The Association of Intraindividual Difference Between Cystatin- and Creatinine-Based Estimated GFR and Contrast-Associated Acute Kidney Injury.

Purpose: The estimated glomerular filtration rate (eGFR) based on creatinine is crucial for the risk assessment of contrast-associated acute kidney injury (CA-AKI). In recent, the difference between cystatin C-based eGFR (eGFRcys) and creatinine-based eGFR (eGFRcr) has been widely documented. We aimed to explore whether intraindividual differences between eGFRcys and eGFRcr had potential value for CA-AKI risk assessment in patients undergoing elective percutaneous coronary intervention (PCI). Patients and Methods: From January 2012 to December 2018, we retrospectively observed 5049 patients receiving elective PCI. To determine eGFR, serum creatinine and cystatin C levels were measured. CA-AKI was defined as serum creatinine being increased ≥ 50% or 0.3 mg/dL within 48 h after contrast agents exposure. Chronic kidney disease (CKD) was defined as the eGFR < 60 mL/min/1.73 m2. Results: Approximately half of the participants (2479, 49.1%) had a baseline eGFRdiff (eGFRcys-eGFRcr) between -15 and 15 mL/min/1.73 m2. Restricted cubic splines analysis revealed a nonlinear relationship between eGFRdiff and CA-AKI. Multivariable logistic regression analysis indicated that compared with the reference group (-15 to 15 mL/min/1.73 m2), the negative-eGFRdiff group (less than -15 mL/min/1.73 m2) had a higher risk of CA-AKI (OR, 3.44; 95% CI, 2.57-4.64). Furthermore, patients were divided into four groups based on CKD identified by eGFRcys or eGFRcr. Multivariable logistic analysis revealed that patients with either CKDcys (OR, 2.94; 95% CI, 2.19-3.95, P < 0.001) or CKDcr (OR, 2.44; 95% CI, 1.19-4.63, P < 0.001) had an elevated risk of CA-AKI compared to those without CKDcys and CKDcr. Conclusion: There are frequent intraindividual differences between eGFRcys and eGFRcr, and these differences can be used to forecast the risk of CA-AKI.

Diverse neolignans and lignans from an aqueous extract of the Angelica sinensis root head.

Neolignans and lignans with diverse new chemical structures, including eleven pairs of separated chiral enantiomers [(+)-/(-)-1-(+)-/(-)-5, (+)-/(-)-8, (+)-/(-)-10, and (+)-/(-)-12-(+)-/(-)-15], two achiral compounds (6 and 9), and an unseparated racemate [(±)-11], together with a new natural product (7) and 21 known derivatives, were isolated from an aqueous extract of the Angelica sinensis root head (guitou). Among the chiral isolates, (+)-/(-)-13 and (+)-/(-)-15 were scalemic pairs with enantiomeric ratios of around 3:1 and 1.5:1, respectively, while others were enantiomeric equivalent pairs. This indicates that the diverse neolignans in A. sinensis are biosynthesized via different pathways with varying degrees of stereo-controlled manners.

Non-Invasive Liver Fibrosis Scores Are Associated With Contrast-Associated Acute Kidney Injury in Patients Undergoing Elective Percutaneous Coronary Intervention.

Previous studies have demonstrated that non-invasive liver fibrosis scores (LFSs) are associated with kidney function deterioration. This study aimed to assess the predictive performance of LFSs in contrast-associated acute kidney injury (CA-AKI) in coronary artery disease (CAD) patients undergoing elective percutaneous coronary intervention (PCI). This retrospective study involved 5627 patients. The frequency of CA-AKI was 6.3% (n = 353). In a multivariate logistic analysis after adjustment, non-invasive LFSs, including fibrosis-5 score (FIB-5), fibrosis-4 score (FIB-4), aspartate aminotransferase to alanine aminotransferase ratio (AAR), and aspartate aminotransferase to platelet ratio index were independent risk factors for CA-AKI (all P < .05), whereas the Forns score was not (P > .05). The highest predictive performance was observed for FIB-5 (area under the curve [AUC] = .644) compared to other LFSs. A restricted cubic spline analysis confirmed approximately linear relationships between LFSs and risks of CA-AKI. Furthermore, adding FIB-5 (AUC = .747; net reclassification improvement [NRI] = .441, P < .001; integrated discrimination improvement [IDI] = .008, P < .001) or AAR (AUC = .747; NRI = .419, P < .001; IDI = .006, P = .010) to an established clinical risk model could significantly improve the prediction of CA-AKI. The LFSs were significantly associated with CA-AKI, possibly serving as predictive tools for early identification of CAD patients undergoing elective PCI that are at high risk of CA-AKI.

Prognostic Value of Different Versions of the Model for End-Stage Liver Disease Score in Patients Undergoing Percutaneous Coronary Intervention.

The model for end-stage liver disease (MELD) score, which can reflect liver and renal function, is associated with poor prognosis. However, the prognostic performance of the modified MELD score in patients undergoing elective percutaneous coronary intervention (PCI) has not been fully evaluated and compared. This study retrospectively enrolled 5324 patients. During a median follow-up of 2.85 years, 412 patients died. Time-dependent receiver operating characteristic curves at 3 years indicated that the MELD including albumin (MELD-Albumin) score had the highest prognostic performance (AUC = .721) than the MELD score (AUC = .630), the MELD excluding the international normalized ratio (MELD-XI) score (AUC = .606), and the MELD including sodium (MELD-Na) score (AUC = .656) (all P < .001). The MELD-Albumin score, the MELD score, and the MELD-Na score were independent predictors of long-term mortality; however, the MELD-XI score was not when treated as a categorical variable (P = .254). Adding the MELD-Albumin score to the model of clinical risk factors could improve the prognostic performance. For the subgroup analysis, the association between the MELD-Albumin score and long-term mortality was more pronounced in patients ≤75 years (interaction P value = .005). The MELD-Albumin score showed the strongest prognostic performance than the other versions of the MELD score in patients undergoing elective PCI.

Shrunken Pore Syndrome: A New and More Powerful Phenotype of Renal Dysfunction Than Chronic Kidney Disease for Predicting Contrast-Associated Acute Kidney Injury.

Background Shrunken pore syndrome (SPS) as a novel phenotype of renal dysfunction is characterized by a difference in renal filtration between cystatin C and creatinine. The manifestation of SPS was defined as a cystatin C-based estimated glomerular filtration rate (eGFR) <60% of the creatinine-based eGFR. SPS has been shown to be associated with the progression and adverse prognosis of various cardiovascular and renal diseases. However, the predictive value of SPS for contrast-associated acute kidney injury (CA-AKI) and long-term outcomes in patients undergoing percutaneous coronary intervention remains unclear. Methods and Results We retrospectively observed 5050 consenting patients from January 2012 to December 2018. Serum cystatin C and creatinine were measured and applied to corresponding 2012 and 2021 Chronic Kidney Disease Epidemiology Collaboration equations, respectively, to calculate the eGFR. Chronic kidney disease (CKD) was defined as a creatinine-based eGFR <60 mL/min per 1.73 m2 without dialysis. CA-AKI was defined as an increase in serum creatinine ≥50% or 0.3 mg/dL within 48 hours after contrast medium exposure. Overall, 649 (12.85%) patients had SPS, and 324 (6.42%) patients developed CA-AKI. Multivariate logistic regression analysis indicated that SPS was significantly associated with CA-AKI after adjusting for potential confounding factors (odds ratio [OR], 4.17 [95% CI, 3.17-5.46]; P<0.001). Receiver operating characteristic analysis indicated that the cystatin C-based eGFR:creatinine-based eGFR ratio had a better performance and stronger predictive power for CA-AKI than creatinine-based eGFR (area under the curve: 0.707 versus 0.562; P<0.001). Multivariate logistic analysis revealed that compared with those without CKD and SPS simultaneously, patients with CKD and non-SPS (OR, 1.70 [95% CI, 1.11-2.55]; P=0.012), non-CKD and SPS (OR, 4.02 [95% CI, 2.98-5.39]; P<0.001), and CKD and SPS (OR, 8.62 [95% CI, 4.67-15.7]; P<0.001) had an increased risk of CA-AKI. Patients with both SPS and CKD presented the highest risk of long-term mortality compared with those without both (hazard ratio, 2.30 [95% CI, 1.38-3.86]; P=0.002). Conclusions SPS is a new and more powerful phenotype of renal dysfunction for predicting CA-AKI than CKD and will bring new insights for an accurate clinical assessment of the risk of CA-AKI.

Dimeric phthalides from an aqueous extract of the Angelica sinensis root head / 药学学报

Ten dimeric phthalide racemates (1-10) were isolated from an aqueous extract of the Angelica sinensis root head (Guitou) by separation techniques of column chromatography over macroporous adsorbent resin, MCI resin, silica gel, and Sephadex LH-20, together with preparative thin-layer chromatography and reversed phase HPLC. The racemates were further separated into (+)-/(-)-1-(+)-/(-)-10 with chiral HPLC. Their structures including absolute configurations were elucidated by comprehensive analysis of spectroscopic data, combined with electronic circular dichroism (ECD) and NMR calculations as well as single crystal X-ray diffractions. Compounds (+)-/(-)-1-(+)-/(-)-10 are either new structure or new natural product, named (+)-/(-)-angelidipthalidic acids A-H [(+)-/(-)-1-(+)-/(-)-8] and (+)-/(-)-angelidipthalidols A and B [(+)-/(-)-9 and (+)-/(-)-10], respectively. Meanwhile, dimeric phthalide mono- and bis-lactone derivatives with 3.3′a,8.6′- and 3.6′,8.3′a-coupling patterns as well as determination of their relative configurations are discussed.

Monoterpenes from an aqueous extract of the Angelica sinensis root head / 药学学报

Eleven monoterpenes including seven new chemical structures or new natural products covering two pairs of scalemic enantiomers, together with four known analogues, were isolated from an aqueous extract of the Angelica sinensis root head (Guitou) by separation techniques of column chromatography over macroporous adsorbent resin, MCI resin, silica gel, Sephadex LH-20, and Toyopearl HW-40C, together with preparative thin-layer chromatography as well as reversed phase and chiral HPLC. Their structures were determined by spectroscopic data analysis, combined with theoretic calculation of electronic circular dichroism (ECD) spectra and single crystal X-ray diffraction. The new structures or new natural products named (+)-/(-)-angelinones A and B [(+)-/(-)-1 and (+)-/(-)-2], angelinones C and D (3 and 4), and angelinol A (5), respectively, while the known analogues were 6β,9-dihydroxy-(+)-α-pinene (6), 1,1,5-trimethyl-2-hydroxymethyl-cyclohexa-2,5-dien-4-one (7), jasminol E (8), and (+)-trans-sobrerol (9). All the isolates were reported in this plant for the first time, except for the previously reported 6 from an ethanol extract of the aerial parts of A. sinensis, of which the structure was confirmed by X-ray crystallography in this study.

The Functions of PCNA in Tumor Stemness and Invasion.

Invasion is the most prominent lethal feature of malignant cancer. However, how cell proliferation, another important feature of tumor development, is integrated with tumor invasion and the subsequent cell dissemination from primary tumors is not well understood. Proliferating cell nuclear antigen (PCNA) is essential for DNA replication in cancer cells. Loss of phosphorylation at tyrosine 211 (Y211) in PCNA (pY211-PCNA) mitigates PCNA function in proliferation, triggers replication fork arrest/collapse, which in turn sets off an anti-tumor inflammatory response, and suppresses distant metastasis. Here, we show that pY211-PCNA is important in stromal activation in tumor tissues. Loss of the phosphorylation resulted in reduced expression of mesenchymal proteins as well as tumor progenitor markers, and of the ability of invasion. Spontaneous mammary tumors that developed in mice lacking Y211 phosphorylation contained fewer tumor-initiating cells compared to tumors in wild-type mice. Our study demonstrates a novel function of PCNA as an essential factor for maintaining cancer stemness through Y211 phosphorylation.

miR-4759 suppresses breast cancer through immune checkpoint blockade.

Programmed cell death protein 1 (PD-1)/ programmed cell death protein ligand 1 (PD-L1) is the key immune checkpoint governing evasion of advanced cancer from immune surveillance. Immuno-oncology (IO) therapy targeting PD-1/PD-L1 with traditional antibodies is a promising approach to multiple cancer types but to which the response rate remains moderate in breast cancer, calling for the need of exploring alternative IO targeting approaches. A miRNA-gene network was integrated by a bioinformatics approach and corroborated with The Cancer Genome Atlas (TCGA) to screen miRNAs regulating immune checkpoint genes and associated with patient survival. Here we show the identification of a novel microRNA miR-4759 which repressed RNA expression of the PD-L1 gene. miR-4759 targeted the PD-L1 gene through two binding motifs in the 3' untranslated region (3'-UTR) of PD-L1. Reconstitution of miR-4759 inhibited PD-L1 expression and sensitized breast cancer cells to killing by immune cells. Treatment with miR-4759 suppressed tumor growth of orthotopic xenografts and promoted tumor infiltration of CD8+ T lymphocytes in immunocompetent mice. In contrast, miR-4759 had no effect to tumor growth in immunodeficient mice. In patients with breast cancer, expression of miR-4759 was preferentially downregulated in tumors compared to normal tissues and was associated with poor overall survival. Together, our results demonstrated miR-4759 as a novel non-coding RNA which promotes anti-tumor immunity of breast cancer.

Association between neutrophil percentage-to-albumin ratio and contrast-associated acute kidney injury in patients without chronic kidney disease undergoing percutaneous coronary intervention.

BACKGROUND: Neutrophil and albumin are well-known biomarkers of inflammation, which are highly related to contrast-associated acute kidney injury (CA-AKI). We aim to explore the predictive value of neutrophil percentage-to-albumin ratio (NPAR) for CA-AKI and long-term mortality in patients without chronic kidney disease (CKD) undergoing elective percutaneous coronary intervention (PCI). METHODS: We retrospectively observed 5083 consenting patients from January 2012 to December 2018. CA-AKI was defined as an increase in serum creatinine ≥50% or 0.3 mg/dL within 48 h after contrast medium exposure. RESULTS: The incidence of CA-AKI was 5.6% (n=286). The optimal cut-off value of NPAR for predicting CA-AKI was 15.7 with 66.8% sensitivity and 61.9% specificity [C statistic=0.679; 95% confidence interval (CI), 0.666-0.691]. NPAR displayed higher area under the curve values in comparison to neutrophil percentage (p < 0.001) and neutrophil-to-albumin ratio (NAR) (p < 0.001), but not albumin (p = 0.063). However, NPAR significantly improved the prediction of CA-AKI assessed by the continuous net reclassification improvement (NRI) and integrated discrimination improvement (IDI) compared to neutrophil percentage (NRI=0.353, 95% CI: 0.234-0.472, p < 0.001; IDI=0.017, 95% CI: 0.010-0.024, p < 0.001) and albumin (NRI=0.141, 95% CI: 0.022-0.260, p = 0.020; IDI=0.009, 95% CI: 0.003-0.015, p = 0.003) alone. After adjusting for potential confounding factors, multivariate analysis showed that NPAR >15.7 was a strong independent predictor of CA-AKI (odds ratio =1.90, 95% CI: 1.38-2.63, p < 0.001). Additionally, NPAR >15.7 was significantly associated with long-term mortality during a median of 2.9 years of follow-up (hazard ratio =1.68, 95% CI: 1.32-2.13; p < 0.001). CONCLUSIONS: NPAR was an independent predictor of CA-AKI and long-term mortality in patients without CKD undergoing elective PCI.

Association Between Different Versions of the Model for End-Stage Liver Disease Score and Contrast-Associated Acute Kidney Injury in Patients Undergoing Elective Percutaneous Coronary Intervention.

BACKGROUND: Pre-procedure liver dysfunction was associated with acute kidney injury after percutaneous coronary intervention (PCI). The aim of this study is to assess and compare the predictive value of different liver function scoring systems for contrast-associated acute kidney injury (CA-AKI) in patients undergoing elective PCI.Methods and Results:A total of 5,569 patients were retrospectively enrolled. The model for end-stage liver disease (MELD) including albumin (MELD-Albumin) score (AUC=0.661) had the strongest predictive value in comparison to the MELD score (AUC=0.627), the MELD excluding the international normalized ratio (MELD-XI) score (AUC=0.560), and the MELD including sodium (MELD-Na) score (AUC=0.652). In the fully adjusted logistic regression model, the MELD-Albumin score and the MELD-Na score were independently associated with CA-AKI regardless of whether they were treated as continuous or categorical variables; however, this was not the case for the MELD score and the MELD-XI score. Furthermore, the addition of the MELD-Albumin score significantly improved the reclassification beyond the fully adjusted logistic regression model. The study further explored the association between different versions of the MELD score and CA-AKI using restricted cubic splines and found a linear relationship between the MELD-Albumin score and the risk of CA-AKI. CONCLUSIONS: The MELD-Albumin score had the highest predictive value for CA-AKI in patients undergoing elective PCI. The addition of the MELD-Albumin score to the existing risk prediction model significantly improved the reclassification for CA-AKI.

Predictive value of aspartate aminotransferase-to-alanine aminotransferase ratio for contrast-associated acute kidney injury in patients undergoing elective percutaneous coronary intervention.

BACKGROUND: Pre-procedure liver insufficiency has been demonstrated as a poor prognostic factor after percutaneous coronary intervention (PCI). Recent research discovered that the aspartate aminotransferase-to-alanine aminotransferase ratio (De-Ritis ratio) reflects the severity of liver insufficiency and was associated with adverse outcomes. We aim to evaluate the predictive value of the De-Ritis ratio for contrast-associated acute kidney injury (CA-AKI) and long-term mortality in patients undergoing elective PCI. METHODS: We retrospectively enrolled 5780 consenting patients undergoing elective PCI between January 2012 and December 2018. CA-AKI was defined as an increase in serum creatinine ≥0.3 mg/dl or ≥50% within 48 h after the administration of contrast media. RESULTS: The incidence of CA-AKI was 6.3% (n = 363). The De-Ritis ratio >1.30 was identified as the best cut-off value for CA-AKI prediction. The De-Ritis ratio showed an area under the curve (AUC) of 0.636 [95% confidence interval (CI): 0.605-0.667] in predicting CA-AKI, which was significantly greater than alanine aminotransferase (p<0.001) and aspartate aminotransferase (p = 0.012) alone. Furthermore, compared to currently recognized liver function assessment tools, the predictive value of the De-Ritis ratio on CA-AKI was similar to the MELD score (AUC: 0.636 vs 0.626, p = 0.631) and higher than the MELD-XI score (AUC: 0.636 vs 0.561, p<0.001). Multivariate logistic analysis showed that the De-Ritis ratio >1.30 was independently associated with CA-AKI (odds ratio=1.551, 95% CI: 1.185-2.030, p = 0.001). The addition of the De-Ritis ratio to the fully adjusted logistic regression model has significant incremental effects on the risk prediction for CA-AKI with a continuous net reclassification improvement of 0.395 (p<0.001) and an integrated discrimination improvement of 0.005 (p = 0.018). Additionally, the De-Ritis ratio >1.30 was significantly associated with long-term mortality (hazard ratio=1.285, 95% CI: 1.007-1.641, p = 0.044). CONCLUSIONS: The De-Ritis ratio was an independent risk factor for CA-AKI and long-term mortality in patients undergoing elective PCI.

Suppression of breast cancer cells resistant to a pure anti-estrogen with CAR-transduced natural killer cells.

Anti-estrogens as hormone therapy are the mainstay treatment for estrogen receptor (ER)-positive breast cancer. ER inhibitors through modulating the transcriptional function of ER have been the frontline anti-estrogens to which refractory phenotype often developed in advanced cancer. The anti-estrogen fulvestrant is currently the only clinically approved pure anti-estrogen which causes ER degradation. However, resistance to fulvestrant still occurs and unfortunately it leaves few choices other than chemotherapy as the later-line treatments to fulvestrant-resistant tumors. Here we show that fulvestrant resistance was accompanied by increased expression of a number of innate immune response genes including the natural killer (NK) cell ligand B7-H6 on the cell surface. In an attempt to overcome the drug resistance phenotype, a NK-based molecular approach taking advantage of a chimeric antigen receptor (CAR) system targeting B7-H6 was established and tested in cells with acquired resistance to fulvestrant. The results demonstrate that the cell therapy approach as a single agent can effectively induce cell death of the resistant cancer cells which is enhanced by the increased expression of cell surface B7-H6. This approach departs from the traditional strategies of conquering anti-estrogen resistant breast cancer and offers a new avenue to eradicate hormone-refractory malignant solid tumors.

Evading immune surveillance via tyrosine phosphorylation of nuclear PCNA.

Increased DNA replication and metastasis are hallmarks of cancer progression, while deregulated proliferation often triggers sustained replication stresses in cancer cells. How cancer cells overcome the growth stress and proceed to metastasis remains largely elusive. Proliferating cell nuclear antigen (PCNA) is an indispensable component of the DNA replication machinery. Here, we show that phosphorylation of PCNA on tyrosine 211 (pY211-PCNA) regulates DNA metabolism and tumor microenvironment. Abrogation of pY211-PCNA blocks fork processivity, resulting in biogenesis of single-stranded DNA (ssDNA) through a MRE11-dependent mechanism. The cytosolic ssDNA subsequently induces inflammatory cytokines through a cyclic GMP-AMP synthetase (cGAS)-dependent cascade, triggering an anti-tumor immunity by natural killer (NK) cells to suppress distant metastasis. Expression of pY211-PCNA is inversely correlated with cytosolic ssDNA and associated with poor survival in patients with cancer. Our results pave the way to biomarkers and therapies exploiting immune responsiveness to target metastatic cancer.

Infliximab treatment of glycogenosis Ib with Crohn's-like enterocolitis: A case report.

BACKGROUND: Glycogen storage disease type Ib (GSD-Ib) is a glycogen metabolism disorder that leads to the manifestations of inflammatory bowel disease (IBD), especially Crohn's disease (CD)-like colitis. Although biological agents are effective for treating CD, their application in the treatment of GSD-Ib with CD-like colitis has been rarely reported. CASE SUMMARY: A 13-year-old Han male was diagnosed with GSD-Ib with CD. The patient was treated with granulocyte colony-stimulating factor. When he had symptoms of CD-like colitis, he was continuously pumped with enteral nutrition and administered oral mesalazine for 2 wk; however, the symptoms did not improve significantly. Hence, infliximab (IFX) was administered. Hitherto, the patient has been followed up for 1 year, and no clinical manifestations have been observed. After 6 mo of treatment (fifth IFX treatment), the disease activity index and all inflammatory indexes decreased, and a review of the colonoscopy data showed that the ulcers appeared smooth. CONCLUSION: In this study, the patient was successfully treated with IFX. In cases of GSD-Ib, IBD should be highly considered.

Imatinib (STI571) Inhibits the Expression of Angiotensin-Converting Enzyme 2 and Cell Entry of the SARS-CoV-2-Derived Pseudotyped Viral Particles.

A group of clinically approved cancer therapeutic tyrosine kinase inhibitors was screened to test their effects on the expression of angiotensin-converting enzyme 2 (ACE2), the cell surface receptor for SARS-CoV-2. Here, we show that the receptor tyrosine kinase inhibitor imatinib (also known as STI571, Gleevec) can inhibit the expression of the endogenous ACE2 gene at both the transcript and protein levels. Treatment with imatinib resulted in inhibition of cell entry of the viral pseudoparticles (Vpps) in cell culture. In FVB mice orally fed imatinib, tissue expression of ACE2 was reduced, specifically in the lungs and renal tubules, but not in the parenchyma of other organs such as the heart and intestine. Our finding suggests that receptor tyrosine kinases play a role in COVID-19 infection and can be therapeutic targets with combined treatments of the best conventional care of COVID-19.

[Clinical characteristics and gene variants of patients with infantile intrahepatic cholestasis].

OBJECTIVE: To explore the clinical characteristics and genetic findings of patients with infantile intrahepatic cholestasis. METHODS: The clinical data were collected in children who were admitted to the Department of Gastroenterology in Children's Hospital, Capital Institute of Pediatrics from June 2017 to June 2019 and were suspected of inherited metabolic diseases. Next generation sequencing based on target gene panel was used for gene analysis in these children. Sanger sequencing technology was used to verify the genes of the members in this family. RESULTS: Forty patients were enrolled. Pathogenic gene variants were identified in 13 patients (32%), including SLC25A13 gene variation in 3 patients who were diagnosed with citrin deficiency, JAG1 gene variation in 3 patients who were diagnosed with Alagille syndrome, ABCB11 gene variation in 3 patients who were diagnosed with progressive familial intrahepatic cholestasis type 2, HSD3B7 gene variation in 1 patient who was diagnosed with congenital bile acid synthesis defect type 1, AKR1D1 gene variation in 1 patient who was diagnosed with congenital bile acid synthesis defect type 1, NPC1 gene variation in 1 patient who was diagnosed with Niemann-Pick disease, and CFTR gene variation in 1 patient who was diagnosed with cystic fibrosis. CONCLUSIONS: The etiology of infantile intrahepatic cholestasis is complex. Next generation sequencing is helpful in the diagnosis of infantile intrahepatic cholestasis.

Clinical characteristics and gene variants of patients with infantile intrahepatic cholestasis / 中国当代儿科杂志

OBJECTIVE@#To explore the clinical characteristics and genetic findings of patients with infantile intrahepatic cholestasis.@*METHODS@#The clinical data were collected in children who were admitted to the Department of Gastroenterology in Children's Hospital, Capital Institute of Pediatrics from June 2017 to June 2019 and were suspected of inherited metabolic diseases. Next generation sequencing based on target gene panel was used for gene analysis in these children. Sanger sequencing technology was used to verify the genes of the members in this family.@*RESULTS@#Forty patients were enrolled. Pathogenic gene variants were identified in 13 patients (32%), including @*CONCLUSIONS@#The etiology of infantile intrahepatic cholestasis is complex. Next generation sequencing is helpful in the diagnosis of infantile intrahepatic cholestasis.

Environmental Regulation, Trade Comparative Advantage, and the Manufacturing Industry's Green Transformation and Upgrading.

This paper is the first to systematically review the theoretical mechanisms of environmental regulation and trade comparative advantage that affect the green transformation and upgrading of the manufacturing industry. On this basis, corresponding hypotheses are put forward. The non-radial and non-angle SBM (slacks-based measure) efficiency measurement model with undesirable outputs was used, combined with the use of the ML (green total factor productivity index) productivity index to measure green total factor productivity. Finally, the theoretical hypothesis was empirically tested using data from 27 manufacturing industries in China from 2005 to 2017. The results show the following: (1) There is a significant inverted U-shaped curve relationship between environmental regulation and the transformation of the manufacturing industry. In other words, as environmental regulation increases, its impact on the transformation and upgrading of the manufacturing industry is first promoted and then suppressed. (2) When there are no environmental regulations, the trade comparative advantage of the manufacturing industry is not conducive to industrial transformation. However, under the constraints of environmental regulations, the comparative advantage of trade will significantly promote the green transformation and upgrading of manufacturing. Therefore, in order to effectively promote transformation and upgrading of the manufacturing, this paper proposes the following policy recommendations: (1) The Chinese government should pay more attention to the impact of environmental regulation intensity on the transformation of manufacturing industries, further increase the intensity of environmental regulation within the reasonable range, and fully exert the positive effects of environmental regulation on the trade patterns and manufacturing industry transformation. (2) We should further optimize the structure of trade, realize the diversification of manufacturing import and export, and promote its transformation into high-end manufacturing. On this basis, green production technology in the manufacturing industry can be improved through the technology spillover effect. (3) Efforts should be made to improve the level of collaborative development between environmental regulation and trade patterns and to explore the transformation path of the manufacturing industry with the integration of environmental regulation and trade patterns.

Long non-coding RNA HOTAIR in circulatory exosomes is correlated with ErbB2/HER2 positivity in breast cancer.

Cancer cells are known to produce and secret extracellular vesicles for intercellular communication through the carried cargos. HOTAIR (HOX transcript antisense intergenic RNA), a well-studied long non-coding RNA (lncRNA), plays a critical role in cancer progression. In several cancer types it has been shown that HOTAIR-containing exosomes are produced by cancer cells. Here we show that circulatory exosomal HOTAIR is present in breast cancer patients and explores the pathological correlation with the disease. Exosomes were isolated by matrix-based precipitation from conditioned media of cultured breast cancer cell lines as well as blood samples of recently recruited breast cancer patients. HOTAIR RNA in exosomes was detected by quantitative reverse transcriptase-mediated polymerase chain reaction (qRT-PCR). Expression of exosomal HOTAIR was positively correlated with status of the receptor tyrosine kinase (RTK) ErbB2 (also known as HER2/neu) in tumor tissues. The causal correlation of ErbB2 and HOTAIR was validated in isogenic breast cancer cell lines with and without ectopic ErbB2 expression. Our finding provides a molecular basis to develop novel liquid biopsy biomarkers and targeted therapies with improved precision for malignant breast cancer.