Risk factors for bloodstream infection (BSI) in patients with severe acute respiratory distress syndrome (ARDS) supported by veno-venous extracorporeal membrane oxygenation (VV-ECMO).

BACKGROUND: There were relatively few studies about the incidence and risk factors for bloodstream infection (BSI) in patients with severe acute respiratory distress syndrome (ARDS) supported by veno-venous extracorporeal membrane oxygenation (VV-ECMO). METHODS: Patients who were diagnosed with severe ARDS and received VV-ECMO treatment in the medical intensive care unit of China-Japan Friendship Hospital from August 2013 to March 2019 were retrospectively studied. The pathogens isolated from blood culture (BC) were identified and analyzed for drug sensitivity. The risk factors for BSI were analyzed by logistic regression. RESULTS: A total of 105 patients were included in this single-center retrospective cohort study. Among them, 23 patients (22%) had BSIs. 19 cases were identified as primary BSI; while the other 4 cases were as secondary BSI. A total of 23 pathogenic strains were isolated from BCs, including gram-negative (G-) bacilli in 21 (91%) cases, gram-positive (G+) cocci in 1 case, fungus in 1 case, and multidrug-resistant (MDR) organisms in 8 cases. Compared with patients without BSI, patients with BSI had a higher Murray score (odds ratio = 6.29, P = 0.01) and more blood transfusion (odds ratio = 1.27, P = 0.03) during ECMO. CONCLUSIONS: The incidence of BSI in patients with severe ARDS supported by VV-ECMO was 22%. G- bacilli was the main pathogen, and most of them were MDR-G- bacilli (MDR-GNB). Higher Murray score and more blood transfusion may be the independent risk factors for BSI.

Establishment and Verification of a Prediction Model for Symptomatic Radiation Pneumonitis in Patients with Esophageal Cancer Receiving Radiotherapy.

BACKGROUND This study aimed to determine the value of the significant index in predicting symptomatic radiation pneumonitis (RP) in esophageal cancer patients, establish a nomogram prediction model, and verify the model. MATERIAL AND METHODS The patients enrolled were divided into 2 groups: a model group and a validation group. According to the logistic regression analysis, the independent predictors for symptomatic RP were obtained, and the nomogram prediction model was established according to these independent predictors. The consistency index (C-index) and calibration curve were used to evaluate the accuracy of the model, and the prediction ability of the model was verified in the validation group. Recursive partitioning analysis (RPA) was used for the risk stratification analysis. RESULTS The ratio of change regarding the pre-albumin at the end of treatment (P=0.001), platelet-to-lymphocyte ratio during treatment (P=0.027), and neutrophil-to-lymphocyte ratio at the end of treatment (P=0.001) were the independent predictors for symptomatic RP. The C-index of the nomogram model was 0.811. According to the risk stratification of RPA, the whole group was divided into 3 groups: a low-risk group, a medium-risk group, and a high-risk group. The incidence of symptomatic RP was 0%, 16.9%, and 57.6%, respectively. The receiver operating characteristic curve also revealed that the nomogram model has good accuracy in the validation group. CONCLUSIONS The developed nomogram and corresponding risk classification system have superior prediction ability for symptomatic RP and can predict the occurrence of RP in the early stage.

Irinotecan-containing doublet treatment versus irinotecan monotherapy as second-line choice for advanced gastric cancer.

BACKGROUND: For patients with advanced gastric cancer (AGC), second-line chemotherapy regimen remains controversial. The efficacy and safety of irinotecan-containing doublet treatment and irinotecan monotherapy were compared in this systematic analysis. METHODS: A search was conducted on EMBASE and Medline databases. All articles compared irinotecan-containing doublet to irinotecan as second-line chemotherapy for AGC. STATA statistical software (Version 12.0) was used to analyze the data. RESULTS: Seven studies, including 905 cases, were included in the analysis. Irinotecan-containing doublet treatment significantly prolonged progression-free survival compared to irinotecan monotherapy (HR = 0.82, 95% CI: 0.70-0.95). However, doublet treatment neither significantly prolong overall survival compared to monotherapy (HR = 0.94, 95% CI: 0.81-1.10), nor did it significantly increase the overall response rates and disease control rates, when compared to monotherapy. In addition, the irinotecan-containing doublet group had an increase in incidences of ≥ Grade 3 neutropenia (RR = 1.23, 95% CI: 1.01-1.51) and anemia (RR = 2.00, 95% CI: 1.37-2.92). CONCLUSIONS: When compared to irinotecan monotherapy, irinotecan-containing doublet treatment increased progression free survival and was tolerable as a second- line chemotherapy for AGC.

Clinical Effect of Radiotherapy Combined with Chemotherapy for Non-Surgical Treatment of the Esophageal Squamous Cell Carcinoma.

BACKGROUND Chemoradiotherapy (CRT) is widely accepted and is considered a standard treatment, particularly for unresectable and inoperable esophageal squamous cell carcinoma (ESCC). However, the optimal use of the combined modalities of chemotherapy (CT) and radiotherapy (RT) remains controversial. In addition, no consensus has been reached regarding the exact efficacy of consolidation chemotherapy (CCT) and the most appropriate radiotherapy dose. MATERIAL AND METHODS Clinical data from 262 ESCC patients treated with CRT (n=165) or RT alone (n=97) were collected and reviewed. The long-term outcomes were analyzed, and treatment related acute toxicity reactions were compared. RESULTS The 1-year, 3-year, and 5-year overall survival (OS) rates were 75.3%, 35.6%, and 25.3%, respectively, for the CRT group and 61.5%, 26.7%, and 17.6% for the RT-alone group (P=0.015). The concurrent chemoradiotherapy (CCRT) and sequential chemoradiotherapy (SCRT) groups exhibited similar survival outcomes (for OS, P=0.568; for progression-free survival (PFS,) P=0.145). CCT after CCRT did not influence OS (P=0.236) but was associated with a more favorable PFS (P=0.020). In addition, high-dose of 60-65 Gy tended to prolong OS compared with low-dose (<60 Gy) or excessive-dose (>65 Gy). The incidence of adverse reactions, such as esophagitis and leukopenia, in the CRT group were significantly higher than in the RT-alone group (P=0.019, P=0.001, respectively), and no significant difference was observed between patients treated with CCRT and CCT after CCRT. CONCLUSIONS Treating non-surgical ESCC patients with CCRT conferred a significant survival benefit compared with RT alone. CCT after CCRT prolongs PFS but does not increase acute toxicity. High-dose (60-65 Gy) CCRT could generate more favorable survival outcomes.

The prognostic significance of human epidermal growth factor receptor family protein expression in operable pancreatic cancer : HER1-4 protein expression and prognosis in pancreatic cancer.

BACKGROUND: Prognostic factors aid in the stratification and treatment of cancer. This study evaluated the prognostic significance of human epidermal growth factor receptor (HER) family members (HER1-4) expression in patients with operable pancreatic cancer. METHODS: The expression of individual HER proteins in patient tissue specimens was detected by immunohistochemistry staining. Patient follow-up time was between 1.0 and 78.1 months. RESULTS: Positive expression of HER1, HER2, HER3 and HER4 was detected in 41.4, 60.0, 24.3 and 65.7% of cases, respectively. Kaplan-Meier analysis revealed that HER3 positive expression was associated with decreased median survival time (12.0 vs. 25.6 months for HER3 positive and negative groups, respectively; P = 0.013). Cox's regression confirmed that positive HER3 expression was an independent predictor of poor survival (RR = 3.684, P = 0.001). In contrast, HER4 negative patients had a significantly decreased median survival time when compared with HER4 positive patients (11.4 vs. 25.6 months, respectively; P = 0.027). However, HER4 was not an independent predictor of survival. No significant association between HER1 or HER2 expression and survival was observed (P = 0.626 & P = 0.859, respectively). CONCLUSIONS: HER3 is an independent prognostic marker for patients with operable pancreatic cancer. HER4 may also be of potential prognostic value in this disease and deserves further attention.

Research on the optimal energy consumption of oil pipeline.

Most of the Chinese crude oil is easy to curdle and has high viscosity, so heating transportation is usually selected. Energy consumption by this method mainly comes from furnaces and pumps. Currently, operating parameters of these pipelines were determined according to experience of dispatch. It cause high energy consumption and high cost of pipeline running, so it could not adapt to energy conservation policy. The present study focused on consuming lowest energy to operate oil transportation line. To begin with, several optimization variables were set which included pump combinations, suction pressure, discharge pressure, and station temperature. Then constraint conditions were set to establish an optimal mathematical model of running transportation line. Furthermore, genetic algorithm was used to solve the model, in meantime, selection operation, cross operation and mutation operation in the genetic algorithm were improved. Finally, a crude oil pipeline running optimization software was developed. Through optimal analyzing, S-L transportation line and contrasting with the actual working conditions, it was found that optimal operation scheme could reduce energy consumption by 5% - 9%. In addition, optimal operation scheme also considered the effect of seasons and flow on energy consumption of S-L transportation line.

Immune Profiling in Gastric Cancer Reveals the Dynamic Landscape of Immune Signature Underlying Tumor Progression.

The profiling of the tumor immune microenvironment (TIME) is critical for guiding immunotherapy strategies. However, how the composition of the immune landscape affects the tumor progression of gastric cancer (GC) is ill-defined. Here, we used mass cytometry to perform simultaneous in-depth immune profiling of the tumor, adjacent tissues, and blood cells from GC patients and revealed a unique GC tumor-immune signature, where CD8+ T cells were present at a lower frequency in tumor tissues compared to adjacent tissues, whereas regulatory T cells and tumor-associated macrophages (TAMs) were significantly increased, indicating strong suppressive TIME in GC. Incorporated with oncogenic genomic traits, we found that the unique immunophenotype was interactively shaped by a specific GC gene signature across tumor progression. Earlier-stage GC lesions with IFN signaling enrichment harbored significantly altered T-cell compartments while advanced GC featured by metabolism signaling activation was accumulated by TAMs. Interestingly, PD-1 expression on CD8+ T cells was relatively higher in earlier-stage GC patients, indicating that these patients may derive more benefits from PD-1 inhibitors. The dynamic properties of diverse immune cell types revealed by our study provide new dimensions to the immune landscape of GC and facilitate the development of novel immunotherapy strategies for GC patients.

BmK86-P1, a New Degradation Peptide with Desirable Thermostability and Kv1.2 Channel-Specific Activity from Traditional Chinese Scorpion Medicinal Material.

Thermally processed Buthus martensii Karsch scorpions are a traditional Chinese medical material for treating various diseases. However, their pharmacological foundation remains unclear. Here, a new degraded peptide of scorpion toxin was identified in Chinese scorpion medicinal material by proteomics. It was named BmK86-P1 and has six conserved cysteine residues. Homology modeling and circular dichroism spectra experiments revealed that BmK86-P1 not only contained representative disulfide bond-stabilized α-helical and ß-sheet motifs but also showed remarkable stability at test temperatures from 20-95 °C. Electrophysiology experiments indicated that BmK86-P1 was a highly potent and selective inhibitor of the hKv1.2 channel with IC50 values of 28.5 ± 6.3 nM. Structural and functional dissection revealed that two residues of BmK86-P1 (i.e., Lys19 and Ile21) were the key residues that interacted with the hKv1.2 channel. In addition, channel chimeras and mutagenesis experiments revealed that three amino acids (i.e., Gln357, Val381 and Thr383) of the hKv1.2 channel were responsible for BmK86-P1 selectivity. This research uncovered a new bioactive peptide from traditional Chinese scorpion medicinal material that has desirable thermostability and Kv1.2 channel-specific activity, which strongly suggests that thermally processed scorpions are novel peptide resources for new drug discovery for the Kv1.2 channel-related ataxia and epilepsy diseases.

Different pharmacological properties between scorpion toxin BmKcug2 and its degraded analogs highlight the diversity of K+ channel blockers from thermally processed scorpions.

Novel degraded potassium channel-modulatory peptides were recently found in thermally processed scorpions, but their pharmacological properties remain unclear. Here, we identified a full-length scorpion toxin (i.e., BmKcug2) and its four truncated analogs (i.e., BmKcug2-P1, BmKcug2-P2, BmKcug2-P3 and BmKcug2-P4) with three conserved disulfide bonds in processed scorpion medicinal material by mass spectrometry. The pharmacological experiments revealed that the recombinant BmKcug2 and BmKcug2-P1 could selectively inhibit the human Kv1.2 and human Kv1.3 potassium channels, while the other three analogs showed a much weaker inhibitory effect on potassium channels. BmKcug2 inhibited hKv1.2 and hKv1.3 channels, with IC50 values of 45.6 ± 5.8 nM and 215.2 ± 39.7 nM, respectively, and BmKcug2-P1 inhibited hKv1.2 and hKv1.3, with IC50 values of 89.9 ± 9.6 nM and 1142.4 ± 64.5 nM, respectively. The chromatographic analysis and pharmacological properties of BmKcug2 and BmKcug2-P1 boiled in water for different times further strongly supported their good thermal stability. Structural and functional dissection indicated that one amino acid, i.e., Tyr36, determined the differential affinities of BmKcug2 and four BmKcug2 analogs. Altogether, this research investigated the different pharmacological properties of BmKcug2 and its truncated analogs, and the findings highlighted the diversity of K+ channel blockers from various scorpion species through thermal processing.

POST1/C12ORF49 regulates the SREBP pathway by promoting site-1 protease maturation.

Sterol-regulatory element binding proteins (SREBPs) are the key transcriptional regulators of lipid metabolism. The activation of SREBP requires translocation of the SREBP precursor from the endoplasmic reticulum to the Golgi, where it is sequentially cleaved by site-1 protease (S1P) and site-2 protease and releases a nuclear form to modulate gene expression. To search for new genes regulating cholesterol metabolism, we perform a genome-wide CRISPR/Cas9 knockout screen and find that partner of site-1 protease (POST1), encoded by C12ORF49, is critically involved in the SREBP signaling. Ablation of POST1 decreases the generation of nuclear SREBP and reduces the expression of SREBP target genes. POST1 binds S1P, which is synthesized as an inactive protease (form A) and becomes fully mature via a two-step autocatalytic process involving forms B'/B and C'/C. POST1 promotes the generation of the functional S1P-C'/C from S1P-B'/B (canonical cleavage) and, notably, from S1P-A directly (non-canonical cleavage) as well. This POST1-mediated S1P activation is also essential for the cleavages of other S1P substrates including ATF6, CREB3 family members and the α/ß-subunit precursor of N-acetylglucosamine-1-phosphotransferase. Together, we demonstrate that POST1 is a cofactor controlling S1P maturation and plays important roles in lipid homeostasis, unfolded protein response, lipoprotein metabolism and lysosome biogenesis.

Proteomics Profiling of Host Cell Response via Protein Expression and Phosphorylation upon Dengue Virus Infection.

Dengue virus (DENV) infection is a worldwide public health threat. To date, the knowledge about the pathogenesis and progression of DENV infection is still limited. Combining global profiling based on proteomic analysis together with functional verification analysis is a powerful strategy to investigate the interplay between the virus and host cells. In the present study, quantitative proteomics has been applied to evaluate host responses (as indicated by altered proteins and modifications) in human cells (using K562 cell line) upon DENV-2 infection, as DENV-2 spreads most widely among all DENV serotypes. Comparative analysis was performed to define differentially expressed proteins in the infected cells compared to the mock-control, and it revealed critical pathogen-induced changes covering a broad spectrum of host cellular compartments and processes. We also discovered more dramatic changes (> 20%, 160 regulated phosphoproteins) in protein phosphorylation compared to protein expression (14%, 321 regulated proteins). Most of these proteins/phosphoproteins were involved in transcription regulation, RNA splicing and processing, immune system, cellular response to stimulus, and macromolecule biosynthesis. Western blot analysis was also performed to confirm the proteomic data. Potential roles of these altered proteins were discussed. The present study provides valuable large-scale protein-related information for elucidating the functional emphasis of host cell proteins and their post-translational modifications in virus infection, and also provides insight and protein evidence for understanding the general pathogenesis and pathology of DENV.

Thermostable potassium channel-inhibiting neurotoxins in processed scorpion medicinal material revealed by proteomic analysis: Implications of its pharmaceutical basis in traditional Chinese medicine.

The neurotoxins of venomous scorpion act on ion channels. Whether these neurotoxins are retained in processed Buthus martensii Karsch scorpions used in traditional Chinese medicine materials is unknown. Comprehensive mass spectrometry-based proteomic characterization of functionally active toxins in the processed medicinal scorpion material revealed 22 full-length and 44 truncated thermostable potassium channel-modulatory toxins that preserved six conserved cysteine residues capable of forming the three disulfide bonds necessary for toxicity. Additionally, a broad spectrum of degraded toxin fragments was found, indicating their relative thermal instability which enabled toxicity reduction. Furthermore, the suppression of interleukin-2 (IL-2) production in Jurkat cells and the reduced delayed-type hypersensitivity (DTH) response demonstrated that the extracts have immunoregulatory activity both in vitro and in vivo. Our work describes the first "map" of functionally active scorpion toxins in processed scorpion medicinal material, which is helpful to unveil the pharmaceutical basis of the processed scorpion medicinal material in traditional Chinese medicine. BIOLOGICAL SIGNIFICANCE: Scorpions have been used as medicinal materials in China for more than one thousand years. This is an example of the well-known "Combat poison with poison" strategy common to traditional Chinese medicine. In the past 30 years, extensive investigations of Chinese scorpions have indicated that the neurotoxins in the scorpion venom are the main toxic components and they target various ion channels in cell membranes. However, whether these neurotoxins are retained in processed Buthus martensii Karsch scorpions used for traditional Chinese medicine remains unknown. Our study described the thermal stability and instability of potassium channel-modulatory neurotoxins in processed scorpions and helps to understand the pharmaceutical basis underling the strategy of "combat poison with poison to cure diseases".

Correlation analysis between molecular subtypes and Nottingham Prognostic Index in breast cancer.

Molecular subtypes and Nottingham Prognostic Index (NPI) are both prognostic models for breast cancer patients. We evaluated the association between molecular subtypes and NPI in 1042 breast cancer patients. The molecular subtypes indicating poorer prognosis were positively correlated to higher NPI (r = 0.138, P = 0.001). ER positive expression and PR high expression were positively correlated with NPI (r = 0.142, P = 0.001; r = 0.139, P = 0.001; respectively) and negatively correlated with histological grade (r = -0.233, P < 0.001; r = -0.176, P < 0.001; respectively). Ki67 status was negatively correlated with NPI and positively correlated with histological grade (r = -0.120, P =0.004; r = 0.197, P < 0.001; respectively). The percentages of cases with NPI score 2.00-3.40 were higher in the luminar A, ER+, PR high expression and Ki67 low expression group, and the percentages of cases with NPI > 5.40 were higher in the HER2 overexpression subtype, basal-like subtype, ER-, PR low/negative expression, and Ki67 high expression groups. The excellent consistence was observed between histological grade and molecular subtypes, ER, PR, Ki67. The difference of histological grade between the HER2 positive and negative group was statistically significant. In conclusion, there was closely association between molecular subtypes and NPI in breast cancer. For further comparing the prognostic significance of molecular subtypes and NPI, survival analyses should be performed on the same population in a large-scale prospective study.

NRG1-dependent activation of HER3 induces primary resistance to trastuzumab in HER2-overexpressing breast cancer cells.

This study was conducted to determine the role of neuregulin 1 (NRG1)-dependent human epidermal growth factor receptor 3 (HER3) activation in trastuzumab primary resistance, and to observe the inhibitory effect of HER3 monoclonal antibody on HER2-overexpressing breast cancer cells. BT474 cells (trastuzumab sensitive) and MDA-MB-453 cells (trastuzumab resistant) were first stimulated with NRG1 and then treated with either trastuzumab, HER3 antibody, or a combination of both. The expression of phospho human epidermal growth factor receptor 2 (p-HER2), phospho human epidermal growth factor receptor 3 (p-HER3), phospho protein kinase B (p-Akt) and phospho mitogen-activated protein kinase (p-MAPK) were detected by western blotting. Apoptosis was detected by flow cytometry. Cell viability was detected by MTT assay. Without NRG1 stimulation, trastuzumab treatment significantly down-regulated the expression of p-HER2, increased early apoptosis, and decreased cell viability in BT474 cells. After NRG1 stimulation, the aforementioned effects weakened or disappeared in the trastuzumab treatment group, whereas in the HER3 antibody treatment group, there was significant downregulation in p-HER3 expression and increase in early apoptosis of BT474 cells. In MDA-MB-453 cells, the HER3 antibody significantly downregulated both p-HER2 and p-HER3 and promoted early apoptosis after NRG1 stimulation, however, trastuzumab hardly played a role. p-Akt and p-MAPK were also significantly downregulated by the HER3 antibody after NRG1 stimulation. The expressions of p-HER2, p-HER3, p-Akt and p-MAPK were all downregulated after HER3 gene silencing, compared to the control. NRG1-dependent activation of HER3 induces primary resistance to trastuzumab in HER2-overexpressing breast cancer cells. HER3 monoclonal antibody combined with trastuzumab may serve as a treatment choice for patients with primary resistance to trastuzumab.