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This study investigated the effects of combining Phragmites australis-based biochar, prepared at 400 °C, with various types of phosphate fertilizers-soluble, insoluble, and organic-on the content and transformation of phosphorus fractions in saline-alkali soil. Additionally, we explored microbiological mechanisms driving these transformations. The results showed that this combination significantly increased the concentrations of dicalcium phosphate (Ca2P), octacalcium phosphate (Ca8P), aluminum phosphate (AlP), moderately labile organic phosphorus (MLOP), and resistant organic phosphorus (MROP) in soil. Conversely, the levels of hydroxyapatite (Ca10P) and highly resistant organic phosphorus (HROP) decreased. The increase in labile organic phosphorus (LOP) content or decrease in iron phosphate (FeP) was found to effectively enhance the availability of Olsen phosphorus (Olsen-P) in soil. Furthermore, the study revealed that biochar mixed with organic phosphate fertilizers increased the activity of soil acid phosphatase (ACP) and neutral phosphatase (NEP), while reducing alkaline phosphatase (ALP) activity. In contrast, biochar combined with soluble and insoluble phosphate fertilizers decreased the activity of ACP (22.59 % and 28.57 %, respectively) and NEP (62.50 % and 11.11 %, respectively), with the combination with insoluble fertilizers also reducing ALP activity by 55.84 %, whereas the soluble combination increased it by 190.34 %. Additionally, the co-application of biochar and phosphate fertilizers altered the composition and abundance of the gene phoD-harboring microbial community, enhancing the abundance of Proteobacteria and reducing that of Actinobacteria. Correlation analysis between phoD-functional microbial species and various phosphorus fractions showed that Rhodopseudomonas was significantly associated with several phosphorus components, exhibiting a positive correlation with Ca2P, Ca8P, AlP, LOP, MLOP, and MROP, but a negative relationship with Ca10P. These findings suggest that the combined application of biochar and phosphate fertilizers could change the abundance of Rhodopseudomonas, potentially influencing phosphorus cycling in the soil. This research provides a strong scientific foundation for the efficient combined use of biochar and phosphate fertilizers in managing saline-alkali soil.
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C-terminal Src kinase (CSK) is the major inhibitory kinase for Src family kinases (SFKs) through the phosphorylation of their C-tail tyrosine sites, and it regulates various types of cellular activity in association with SFK function. As a cytoplasmic protein, CSK needs be recruited to the plasma membrane to regulate SFKs' activity. The regulatory mechanism behind CSK activity and its subcellular localization remains largely unclear. In this work, we developed a genetically encoded biosensor based on fluorescence resonance energy transfer (FRET) to visualize the CSK activity in live cells. The biosensor, with an optimized substrate peptide, confirmed the crucial Arg107 site in the CSK SH2 domain and displayed sensitivity and specificity to CSK activity, while showing minor responses to co-transfected Src and Fyn. FRET measurements showed that CSK had a relatively mild level of kinase activity in comparison to Src and Fyn in rat airway smooth muscle cells. The biosensor tagged with different submembrane-targeting signals detected CSK activity at both non-lipid raft and lipid raft microregions, while it showed a higher FRET level at non-lipid ones. Co-transfected receptor-type protein tyrosine phosphatase alpha (PTPα) had an inhibitory effect on the CSK FRET response. The biosensor did not detect obvious changes in CSK activity between metastatic cancer cells and normal ones. In conclusion, a novel FRET biosensor was generated to monitor CSK activity and demonstrated CSK activity existing in both non-lipid and lipid raft membrane microregions, being more present at non-lipid ones.
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Técnicas Biosensibles , Proteína Tirosina Quinasa CSK , Transferencia Resonante de Energía de Fluorescencia , Humanos , Animales , Proteína Tirosina Quinasa CSK/metabolismo , Ratas , Familia-src Quinasas/metabolismo , Fosforilación , Microdominios de Membrana/metabolismo , Dominios Homologos srcRESUMEN
PURPOSE: Flattening filter-free (FFF)-based volumetric modulated arc therapy (VMAT) has been shown to be feasible and significantly improves treatment efficiency and lung protection for synchronous bilateral breast irradiation (SBBI). This research compared the commonly used VMAT field arrangements using FFF beams. METHODS: Twenty-eight patients underwent SBBI were retrospectively enrolled to design irradiation plans using tangential arc VMAT (taVMAT), half arc VMAT (haVMAT), and large arc VMAT (laVMAT). Dosimetric and delivery parameters of all designed plans were recorded and compared. RESULTS: Comparable target volume coverage was observed for all field arrangements. taVMAT significantly reduced the dose to spinal cord and the volume covered by 5 Gy (V5Gy) and V7Gy of the lungs while decreasing the conformity index of the target volume. It also increased the volume covered by 105% of the prescription dose (V105%) and V107% of the target volume. haVMAT considerably decreased V20 Gy and V30 Gy of the lungs, mean dose (Dmean) and V30 Gy of the heart and the liver. It also notably reduced Dmean and V40 Gy of the left anterior descending coronary artery while increasing the beam-on time. laVMAT significantly reduced the mean treatment time (range, 113-117 seconds) compared with the other field arrangements. CONCLUSIONS: There were distinct differences in various dosimetric and delivery parameters for different field arrangements, highlighting the importance of selecting the appropriate field arrangement based on specific treatment goals and considerations. This study contributes valuable insights into the use of FFF-based VMAT techniques in SBBI.
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We conducted a study to examine the growth and physiological changes in 12 different ecotypes of Sesuvium portulacastrum collected from Hainan Island in China. These ecotypes were subjected to different concentrations (0, 200, 400, and 600 mmol/L) of sodium chloride (NaCl) salt stress for 14 days. We also analyzed the expression of metabolic genes related to stress response. Under low salt stress, indicators such as plant height in region K (0 mmol/L: 45% and highest at 200 mmol/L: 80%), internode length (0 mmol/L: 0.38, 200 mmol/L: 0.87, 400 mmol/L: 0.25, and 600 mmol/L: 1.35), as well as leaf area, relative water content, fresh weight, and dry weight exhibited an overall increasing trend with the increase in salt concentration. However, as the salt concentration increased, these indicators showed a decreasing trend. Proline and malondialdehyde contents increased with higher salt concentrations. When the NaCl concentration was 400 mmol/L, MDA content in the leaves was highest in the regions E (196.23%), F (94.28%), J (170.10%), and K (136.08%) as compared to the control group, respectively. Most materials demonstrated a significant decrease in chlorophyll a, chlorophyll b, and total chlorophyll content compared to the control group. Furthermore, the ratio of chlorophyll a to chlorophyll b (Rab) varied among different materials. Using principal component analysis, we identified three ecotypes (L from Xinglong Village, Danzhou City; B from Shuigoupo Village, Lingshui County; and J from Haidongfang Park, Dongfang City) that represented high, medium, and low salt tolerance levels, respectively, based on the above growth and physiological indexes. To further investigate the expression changes of related genes at the transcriptional level, we employed qRT-PCR. The results showed that the relative expression of SpP5CS1, SpLOX1, and SpLOX1 genes increased with higher salt concentrations, which corresponded to the accumulation of proline and malondialdehyde content, respectively. However, the relative expression of SpCHL1a and SpCHL1b did not exhibit a consistent pattern. This study contributes to our understanding of the salt tolerance mechanism in the true halophyte S. portulacastrum, providing a solid theoretical foundation for further research in this field.
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Aizoaceae , Ecotipo , Clorofila A , Cloruro de Sodio/farmacología , Cloruro de Sodio/metabolismo , Estrés Salino/genética , Expresión Génica , Aizoaceae/metabolismo , Prolina/metabolismoRESUMEN
BACKGROUND: The liver manifestations of Alagille syndrome (ALGS) are highly variable, and factors affecting its prognosis are poorly understood. We asked whether the composition of bile acids in ALGS patients with good clinical outcomes differs from that in patients with poor outcomes and whether bile acids could be used as prognostic biomarkers. METHODS: Blood for bile acid profiling was collected from genetically confirmed JAG1-associated ALGS patients before one year of age. A good prognosis was defined as survival with native liver and total bilirubin (TB) < 85.5 µmol/L, while a poor prognosis was defined as either liver transplantation, death from liver failure, or TB ≥ 85.5 µmol/L at the last follow-up. RESULTS: We found that the concentrations of two poly-hydroxylated bile acids, tauro-2ß,3α,7α,12α-tetrahydroxylated bile acid (THBA) and glyco-hyocholic acid (GHCA), were significantly increased in patients with good prognosis compared to those with poor prognosis [area under curve (AUC) = 0.836 and 0.782, respectively] in the discovery cohort. The same trend was also observed in the molar ratios of GHCA to glyco- chenodeoxycholic acid (GCDCA) and tetrahydroxylated bile acid (THCA) to tauro-chenodeoxycholic acid (TCDCA) (both AUC = 0.836). A validation cohort confirmed these findings. Notably, tauro-2ß,3α,7α,12α-THBA achieved the highest prediction accuracy of 88.00% (92.31% sensitivity and 83.33% specificity); GHCA at > 607.69 nmol/L was associated with native liver survival [hazard ratio: 13.03, 95% confidence interval (CI): (2.662-63.753), P = 0.002]. CONCLUSIONS: We identified two poly-hydroxylated bile acids as liver prognostic biomarkers of ALGS patients. Enhanced hydroxylation of bile acids may result in better clinical outcomes.
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Síndrome de Alagille , Ácidos y Sales Biliares , Humanos , Síndrome de Alagille/diagnóstico , Pronóstico , Ácido Quenodesoxicólico , BiomarcadoresRESUMEN
Background & Aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. Methods: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS. Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (p <0.001). Without siEHC, NLS in the BSEP1/3 group was similar to that in BSEP3/3, but considerably lower than in BSEP1/1 (at age 10 years: 38%, 30%, and 71%, respectively; p = 0.003). After siEHC, BSEP1/3 and BSEP3/3 were associated with similarly low NLS, while NLS was much higher in BSEP1/1 (10 years after siEHC, 27%, 14%, and 92%, respectively; p <0.001). Conclusions: Individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment. Impact and implications: This manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until now, it had always been assumed that the mild mutation would be enough to ensure a relatively good prognosis. However, our manuscript shows that the prognosis of these patients is just as poor as that of patients with two severe mutations. They do not respond to biliary diversion surgery and will likely not respond to the new IBAT (ileal bile acid transporter) inhibitors, which have recently been approved for use in BSEP deficiency.
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BACKGROUND AND AIMS: Alagille syndrome (ALGS) is a multisystem disorder, characterized by cholestasis. Existing outcome data are largely derived from tertiary centers, and real-world data are lacking. This study aimed to elucidate the natural history of liver disease in a contemporary, international cohort of children with ALGS. APPROACH AND RESULTS: This was a multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born between January 1997 and August 2019. Native liver survival (NLS) and event-free survival rates were assessed. Cox models were constructed to identify early biochemical predictors of clinically evident portal hypertension (CEPH) and NLS. In total, 1433 children (57% male) from 67 centers in 29 countries were included. The 10 and 18-year NLS rates were 54.4% and 40.3%. By 10 and 18 years, 51.5% and 66.0% of children with ALGS experienced ≥1 adverse liver-related event (CEPH, transplant, or death). Children (>6 and ≤12 months) with median total bilirubin (TB) levels between ≥5.0 and <10.0 mg/dl had a 4.1-fold (95% confidence interval [CI], 1.6-10.8), and those ≥10.0 mg/dl had an 8.0-fold (95% CI, 3.4-18.4) increased risk of developing CEPH compared with those <5.0 mg/dl. Median TB levels between ≥5.0 and <10.0 mg/dl and >10.0 mg/dl were associated with a 4.8 (95% CI, 2.4-9.7) and 15.6 (95% CI, 8.7-28.2) increased risk of transplantation relative to <5.0 mg/dl. Median TB <5.0 mg/dl were associated with higher NLS rates relative to ≥5.0 mg/dl, with 79% reaching adulthood with native liver ( p < 0.001). CONCLUSIONS: In this large international cohort of ALGS, only 40.3% of children reach adulthood with their native liver. A TB <5.0 mg/dl between 6 and 12 months of age is associated with better hepatic outcomes. These thresholds provide clinicians with an objective tool to assist with clinical decision-making and in the evaluation of therapies.
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Síndrome de Alagille , Colestasis , Hipertensión Portal , Humanos , Niño , Masculino , Femenino , Síndrome de Alagille/epidemiología , Estudios Retrospectivos , Hipertensión Portal/etiologíaRESUMEN
Increasing evidence has demonstrated that STAT3 phosphorylation at Tyr705 and Ser727 is closely associated with the progression and poor prognosis of pancreatic cancer. Herein, we report the function-based screening, SAR studies, and biological activity evaluation of a series of novel STAT3 dual phosphorylation inhibitors with an indole-containing tetra-aromatic heterocycle scaffold. Our efforts led to the discovery of optimal compound 4c among the investigated ones, showing desirable ADME properties and highly potent antitumor activities in vitro and in vivo. By targeting the STAT3 SH2 domain, 4c significantly blocked p-Tyr705 and p-Ser727 and caused the abrogation of the corresponding nuclear transcription and mitochondrial oxidative phosphorylation functions of STAT3 in the low nanomolar range. Except for nanomolar antiproliferation activities in vitro, oral treatment of 4c exhibited significant suppressive effects and tolerance in a pancreatic cancer xenograft model, indicating that 4c could be useful for pancreatic cancer treatment as a STAT3 dual phosphorylation inhibitor.
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Antineoplásicos , Neoplasias Pancreáticas , Humanos , Fosforilación , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Proliferación Celular , Factor de Transcripción STAT3/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Ensayos Antitumor por Modelo de Xenoinjerto , Apoptosis , Neoplasias PancreáticasRESUMEN
In this work, the single crystal to single crystal (SCSC) transformations in three mononuclear copper complexes [CuL22]Cl2·2H2O (1), [CuL12Cl2] (2), and [CuL22]Cl2·4H2O (3) (L1 = di-2-pyridyl ketone, L2 = di(pyridin-2-yl)methanediol) are realized by the irreversible dehydration and hydration reaction of L1 and L2. Dark purple crystal 1 is obtained by self-assembly of L1 and CuCl2·2H2O in solvothermal reactions, in which the carbonyl group of L1 undergoes a hydration addition reaction to form L2. On heating, 1 transforms to 2 by dehydrating water accompanied by the change of the color and coordination octahedron of CuII ions. In a saturated water vapor environment, 2 can absorb six water molecules and transform to 3 with the same color and coordination environment with 1 but different lattice water. The SCSC process from 2 to 3 is reversible: 3 can transform back to 2 on heating like that of 1. Chroma rewritable behaviors in the structural transformation of the complexes make them visually identifiable temperature or water probes.
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BACKGROUND AND OBJECTIVES: Both bioelectrical impedance analysis (BIA) and electron computed tomography (CT) can be used as tools for assessing skeletal muscle mass. In order to find a more suitable method for assessing skeletal muscle mass in lung cancer patients, this study conducted a comprehensive comparative analysis of the two methods. METHODS AND STUDY DESIGN: We collected baseline data from patients admitted to the oncology department of the First Hospital of Hebei Medical University from October 2017 to December 2021, and collected data through physical examination, body composition analysis measurements and CT examinations. Then we calculated skeletal muscle mass index (ASMI), relative skeletal muscle index (RASM), and third lumbar spine skeletal muscle index (L3 SMI), respectively. Finally we analyzed the correlation between the three methods and body composition and biochemical indicators and the validity of the three methods. RESULTS: A total of 63 patients, 41 males and 22 females, were screened and eligible for enrollment, and the validity of RASM and ASMI was analyzed using L3 SMI as the diagnostic criteria: the sensitivity of RASM and ASMI were 66.67% and 13.33%, respectively, and the specificity was 70.83% and 39.58%, respectively, and the AUC of ROC was 0.736 (p<0.05), 0.264 (p<0.05). CONCLUSIONS: In this study, L3 SMI was used as the diagnostic criterion and after calculating and comparing the valid parameters of RASM and ASMI, RASM was recommended as the assessment criterion for skeletal muscle mass in Chinese lung cancer patients.
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Neoplasias Pulmonares , Sarcopenia , Composición Corporal/fisiología , Femenino , Humanos , Neoplasias Pulmonares/diagnóstico , Masculino , Músculo Esquelético , Sarcopenia/diagnóstico , Tomografía Computarizada por Rayos XAsunto(s)
COVID-19 , SARS-CoV-2 , China/epidemiología , Brotes de Enfermedades , Genoma Viral , Humanos , SARS-CoV-2/genéticaRESUMEN
BACKGROUND AND AIMS: Alagille syndrome (ALGS) type 2 caused by mutations in NOTCH2 has genotypic and phenotypic heterogeneity. Diagnosis in some atypical patients with isolated hepatic presentation could be missed. METHODS: Using 2087 patients with paediatric liver manifestations, NOTCH2 allele frequencies, in-silico prediction, protein domains and clinical features were analysed to define the pathogenicity of NOTCH2 variants for diagnosis of ALGS type 2. RESULTS: Among 2087 patients with paediatric liver manifestations, significantly more NOTCH2 variants were absent in gnomAD in patients with elevated γ-glutamyltransferase (GGT) (p = .041). Significantly more NOTCH2 variants which were absent in gnomAD were located in protein functional domains (p = .038). When missense variants were absent in gnomAD and predicted to be pathogenic by at least three out of seven in-silico tools, they were found to be significantly associated with liver manifestations with elevated GGT (p = .003). Comparing this to patients with likely benign (LB) variants, the patients with likely-pathogenic (LP) variants have significantly more liver manifestations with elevated GGT (p = .0001). Significantly more patients with LP variants had extra-hepatic phenotypes of ALGS compared with those patients with LB variants (p = .0004). CONCLUSION: When NOTCH2 variants are absent in gnomAD, null variants and missense variants which were predicted to be pathogenic by at least three in-silico tools could be considered pathogenic in patients with high GGT chronic liver diseases.
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Síndrome de Alagille , Receptor Notch2 , Síndrome de Alagille/diagnóstico , Síndrome de Alagille/genética , Humanos , Proteína Jagged-1/genética , Proteína Jagged-1/metabolismo , Mutación , Fenotipo , Receptor Notch2/genética , Receptor Notch2/metabolismo , VirulenciaRESUMEN
Novel 3D metal formate frameworks {[Ba4Cl][M3(HCO2)13]}n (M = Mn for 1, Co for 2, and Mg for 3) were successfully assembled via microwave-assisted synthesis. The complexes are rare coordination polymers crystallized at space group P4cc with the polar point group C4v. In the structure, the MII ions are bridged by two types of anti-anti formate in forming a 3D pcu framework, and additional formates coordinate to the unsaturated sites of the MII ions in the framework, giving an anionic M-formate net. Ba4Cl clusters take the cavities of the net as charge balance, in which the chloride ion deviates from the center of the barium ions. The asymmetric Ba4Cl structure is transmitted throughout the crystal resulting in polar structure, which is further confirmed by nonlinear optical and piezoelectric test. Nonlinear optical activity tests of 1 and 3 show SHG signals 0.32 and 0.28 times that of KDP, while 2 has a piezoelectric coefficient d33 of 6.8 pC/N along polar axis. Magnetic studies reveal antiferromagnetic coupling between MII ions in 1 and 2. Spin canting was found only in 2 with anisotropic CoII ions, and 2 is a canted antiferromagnetically with TN = 5 K. Further field-induced spin flop was also found in 2 with a critical field 0.9 T.
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The progression of breast cancer is closely related to obstructive sleep apnea-hypopnea syndrome (OSAHS). Low concentrations of cannabinoids promote tumor proliferation. However, the role of cannabinoid receptors (CBs) in chronic intermittent hypoxia (CIH)-induced breast cancer has not been reported. The migration and invasion of breast cancer cell lines (MCF-7 and T47D) were measured by scratch assay and transwell assay. Gene and protein expressions were analyzed by qPCR and western blotting. Tumor xenograft mice model were established to evaluate the function of CBs. We observed that chronic hypoxia (CH) and CIH increased CBs expression and promoted migration and invasion in breast cancer. Mice grafted with MCF-7 exhibited obvious tumor growth, angiogenesis, and lung metastasis in CIH compared with CH and control. In addition, CIH induced CBs expression, which subsequently activated insulin-like growth factor-1 receptor (IGF-1R)/AKT/glycogen synthase kinase-3ß (GSK-3ß) axis. Knockdown of CBs alleviated CIH-induced migration and invasion of breast cancer in vitro. Furthermore, CIH exaggerated the malignancy of breast cancer and silencing of CBs suppressed tumor growth and metastasis in vivo. Our study contributed to understanding the role of CIH in breast cancer development modulation.
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Progressive familial intrahepatic cholestasis type 1 (PFIC1) results from biallelic pathogenic variants in ATP8B1. This study sought second pathogenic variants in ATP8B1 by whole-genome sequencing (WGS) in four unrelated low γ-glutamyl transpeptidase cholestasis patients in whom clinical suspicion of PFIC1 was high and gene-panel or Sanger sequencing had identified only one pathogenic variant in ATP8B1. Sanger sequencing confirmed WGS findings and determined the origin of each variant. Novel nonrecurrent structural variants in three patients (patient 1 to patient 3) were identified in trans: g.55396652_55403080del (6427-bp deletion), g.55335906_55346620dup (10,715-bp duplication), and g.55362063_55364293dup (2231-bp duplication). One synonymous variant in patient 4 was recognized in trans (c.1029G>A, p. Thr343Thr) and demonstrated as deleterious. In conclusion, WGS improves genetic diagnostic yield in PFIC1. These findings expand the gene-variant spectrum associated with familiar intrahepatic cholestasis 1 (FIC1) disease and for the first time report tandem duplication in ATP8B1 associated with cholestasis.
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Adenosina Trifosfatasas/genética , Colestasis Intrahepática/genética , Eliminación de Gen , Duplicación de Gen , Secuenciación Completa del Genoma/métodos , Ácidos y Sales Biliares/sangre , Niño , Preescolar , Colestasis Intrahepática/sangre , Variaciones en el Número de Copia de ADN , Femenino , Pruebas Genéticas/métodos , Humanos , Mutación INDEL , Lactante , Recién Nacido , Masculino , Fenotipo , Polimorfismo de Nucleótido Simple , Secuencias Repetidas en Tándem/genética , gamma-Glutamiltransferasa/sangreRESUMEN
BACKGROUND: S100A11 is a member of the S100 family of proteins containing two EF-hand calcium-binding motifs. The dysregulated expression of the S100A11 gene has been implicated in tumour metastasis. However, the role of S100A11 protein in tumour cell response to chemotherapeutic drugs has not been characterised. METHODS: Transcript levels of S100A11 in gastric cancer were evaluated using an in-house patient cohort. Protein expression of S100A11 in gastric cancer was estimated by immunohistochemistry of a tissue microarray. The stable gastric cancer cell lines were established using lentiviral shRNA vectors. The knockdown of S100A11 was validated by qRT-PCR, PCR, and Western blot. The cellular function of S100A11 was estimated by assays of cell adhesion, migration, and invasion. The cell cytotoxic assay was performed to investigate the response to chemotherapeutic drugs. An unsupervised hierarchical clustering and principal component analysis (HCPC) was applied to unveil the dimensional role of S100A11 among all S100 family members in gastric cancer. RESULTS: High expression of S100A11 is associated with poor survival of gastric cancer patients (p < 0.001, HR = 1.85) and is an independent prognostic factor of gastric cancer. We demonstrate that S100A11 plays its role as a tumour promoter through regulating the MMP activity and the epithelial-mesenchymal transition (EMT) process. The stable knockdown of S100A11 suppresses the metastatic properties of gastric cancer cells, which include enhancing cell adhesion, but decelerating cell migration and invasion. Furthermore, the knockdown of S100A11 gene expression dramatically induces the cellular response of gastric cancer cells to the first-line chemotherapeutic drugs fluoropyrimidine 5-fluorouracil (5-FU) and cisplatin. CONCLUSION: The present study identifies S100A11 as a tumour promoter in gastric cancer. More importantly, the S100A11-specific targeting potentially presents dual therapeutic benefits by not only controlling tumour progression but also sensitising chemotherapeutic cytotoxic response.
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BACKGROUND AND AIMS: Mutations in ATPase phospholipid transporting 8B1 (ATP8B1) can lead to familial intrahepatic cholestasis type 1 (FIC1) deficiency, or progressive familial intrahepatic cholestasis type 1. The rarity of FIC1 deficiency has largely prevented a detailed analysis of its natural history, effects of predicted protein truncating mutations (PPTMs), and possible associations of serum bile acid (sBA) concentrations and surgical biliary diversion (SBD) with long-term outcome. We aimed to provide insights by using the largest genetically defined cohort of patients with FIC1 deficiency to date. APPROACH AND RESULTS: This multicenter, combined retrospective and prospective study included 130 patients with compound heterozygous or homozygous predicted pathogenic ATP8B1 variants. Patients were categorized according to the number of PPTMs (i.e., splice site, frameshift due to deletion or insertion, nonsense, duplication), FIC1-A (n = 67; no PPTMs), FIC1-B (n = 29; one PPTM), or FIC1-C (n = 34; two PPTMs). Survival analysis showed an overall native liver survival (NLS) of 44% at age 18 years. NLS was comparable among FIC1-A, FIC1-B, and FIC1-C (% NLS at age 10 years: 67%, 41%, and 59%, respectively; P = 0.12), despite FIC1-C undergoing SBD less often (% SBD at age 10 years: 65%, 57%, and 45%, respectively; P = 0.03). sBAs at presentation were negatively associated with NLS (NLS at age 10 years, sBAs < 194 µmol/L: 49% vs. sBAs ≥ 194 µmol/L: 15%; P = 0.03). SBD decreased sBAs (230 [125-282] to 74 [11-177] µmol/L; P = 0.005). SBD (HR 0.55, 95% CI 0.28-1.03, P = 0.06) and post-SBD sBA concentrations < 65 µmol/L (P = 0.05) tended to be associated with improved NLS. CONCLUSIONS: Less than half of patients with FIC1 deficiency reach adulthood with native liver. The number of PPTMs did not associate with the natural history or prognosis of FIC1 deficiency. sBA concentrations at initial presentation and after SBD provide limited prognostic information on long-term NLS.
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Adenosina Trifosfatasas/deficiencia , Ácidos y Sales Biliares/sangre , Colestasis Intrahepática/mortalidad , Adenosina Trifosfatasas/genética , Adolescente , Conductos Biliares Intrahepáticos/cirugía , Niño , Preescolar , Colestasis Intrahepática/sangre , Colestasis Intrahepática/genética , Colestasis Intrahepática/cirugía , Codón sin Sentido , Femenino , Estudios de Seguimiento , Humanos , Lactante , Trasplante de Hígado/estadística & datos numéricos , Masculino , Pronóstico , Estudios Prospectivos , Estudios Retrospectivos , Medición de Riesgo/métodos , Medición de Riesgo/estadística & datos numéricos , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
The accurate source tracing of volatile organic compounds (VOCs) in complicated source environments is challenging to perform, as similar pollutants may be emitted from different chemical processes. An emission profile-based source tracing method, based on comparing similarities between source profiles and ambient air profiles, was evaluated, and was found to improve the tracing efficiency. Emission profiles were acquired from a typical chemical industrial park in the Yangtze River Delta, China. A total of 30 process-based emission profiles comprising 107 VOC species were investigated and similarities among them were calculated. This analysis demonstrated that the similarities between emissions from various chemical processes are universal. Source tracing was then conducted for six air pollution episodes, based on the emission profile-based source tracing method combined with wind speed and direction data. The results showed that the proposed approach represents an efficient method for source tracing. This study enriches the database of source profiles for petroleum-related industries. The emission profiles from references and the air pollution episodes augment the emission profile database, especially under abnormal emission conditions. The database will more effectively serve future source-tracing cases, creating a virtuous circle that improves source tracing efficiency.
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Dichlorodiphenyltrichloroethane (DDT) is well known for its harmful effects and has been banned around the world. However, DDT is still frequently detected in natural environments, particularly in aquaculture and harbor sediments. In this study, 15 surface sediment samples were collected from a typical tropical bay (Zhanjiang Bay) in the South China Sea, and the levels of DDT and its metabolites in sediment and porewater samples were investigated. The results showed that concentrations of DDXs (i.e., DDT and its metabolites) in bulk sediments were 1.58-51.0 ng g-1 (mean, 11.5 ng g-1). DDTs (DDT and its primary metabolites, dichlorodiphenyldichloroethane (DDD) and dichlorodiphenyldichloroethylene (DDE)) were the most prominent, accounting for 73.2%-98.3% (86.1% ± 12.8%) of the DDXs. Additionally, high-order metabolites (i.e., 1-chloro-2,2-bis(4'-chlorophenyl)ethylene (p,p'-DDMU), 2,2-bis(p-chlorophenyl)ethylene (p,p'-DDNU), 2,2-bis(p-chlorophenyl)ethanol (p,p'-DDOH), 2,2-bis(p-chlorophenyl)methane (p,p'-DDM), and 4,4'-dichlorobenzophenone (p,p'-DBP)) were also detected in most of the sediment and porewater samples, with DDMU and DBP being predominant. The DDTs concentration differed among the sampling sites, with relatively high DDTs concentrations in the samples from the aquaculture zone and an area near the shipping channel and the Haibin shipyard. The DDD/DDE ratios indicated a reductive dichlorination of DDT to DDD under anaerobic conditions at most of the sampling sites of Zhanjiang Bay. The possible DDT degradation pathway in the surface sediments of Zhanjiang Bay was p,p'-DDT/p,p'-DDD(p,p'-DDE)/p,p'-DDMU/p,p'-DDNU/ /p,p'-DBP. The DDXs in the sediments of Zhanjiang Bay were mainly introduced via mixed sources of industrial DDT and dicofol, including fresh input and historical residue. The concentrations of DDXs in porewater samples varied from 66.3 to 250 ng L-1, exhibiting a distribution similar to that in the accompanying sediments. However, the content of high-order metabolites was relatively lower in porewater than in sediment, indicating that high-order degradation mainly occurs in particles. Overall, this study helps in understanding the distribution, source, and degradation of DDT in a typical tropical bay.