIs was not associated with increased hepatotoxicity.

Changes in soil aggregate stability and aggregate-associated organic carbon during old-field succession in karst valley.

Soil is the largest carbon pool whose change will have an impact on the terrestrial carbon cycle in the terrestrial ecosystem. Old-field succession on abandoned farmland, which usually has a noticeable effect on soil status, is a common phenomenon in karst valley where human activity alters frequently. In order to understand the changes in the accumulation of organic carbon (OC) in aggregates and bulk soil in different stages of old-field succession on abandoned farmland in the karst valley area, soil samples were collected at 0-10-cm and 10-20-cm depth representing three typical stages of old-field succession, i.e., abandoned farmland, secondary grass, and secondary shrub in Qingmuguan karst valley area, Chongqing City, Southwest China. Results displayed that during old-field succession (1) the mean weight diameter and geometric mean diameter of the aggregates increased and the fractal dimension decreased; (2) OC content within aggregates and bulk soil had no significant change in topsoil (0-10 cm); OC content within microaggregates and bulk soil had a significant reduction in subsoil (10-20 cm); the OC content within silt and clay fractions was significantly higher than that within the other two kinds of aggregates; (3) bulk-soil OC storage had no significant change but its accumulation relied more on the increase in the number of larger aggregates. It is concluded that the old-field succession in karst valley was beneficial to protect against soil erosion by improving soil aggregate stability, but had a limited effect on soil organic carbon sequestration.

Uterine inflammatory myofibroblastic tumor harboring novel NUDCD3-ROS1 and NRP2-ALK fusions: clinicopathologic features of 4 cases and literature review.

Inflammatory myofibroblastic tumor (IMT) is a mesenchymal neoplasm of intermediate biologic potential, which occurs mostly in the lung and abdomen cavity of children and young adults. Uterine IMTs are rare. Herein, we presented clinicopathologic features of 4 uterine IMTs. All four patients were initially diagnosed as leiomyosarcoma by other hospitals and corrected to uterine IMT after pathological consultation. Patient age ranged from 44 to 64 years old. Two cases demonstrated multiple masses. Microscopically, three tumors were composed of fascicular spindled cells with eosinophilic cytoplasm, and the other one was densely composed of spindled and epithelioid cells with bizarre and multinucleated cells. Tumor cells showed variable nuclear atypia, ranging from mild to severe. Prominent inflammatory cell infiltration was found in one case, and necrosis in two tumors. Immunochemistry staining revealed expression of smooth muscle markers in all four tumors, including a-SMA and desmin. Three tumors were positive for ALK protein expression. FISH analysis demonstrated ROS1 rearrangement in one tumor and ALK rearrangement in the other 3 tumors. NGS analysis showed novel NUDCD3-ROS1 and NRP2-ALK fusions in two tumors and TNS1-ALK fusion in the other two tumors. Gene aberrations involving p53 signaling pathway were identified in all four cases. All patients received surgery as primary treatment, and one had neoadjuvant chemotherapy. Three patients recurred within 12 months, and the other one recurred after 7 years. Patients with recurrence were treated with a combination of chemotherapy, targeted therapy, or surgery. In conclusion, the diagnosis of uterine IMTs can be challenging. Ancillary studies including ALK IHC, FISH, and NGS are helpful to establish diagnosis and to discover novel gene rearrangement potentially for targeted therapy.

Earliest domestication of common millet (Panicum miliaceum) in East Asia extended to 10,000 years ago.

The origin of millet from Neolithic China has generally been accepted, but it remains unknown whether common millet (Panicum miliaceum) or foxtail millet (Setaria italica) was the first species domesticated. Nor do we know the timing of their domestication and their routes of dispersal. Here, we report the discovery of husk phytoliths and biomolecular components identifiable solely as common millet from newly excavated storage pits at the Neolithic Cishan site, China, dated to between ca. 10,300 and ca. 8,700 calibrated years before present (cal yr BP). After ca. 8,700 cal yr BP, the grain crops began to contain a small quantity of foxtail millet. Our research reveals that the common millet was the earliest dry farming crop in East Asia, which is probably attributed to its excellent resistance to drought.

HER2 Positivity Is Affected by the Papillary Structure and Has a Bidirectional Prognostic Value for Gallbladder Carcinoma.

Gallbladder carcinoma (GBC) is responsible for 80%-95% of biliary tract malignancies and has a dismal prognosis. Human epidermal growth factor receptor 2 (HER2) is a promising therapeutic target of GBC. Through immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) methods, HER2 expression and gene amplification were identified on high-output tissue microarrays (TMAs) developed in 306 GBC cases to investigate its relationship with GBC and clinicopathological characteristics. Adenocarcinomas accounted for 223 (72.9%) of the cases, with 62 (27.8%) being papillary adenocarcinoma or having partial papillary structure. HER2 positivity was studied in 16.1% (36/223) of patients with adenocarcinoma and 41.9% (26/62) in adenocarcinoma with papillary structures. For 143 radically resected primary GBC cases with 24 HER2-positive tumors, survival data were valid; the median survival time was not reached, and the 5-year survival rate was 52.9%. All patients in stages 0-I survived, and the results of the HER2-positive group and the stage II HER2-negative group were similar (p = 0.354). However, in stage III, the mortality rate in the HER2-positive group was reduced (p = 0.005) and that in stage IV was higher (p = 0.005). In conclusion, HER2 positivity was significantly higher in patients with papillary GBC. The predictive value of HER2 varies by clinical stage, with no prediction in the early stages, better in stage III, and worse in stage IV.

S100A4 overexpression in pancreatic ductal adenocarcinoma: imaging biomarkers from whole-tumor evaluation with MRI and texture analysis.

OBJECTIVE: To investigate the relationship between imaging findings and S100A4 overexpression in pancreatic ductal adenocarcinoma (PDAC) and to determine imaging biomarkers of S100A4 overexpression from whole-tumor evaluation with MRI and texture analysis. METHODS: A total of 60 patients with pathologically confirmed PDAC were included in the study. All patients underwent preoperative abdominal contrast-enhanced MRI examination with Magnetom Aera (Siemens Healthcare, Germany, 1.5 T) at our institute. Whole-tumor evaluation including texture analysis was performed. Sections of specimens were reviewed, and the S100A4 expression status was quantitatively evaluated. Univariate and multivariate logistic regression analyses were conducted to find imaging biomarkers that could predict S100A4 overexpression. RESULTS: Twenty-four tumors (40.0%) had negative results for S100A4 overexpression, and 36 tumors (60.0%) exhibited overexpression. After univariate and multivariate analysis, distal pancreatic duct dilatation, T1WI_10th percentile and the enhancement rate difference between delayed phase (DP) and portal venous phase (PVP) were identified to predict S100A4 overexpression in PDAC independently (p = 0.009, 0.012 and 0.044), with odds ratios (ORs) of 0.102, 0.139 and 4.645, respectively. The area under the ROC curve (AUC) values were 0.715, 0.707 and 0.691. The AUC value of the proposed model was 0.877 with a sensitivity of 80.6% and specificity of 75.0%. CONCLUSION: A model including distal pancreatic duct dilatation, T1WI_10th percentile and the enhancement rate difference between the DP and PVP could predict S100A4 overexpression in PDAC as imaging biomarkers.

CDK4 Amplification in Esophageal Squamous Cell Carcinoma Associated With Better Patient Outcome.

In the present study, we aimed to investigate the clinical and prognostic values of CDK4 amplification and improve the risk stratification in patients with esophageal squamous cell carcinoma. CDK4 amplification was analyzed by fluorescence in situ hybridization using tissue microarray consisting of representative tissues of 520 patients with esophageal squamous cell carcinoma, and its correlation with clinicopathological features and clinical outcomes were evaluated. CDK4 amplification was found in 8.5% (44/520) of patients with esophageal squamous cell carcinoma. CDK4 amplification was negatively correlated with disease progression (P = 0.003) and death (P = 0.006). Patients with CDK4 amplification showed a significantly better disease-free survival (P = 0.016) and overall survival (P = 0.023) compared with those patients without CDK4 amplification. When patients were further stratified into I-II stage groups and III-IV stage groups, CDK4 amplification was significantly associated with both better disease-free survival (P = 0.023) and overall survival (P = 0.025) in the I-II stage group rather than the III-IV stage group. On univariate and multivariate analysis, invasive depth and CDK4 amplification were associated with disease-free survival and overall survival. Taken together, CDK4 amplification was identified as an independent prognostic factor for survival, which could be incorporated into the tumor-node-metastasis staging system to refine risk stratification of patients with esophageal squamous cell carcinoma.

[Impact of Urbanization on the Sources of Dissolved n-alkane in Underground River].

To investigate the influence of urbanization on the component features of dissolved n-alkanes (D-ALK) in the underground river in the dry season, water samples were collected respectively at the outlet of the two underground rivers. Components of D-ALK in these samples were quantitatively analyzed by gas chromatography-mass spectrometry (GC-MS). The results showed that the distribution of D-ALK carbon number at the two sites ranged from nC14 to nC35 in dry season. The total concentration of D-ALK (DT-ALK) in Jiangjia spring ranged from 102 to 356 ng·L-1, with an average of 230 ng·L-1. The low-number carbons were predominant in December 2014, January and April 2015. The ratios of LMH/HMH (nC21-/nC22+) ranged from 2.0 to 10. The carbon preference index (CPI) between nC14 and nC25 ranged from 0.19 to 0.57, with a maximum of C16 (Cmax16). However, in November 2014, February and March 2015, these samples had a bimodal distribution in n-alkane. All of the CPI14-25 and the ratios of LMH/HMH were less than 1. The CPI24-35 ranged from 1.2 to 23 with the Cmax 31 or Cmax33. During the three months, the values of Paq were 0.2, 0.7 and 0.1, respectively. The alkane indexes (AI) in November 2014 and March 2015 were 0.95 and 0.98, respectively. The values of DT-ALK in Laolongdong ranged from 110 to 697 ng·L-1 with an average of 310 ng·L-1. The carbon number distribution of each month had a low predominance, and the CPI14-25 was less than 1. In the dry season, under the influence of different human activities, the content and component of D-AKL in Laolongdong which originated mainly from microorganisms was more stable than that in Jiangjia spring, which was mainly derived from microorganisms and a mixture of microorganisms and plants.

[Sources, Migration and Conversion of Dissolved Sterols in Qingmuguan Underground River].

Water samples were collected from the Qinmuguan underground river from July to November in 2013. By gas chromatography-mass spectrometer (GC-MS), dissolved sterols were quantitatively analyzed. The results show that the average variation content of dissolved sterols ranges from 415 to 629 ng x L(-1), with the increasing migration distance of dissolved sterols in underground river, its contents are decreased. Between the inlet and outlet of Qingmuguan underground river, the average variation contents of dissolved sterol are between 724 and 374 ng x L(-1), and the average variation ratios of the content of stigmasterol with cholesterol range from 0.29 to 0.12. In short, their values are decreased accompanied by the increasing migration distance of underground river. The composing component in dissolved sterols varied differently between July to December, and the main component of dissolved sterols is cholesterin, the ratios of the content of dissolved sterols with cholesterin to the total dissolved sterols range from 37.30% to 94.85%. In addition, the ratios of the content of dissolved sterols with coprostanol to cholesterin, coprostanol to cholesterin are below 0.2 respectively, indicating the water quality of underground river is not contaminated by domestic sewage, but with the passage of time water quality tends to deterioration.

[Hydrogen and oxygen isotopes of lake water and geothermal spring water in arid area of south Tibet].

The condition of water cycles in Tibet Plateau is a complex process, and the hydrogen and oxygen isotopes contain important information of this process. Based on the analysis of isotopic composition of freshwater lake, saltwater lake and geothermal water in the southern Tibetan Plateau, this study investigated water cycling, composition and variation of hydrogen and oxygen isotopes and the influencing factors in the study area. The study found that the mean values of delta18O and deltaD in Daggyaima lake water (-17.0 per thousand for delta18O and -138. 6 per thousand for deltaD), Langcuo lake water (-6.4 per thousand for delta18O and -87.4 per thousand for deltaD) and Dagejia geothermal water (-19.2 per thousand for delta18 and -158.2 per thousand for deltaD) all showed negative delta18O and deltaD values in Tibetan Plateau by the influence of altitude effects. Lake water and geothermal water were influenced by evaporation effects in inland arid area, and the slope of evaporation line was less than 8. Deuterium excess parameters of lake water and geothermal water were all negative. The temperature of geothermal reservoirs in Dagejia geothermal field was high,and oxygen shift existed in the relationship of hydrogen and oxygen isotopes.

[Contamination and source of polycyclic aromatic hydrocarbons in epikarst spring water].

The water samples were collected from four typical epikarst springs in Nanchuan District, Chongqing Municipality between October 2010 and October 2011. Sixteen priority polycyclic aromatic hydrocarbons in epikarst spring waters were quantitatively analyzed by the gas chromatography-mass spectrometer (GC-MS). The objectives of this study were to investigate the seasonal variations of polycyclic aromatic hydrocarbons' concentration, composition, source and contamination characterization in epikarst springs water. The results showed that the detection ratios of 16 PAHs in four springs were 100%. The total concentrations of 16 PAHs fluctuated greatly in epikarst spring water during one year observation, and the concentration ranged from 341 to 4 968 ng x L(-1), with a mean value of 1772 ng x L(-1). The total concentrations of 7 carcinogenic PAHs in rain season were all higher than those in dry season in four epikarst springs. The PAHs profiles were dominated by (2-3) rings PAHs in spring water, which accounted for more than 50% of 16 PAHs. The PAHs in spring water mainly originated from the combustion of coal, biomass and petroleum, and during June to October 2011, PAHs originated from the combustion of coal and biomass had a larger contribution. The ratios of Ant/( Ant + Phe) and Fla/( Fla + Pyr) changing with seasons showed that Ant, Phe, Fla and Pyr were easy to migrate in epikarst soils. In 4 isomeric ratios, the ratios of Fla/(Fla + Pyr) were more sensitive to reflect the information of sources. Compared to other areas in the world, the concentration of 16 PAHs in epikarst spring water is at a higher level, which shows the epikarst spring water has been suffered the PAHs pollution.

[Characteristics and evolution of hydrochemical compositions of freshwater lake in Tibetan plateau].

Freshwater lake of the Tibetan plateau has great ecological value and extreme vulnerability. The water samples have been collected in Daggyaima Co at an altitude of 5 080 m +/- 10 m. This study has investigated the sources, the major controlling factors of the major ions, and hydrochemical evolution trend according to the hydrochemical composition of water samples. The results showed that the major cations and anion of lake water were Ca(2+), Na(+) and HCO3(-), respectively, and the hydrochemical type was HCO3 -Ca, The total dissolved solid (TDS) was in the range of 71.2-199.8 mg x L(-1). The concentrations of EC, Ca(2+) and HCO3(-) in water samples from Southeast areas were relatively low resulted from the rich aluminum and poor calcium of geological background and the dilution effect of surface runoff. The Na(+)/(Na(+) + Ca(2+)) of water samples was 0.08-0.75, Cl(-) /(Cl(-) + HCO3(-)) was 0.11-0.35, Ca/Na was 0.58, Mg/Ca was 0.12, and HCO3/Na was 1.46, which suggested that the hydrochemical composition of the lake water was mainly controlled by silicate rock weathering based on Gibbs model and analysis of elemental stoichiometry. The minerals participated in weathering processes included plagioclase (anorthite, albite), potassium feldspar, biotite, calcite, dolomite, gypsum, rock salt, etc. The average value of K/Na was 0.059, indicating the weathering level of potassium feldspar was relatively low. The saturation index (SI) of calcite, dolomite, gypsum, quartz and hematite contained in the lake was higher than zero, while the SI of rock salt was lower than 0, revealing the trend that the freshwater lake is turning into salt water lake in Tibetan Plateau.

[Weathering seasonal variations in karst valley in southwest China].

Jialing River is a 1st grade tributary of upstream Yangzi River. In two years, Samples were collected monthly in Wentang Gorge section of Jialing River and analyzed multi-parameters including hydrochemistry and isotopes. Thus, a general result was concluded that the hydrochemical characteristic of Jialing River in Wentang gorge is controlled by weathering of stratum and the hydrochemical type is HCO3(-) -Ca. Most irons were influenced by dilution, which had higher concentrations in dry season than that in rainy season, but nitrate. Nitrate, which was controlled by human activities, has higher concentrations in rainy season. However, some other analyst revealed weathering impacts. The contrast ratio of (Ca(2+) + Mg2+) and HCO3- were between 0.5-1, the same as (Ca(2+) + Mg2+) and (HCO3(-) + SO4(2-)), Which implied that the weathering impacts in this basin was mainly carbonated and sulfate weathering of carbonated, and sulphate rocks weathering was not so significant. The values of delta13C(HCO3- in Jialing River were -8.74 per thousand(-) - 7.36 per thousand, and delta34S(SO)(4)2 - was 14.43 per thousand in dry season and 12.21 per thousand in rainy season. The data of isotopes inferred that, in rainy season sulfate weathering of carbonated and sulphate rocks weathering both had more impacts and sulphate rocks weathering played a more important role than sulfate weathering of carbonated, but, in dry season, carbonated weathering of carbonated was more meaningful.

[Spatial and temporal variability of nitrate contaminant in groundwater in Jinfo Mt. area, Chongqing, China].

The geochemical background of nitrate in groundwater in Jinfo Mt. area was determined, and spatial and temporal variability of nitrate contaminant was analyzed using geochemical, statistical and GIS methods. Twenty-three samples were collected from groundwater discharge points in the study area during 1976-1977, 2004-2006 and 2009, and mass concentration of nitrate in groundwater was tested. The results showed that the geochemical background of nitrate in groundwater in study area was in the range of 0.72-2. 00 mg x L(-1), and the threshold of anomaly was 3.20 mg x L(-1). During 2004-2006 and 2009, the average values of nitrate concentration in groundwater in Jinfo Mt. natural reserve were 2.08, 2.67, 2.59 and 3.92 mg x L(-1); and were 39.08, 25.46, 17.99 and 13.73 mg x L(-1) in the groundwater out of the reserve; the average over-limit rates (standard limit NO3(-) -N < or = 10mg x L(-1)) were 451.64%, 478.61%, 331.85% and 145.67%; the maximum over-limit rates were 1 475.81%, 1 080.39%, 538.20% and 361.78%. Results of interpolation showed that the high value centers of nitrate concentration in groundwater in study area were changing over time, but districts with low nitrate concentration in groundwater in study area were distributed along Jinfo Mt. natural reserve. The application of environmental policy measures and industrial restructuring implemented were reasonable and successful, which had a positive effect to environmental protection.