Diagnosis of benign and malignant nodules with a radiomics model integrating features from nodules and mammary regions on DCE-MRI.

Objectives: To establish a radiomics model for distinguishing between the benign and malignant mammary gland nodules via combining the features from nodule and mammary regions on DCE-MRI. Methods: In this retrospective study, a total of 103 cases with mammary gland nodules (malignant/benign = 80/23) underwent DCE-MRI, and was confirmed by biopsy pathology. Features were extracted from both nodule region and mammary region on DCE-MRI. Three SVM classifiers were built for diagnosis of benign and malignant nodules as follows: the model with the features only from nodule region (N model), with the features only from mammary region (M model) and the model combining the features from nodule region and mammary region (NM model). The performance of models was evaluated with the area under the curve of receiver operating characteristic (AUC). Results: One radiomic features is selected from nodule region and 3 radiomic features is selected from mammary region. Compared with N or M model, NM model exhibited the best performance with an AUC of 0.756. Conclusions: Compared with the model only using the features from nodule or mammary region, the radiomics-based model combining the features from nodule and mammary region outperformed in the diagnosis of benign and malignant nodules.

An Intraoperative Sub-Anesthetic Dose of Esketamine on Postoperative Depressive Symptoms in Perimenopausal Women with Breast Cancer Undergoing Modified Radical Mastectomy: Protocol for a Randomized, Triple-Blinded, Controlled Trial.

Background: Depressive symptoms are common among perimenopausal women with breast cancer having modified radical mastectomy. Esketamine exerts antidepressant effects. This study aims to assess whether an intraoperative sub-anesthetic dose of esketamine prevents postoperative depressive symptoms in these patients. Methods: In this randomized, triple-blinded, placebo-controlled trial, we will enroll 130 perimenopausal women (aged 45-60 years) with breast cancer undergoing unilateral modified radical mastectomy. Patients will be randomly assigned with a 1:1 ratio to receive either esketamine (0.25 mg/kg i.v.) or normal saline after anesthesia induction and before skin incision. The primary outcome is the incidence of depressive symptoms at day 30 postoperatively, assessed using the Beck's Depression Inventory (BDI). Secondary outcomes include incidence of depressive symptoms and BDI scores at day 1, 3, and 180 postoperatively, anxiety symptoms and scores at day 1, 3, 30, and 180 postoperatively, pain intensity and quality of recovery at day 1 and 2 postoperatively, nausea and vomiting within 48 hours postoperatively, length of postoperative hospital stay, and cancer-specific outcomes. Data will be analyzed in the modified intention-to-treat population. Discussion: This is the first trial to evaluate the effects of a sub-anesthetic dose of esketamine on depressive symptoms in perimenopausal women after modified radical mastectomy. The results of this study will help to improve their mental health and recovery after breast cancer surgery. Trial Registration: Chinese Clinical Trial Registry (ChiCTR2200064348).

The RNA polymerase II subunit B (RPB2) functions as a growth regulator in human glioblastoma.

Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor with a poor prognosis. The growth of GBM cells depends on the core transcriptional apparatus, thus rendering RNA polymerase (RNA pol) complex as a candidate therapeutic target. The RNA pol II subunit B (POLR2B) gene encodes the second largest subunit of the RNA pol II (RPB2); however, its genomic status and function in GBM remain unclear. Certain GBM data sets in cBioPortal were used for investigating the genomic status and expression of POLR2B in GBM. The function of RPB2 was analyzed following knockdown of POLR2B expression by shRNA in GBM cells. The cell counting kit-8 assay and PI staining were used for cell proliferation and cell cycle analysis. A xenograft mouse model was established to analyze the function of RPB2 in vivo. RNA sequencing was performed to analyze the RPB2-regulated genes. GO and GSEA analyses were applied to investigate the RPB2-regulated gene function and associated pathways. In the present study, the genomic alteration and overexpression of the POLR2B gene was described in glioblastoma. The data indicated that knockdown of POLR2B expression suppressed tumor cell growth of glioblastoma in vitro and in vivo. The analysis further demonstrated the identification of the RPB2-regulated gene sets and highlighted the DNA damage-inducible transcript 4 gene as the downstream target of the POLR2B gene. The present study provides evidence indicating that RPB2 functions as a growth regulator in glioblastoma and could be used as a potential therapeutic target for the treatment of this disease.

Dose pulmonary hemorrhage increase the risk of bronchopulmonary dysplasia in very low birth weight infants?

OBJECTIVE: To evaluate the association between pulmonary hemorrhage and bronchopulmonary dysplasia (BPD) in very low birth weight infants (VLBWIs). METHODS: The study participants were all VLBW newborns admitted from January 1, 2019 to December 31, 2021. The BPD subjects finally included were VLBWIs who survived until the diagnosis was established. This study was divided into pulmonary hemorrhage group (PH group, n = 35) and non-pulmonary hemorrhage group (Non-PH group, n = 190). RESULTS: By univariate analysis it was found that premature rupture of membranes, tracheal intubation in the delivery room, duration of mechanical ventilation, course of invasive ventilation (≥3 courses), pulmonary surfactant (>1 dose), medically and surgically treated patent ductus arteriosus, grade III-IV RDS, early onset sepsis, BPD and moderate to severe BPD showed significant differences between groups (p < .05). By Multivariate analysis, pulmonary hemorrhage did not increase the risks of BPD and moderate to severe BPD (adjusted OR for BPD = 1.710, 95% CI 0.581-5.039; adjusted OR for moderate to severe BPD = 2.401, 95% CI 0.736-7.834). CONCLUSION: It suggests that pulmonary hemorrhage is not associated with the development of BPD and moderate to severe BPD in VLBWIs.

Effectiveness and safety of rectal dexibuprofen versus oral ibuprofen for closure of patent ductus arteriosus in preterm infants with gestational age<34 weeks: A pilot study.

This pilot study aimed to explore the effectiveness and safety of dexibuprofen suppository in the treatment of PDA in preterm infants. Preterm infants with gestational age <34 weeks and color Doppler echocardiographic evidence of hemodynamically significant PDA (hs PDA) with systemic hypoperfusion was intended to be included into this study since January 2020. As of January 1, 2021, this trial had recruited 87 preterm infants who met the inclusion criteria. Neonates were admitted into hospital within 1 hour after birth and were randomly assigned into two groups. Group one included 44 preterm newborns administered with oral ibuprofen. Group two included 43 preterm newborns administered with dexibuprofen suppository. This preliminary study showed that rectal dexibuprofen and oral ibuprofen were both effective for the closure of PDA, and the closure rate of dexibuprofen suppository was comparable to that of oral ibuprofen after the 1st and 2nd courses of treatment. In addition, rectal dexibuprofen did not increase the incidence of adverse outcomes, including bronchopulmonary dysplasia, intraventricular hemorrhage, sepsis, and necrotising enterocolitis. This pilot study showed dexibuprofen suppository is as effective and safe as oral ibuprofen; yet, better designed, muticenter controlled studies are still needed.

RNA sequencing and bioinformatics analysis of circular RNAs in asphyxial newborns with acute kidney injury.

As one kind of novel noncoding RNA, circular RNAs (circRNAs) are involved in different biological processes. Although growing evidences have supported the important role of circRNAs in renal diseases, the mechanism remains unclear in neonatal acute kidney injury (AKI). High-throughput sequencing analysis was used to investigate the expression of circRNAs between hypoxia-induced AKI neonates and controls. Bioinformatics analysis was conducted to predict the function of differentially expressed circRNAs. Finally, the differentially expressed circRNAs were screened and determined by quantitative real-time PCR (qPCR). (1) A total of 296 differentially expressed circRNAs were identified (Fold change >2 and p < 0.05). Of them, 184 circRNAs were markedly upregulated, and 112 were significantly downregulated in the AKI group. (2) The pathway analysis showed that ubiquitin-mediated proteolysis, renal cell carcinoma, Jak-STAT, and HIF-1 signaling pathways participated in AKI. (3) Top five upregulated and five downregulated circRNAs with higher fold changes were selected for qPCR validation. Hsa_circ_0008898 (Fold Change = 5.48, p = 0.0376) and hsa_circ_0005519 (Fold Change = 4.65, p = 0.0071) were significantly upregulated, while hsa_circ_0132279 (Fold Change = -4.47, p = 0.0008), hsa_circ_0112327 (Fold Change = -4.26, p = 0.0048), and hsa_circ_0017647 (Fold Change = -4.15, p = 0.0313) were significantly downregulated in asphyxia-induced AKI group compared with the control group. This study could contribute to future research on neonatal AKI and facilitate the identification of novel therapeutic targets.

Effect of different carbon sources on sulfate reduction and microbial community structure in bioelectrochemical systems.

Microbial electrolysis cells (MECs) have rapidly developed into a promising technology to treat sulfate-rich wastewater that lacks electron donors. Hence, a better understanding of the effect on the microbial community structure caused by different sources in bioelectrochemical systems is required. This study sought to investigate the effect of different carbon sources (NaHCO3, ethanol, and acetate were employed as sole carbon source respectively) on the performance of sulfate-reducing biocathodes. The sulfate reduction efficiency enhanced by the bioelectrochemical systems was 8.09 - 11.57% higher than that of open-circuit reference experiments. Furthermore, the optimum carbon source was ethanol with a maximum sulfate reduction rate of 170 mg L-1 d-1 in the bioelectrochemical systems. The different carbon sources induced significant differences in sulfate reduction efficiency as demonstrated by the application of a micro-electrical field. Microbial community structure and network analysis revealed that all three kinds of carbon source systems enriched large proportions of sulfate-reducing bacteria and electroactive bacteria but were significantly distinct in composition. The dominant sulfate-reducing bacteria that use NaHCO3 and acetate as carbon sources were Desulfobacter and Desulfobulbus, whereas those that use ethanol as carbon source were Desulfomicrobium and Desulfovibrio. Our results suggest that ethanol is a more suitable carbon source for sulfate reduction in bioelectrochemical systems.

[Pulmonary hemorrhage in very low birth weight infants: risk factors and clinical outcome]. / æžä½Žå‡ºç”Ÿä½“é‡å„¿å‘ç”Ÿè‚ºå‡ºè¡€çš„å±é™©å› ç´ åŠå ¶ä¸´åºŠè½¬å½’.

OBJECTIVES: To investigate the risk factors for pulmonary hemorrhage and its clinical outcome in very low birth weight infants (VLBWIs). METHODS: The medical data were collected from all live VLBWIs (gestational age <35 weeks) who were admitted to Jiangsu Women and Children Health Hospital and Children's Hospital of Nanjing Medical University between January 1, 2020 and December 31, 2021. Based on inclusion and exclusion criteria, 574 VLBWIs were included in the study, with 44 VLBWIs in the pulmonary hemorrhage group and 530 VLBWIs in the non-pulmonary hemorrhage group. The clinical data were compared between the two groups. A multivariate logistic regression analysis was used to identify the risk factors for pulmonary hemorrhage. RESULTS: There were significant differences between the two groups in maternal age, rate of positive-pressure ventilation for resuscitation, rate of tracheal intubation for resuscitation, and minimum body temperature within 1 hour after birth (P<0.05). The pulmonary hemorrhage group had a higher proportion of VLBWIs with grade Ⅲ-Ⅳ respiratory distress syndrome or early-onset sepsis than the non-pulmonary hemorrhage group (P<0.05). The pulmonary hemorrhage group also had a higher proportion of VLBWIs with a capillary refilling time of >3 seconds within 1 hour after birth and with the maximum positive end-expiratory pressure (PEEP) of <5 cmH2O within 24 hours after birth (P<0.05). The multivariate regression analysis showed that maternal age of 30-<35 years (OR=0.115, P<0.05) was a protective factor against pulmonary hemorrhage, while a lower temperature (<34°C) within 1 hour after birth, the maximum PEEP of <5 cm H2O within 24 hours after birth, and early-onset sepsis were risk factors for pulmonary hemorrhage (OR=11.609, 11.118, and 20.661, respectively; P<0.05). For all VLBWIs, the pulmonary hemorrhage group had a longer duration of invasive ventilation and a higher mortality rate than the non-pulmonary hemorrhage group (P<0.05); for the survival VLBWIs, the pulmonary hemorrhage group had a higher incidence rate of bronchopulmonary dysplasia than the non-pulmonary hemorrhage group (P<0.05). CONCLUSIONS: Maintaining the stability of temperature, giving appropriate PEEP, and identifying sepsis as early as possible can reduce the incidence rate of pulmonary hemorrhage, thereby helping to reduce the incidence of bronchopulmonary dysplasia and mortality in VLBWIs.

Strengthening container shipping network connectivity during COVID-19: A graph theory approach.

A container shipping network connects coastal countries with each other and facilitates most of the world merchandise trade. Reliable maritime connectivity ensures the availability of commodities and economic growth. The global spread of COVID-19 has led to port failures and service cancellations, resulting in decreased connectivity level of container ports. To mitigate the impact of the pandemic, a graph theory approach is proposed to strength the container shipping network connectivity by considering topology and the possibility of opening new shipping links between ports. It is designed to maximize network connectivity with limited addable routes. The network connectivity is measured by algebraic connectivity, and the possibility of opening new shipping links is estimated by an extended gravity model. A heuristic algorithm based on Fiedler vector is introduced to obtain the optimal solutions. The performance of the proposed model and algorithm are verified by testing on a real-world container shipping network based on the Alphaliner database. Experimental results illustrate that the presented model is efficient and effective for strengthening the connectivity. Policy makers can refer to the suggested optimal shipping links to facilitate better shipping network connectivity in the context of the COVID-19 pandemic.

A case-case study on the effect of primary and booster immunization with China-produced COVID-19 vaccines on prevention of pneumonia and viral load among vaccinated persons infected by Delta and Omicron variants.

Using a three-prefecture, two-variant COVID-19 outbreak in Henan province in January 2022, we evaluated the associations of primary and booster immunization with China-produced COVID-19 vaccines and COVID-19 pneumonia and SARS-CoV-2 viral load among persons infected by Delta or Omicron variant. We obtained demographic, clinical, vaccination, and multiple Ct values of infections ≥3 years of age. Vaccination status was either primary series ≥180 days prior to infection; primary series <180 days prior to infection, or booster dose recipient. We used logistic regression to determine odds ratios (OR) of Delta and Omicron COVID-19 pneumonia by vaccination status. We analysed minimum Ct values by vaccination status, age, and variant. Of 826 eligible cases, 405 were Delta and 421 were Omicron cases; 48.9% of Delta and 19.0% of Omicron cases had COVID-19 pneumonia. Compared with full primary vaccination ≥180 days before infection, the aOR of pneumonia was 0.48 among those completing primary vaccination <180 days and 0.18 among booster recipients among these Delta infections. Among Omicron infections, the corresponding aOR was 0.34 among those completing primary vaccination <180 days. There were too few (ten) Omicron cases among booster dose recipients to calculate a reliable OR. There were no differences in minimum Ct values by vaccination status among the 356 Delta cases or 70 Omicron cases. COVID-19 pneumonia was less common among Omicron cases than Delta cases. Full primary vaccination reduced pneumonia effectively for 6 months; boosting six months after primary vaccination resulted in further reduction. We recommend accelerating the pace of booster dose administration.

SRSF3-mediated regulation of N6-methyladenosine modification-related lncRNA ANRIL splicing promotes resistance of pancreatic cancer to gemcitabine.

Serine/arginine-rich splicing factor 3 (SRSF3) regulates mRNA alternative splicing of more than 90% of protein-coding genes, providing an essential source for biological versatility. This study finds that SRSF3 expression is associated with drug resistance and poor prognosis in pancreatic cancer. We also find that SRSF3 regulates ANRIL splicing and m6A modification of ANRIL in pancreatic cancer cells. More importantly, we demonstrate that m6A methylation on lncRNA ANRIL is essential for the splicing. Moreover, our results show that SRSF3 promotes gemcitabine resistance by regulating ANRIL's splicing and ANRIL-208 (one of the ANRIL spliceosomes) can enhance DNA homologous recombination repair (HR) capacity by forming a complex with Ring1b and EZH2. In conclusion, this study establishes a link between SRSF3, m6A modification, lncRNA splicing, and DNA HR in pancreatic cancer and demonstrates that abnormal alternative splicing and m6A modification are closely related to chemotherapy resistance in pancreatic cancer.

The effect of erythropoietin on neonatal hypoxic-ischemic encephalopathy: An updated meta-analysis of randomized control trials.

Objective: Erythropoietin (EPO) seems to have a good application prospect both in experimental models and patients with hypoxic ischaemic encephalopathy (HIE). Data regarding the effect of EPO on death or neurodevelopmental impairment are conflicting. Methods: A search was conducted by two investigators involved in this research in PubMed, Embase, and Cochrane databases for studies in English, in Wanfang, VIP, and Cnki databases for Chinese studies (all last launched on 2022/08/31). Ultimately, we identified 11 original studies, including the EPO group (n = 636) and the control group (n = 626). Odds ratio (OR) and weighted mean difference were calculated using a random effects or fixed effects model, depending on the data type and heterogeneity of the included studies. Results: 1. The comparison of effectiveness of EPO treatment on HIE: (1) With respect to death, data showed no significant difference between EPO and control groups (OR = 0.97, 95% CI, 0.66-1.43; P = 0.88); Considering the additional effect of mild hypothermia treatment (MHT), no significant difference was found between EPO + MHT/control + MHT groups either (OR = 1.09, 95% CI, 0.69-1.73; P = 0.72); With respect to the interference of different routes of medication administration, Meta-analysis further showed no difference between intravenous EPO/control groups (OR = 1.13, 95% CI, 0.70-1.82; P = 0.62). (2) With respect to cerebral palsy, the analysis showed no significant difference (OR = 0.76, 95% CI, 0.50-1.15; P = 0.20); Considering the effect of MHT and routes of medication administration, data further showed no difference between EPO group and control group (OR = 1.26, 95% CI, 0.73-2.19; P = 0.41). (3) Regarding epilepsy, no significant difference was found (OR = 0.49, 95% CI, 0.20-1.19; P = 0.12). MR abnormality was less common in EPO group (OR = 0.39, 95% CI, 0.19-0.79; P = 0.008). 2. The comparison of possible adverse events of EPO: EPO treatment would not increase the risk of thrombocytopenia, hypotension, and hepatic and kidney injury. Conclusions: This meta-analysis showed that EPO treatment is not beneficial for reducing death and improving neurological impairment, though it would not increase the risk of adverse events.

Application and progress of medical imaging in total mesopancreas excision for pancreatic head carcinoma.

Pancreatic head carcinoma (PHC) is one of the common gastrointestinal malignancies with a high morbidity and poor prognosis. At present, radical surgery is still the curative treatment for PHC. However, in clinical practice, the actual R0 resection rate, the local recurrence rate, and the prognosis of PHC are unsatisfactory. Therefore, the concept of total mesopancreas excision (TMpE) is proposed to achieve R0 resection. Although there have various controversies and discussions on the definition, the range of excision, and clinical prognosis of TMpE, the concept of TMpE can effectively increase the R0 resection rate, reduce the local recurrence rate, and improve the prognosis of PHC. Imaging is of importance in preoperative examination for PHC; however, traditional imaging assessment of PHC does not focus on mesopancreas. This review discusses the application of medical imaging in TMpE for PHC, to provide more accurate preoperative evaluation, range of excision, and more valuable postoperative follow-up evaluation for TMpE through imaging. It is believed that with further extensive research and exploratory application of TMpE for PHC, large-sample and multicenter studies will be realized, thus providing reliable evidence for imaging evaluation.

CEBPG promotes acute myeloid leukemia progression by enhancing EIF4EBP1.

BACKGROUND: Acute myeloid leukemia (AML) is a myeloid neoplasm accounts for 7.6% of hematopoietic malignancies. AML is a complex disease, and understanding its pathophysiology is contributing to the improvement in the treatment and prognosis of AML. In this study, we assessed the expression profile and molecular functions of CCAAT enhancer binding protein gamma (CEBPG), a gene implicated in myeloid differentiation and AML progression. METHODS: shRNA mediated gene interference was used to down-regulate the expression of CEBPG in AML cell lines, and knockdown efficiency was detected by RT-qPCR and western blotting. The effect of knockdown on the growth of AML cell lines was evaluated by CCK-8. Western blotting was used to detect PARP cleavage, and flow cytometry were used to determine the effect of knockdown on apoptosis of AML cells. Genes and pathways affected by knockdown of CEBPG were identified by gene expression analysis using RNA-seq. One of the genes affected by knockdown of CEBPG was Eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1), a known repressor of translation. Knockdown of EIF4EBP1 was used to assess its potential role in AML progression downstream of CEBPG. RESULTS: We explored the ChIP-Seq data of AML cell lines and non-AML hematopoietic cells, and found CEBPG was activated through its distal enhancer in AML cell lines. Using the public transcriptomic dataset, the Cancer Cell Line Encyclopedia (CCLE) and western blotting, we also found CEBPG was overexpressed in AML. Moreover, we observed that CEBPG promotes AML cell proliferation by activating EIF4EBP1, thus contributing to the progression of AML. These findings indicate that CEBPG could act as a potential therapeutic target for AML patients. CONCLUSION: In summary, we systematically explored the molecular characteristics of CEBPG in AML and identified CEBPG as a potential therapeutic target for AML patients. Our findings provide novel insights into the pathophysiology of AML and indicate a key role for CEBPG in promoting AML progression.

Accuracy of ultrasonography in diagnosis of fetal central nervous system malformation.

BACKGROUND: Prenatal examination is an important measure for the screening and diagnosis of fetal malformations. AIM: To investigate the accuracy of ultrasonography in the diagnosis of fetal central nervous system (CNS) malformations. METHODS: One hundred and thirteen pregnant women suspected of having fetal CNS malformations were examined at our hospital from December 2018 to October 2020 using two-dimensional ultrasonography and three-dimensional ultrasonography, respectively. RESULTS: According to the pathological results, there were 79 cases of CNS malformations and 34 cases of non-CNS malformations among the 113 pregnant women suspected of having fetal CNS malformation. Fifty-one cases of CNS malformation and 26 cases of non-CNS malformation were detected by two-dimensional ultrasonography, and 73 cases of CNS malformation and 30 cases of non-CNS malformation were detected by three-dimensional ultrasonography. The diagnostic sensitivity (92.41%) and accuracy (91.15%) of three-dimensional ultrasonography were higher than those of two-dimensional ultrasonography (64.56% and 68.14%, respectively) (P = 0.000). The specificity of three-dimensional ultrasonography (88.24%) was higher than that of two-dimensional ultrasonography (76.47%); however, the difference was not significant (P = 0.203). CONCLUSION: Three-dimensional ultrasonography has high application value in the diagnosis of fetal CNS malformations. In addition, the image quality is clear, and the diagnostic sensitivity and accuracy are high.

MI-773, a breaker of the MDM2/p53 axis, exhibits anticancer effects in neuroblastoma via downregulation of INSM1.

Neuroblastoma (NB) is a common pediatric malignancy associated with poor outcomes. Recent studies have shown that murine double minute2 homolog (MDM2) protein inhibitors are promising anticancer agents. MI-773 is a novel and specific antagonist of MDM2, however, the molecular mechanism of its anti-NB activity remains unclear. NB cell viability was measured by Cell Counting Kit-8 assay following MI-773 treatment. Cell cycle progression was analyzed using PI staining and apoptosis was assessed using Annexin V/PI staining. The molecular mechanisms by which MI-773 exerted its effects were investigated using a microarray. The results showed that disturbance of the MDM2/p53 axis by MI-773 resulted in potent suppression of proliferation, induction of apoptosis and cell cycle arrest in NB cells. In addition, microarray analysis showed that MI-773 led to significant downregulation of genes involved in the G2/M phase checkpoint and upregulation of hallmark gene associated with the p53 pathway. Meanwhile, knockdown of insulinoma-associated 1 decreased proliferation and increased apoptosis of NB cells. In conclusion, the present study demonstrated that MI-773 exhibited high selectivity and blockade affinity for the interaction between MDM2 and TP53 and may serve as a novel strategy for the treatment of NB.

CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2 and promotes growth and metastasis of pancreatic cancer.

BACKGROUND: Both aberrant alternative splicing and m6A methylation play complicated roles in the development of pancreatic cancer (PC), while the relationship between these two RNA modifications remains unclear. METHODS: RNA sequencing (RNA-seq) was performed using 15 pairs of pancreatic ductal adenocarcinoma (PDAC) tissues and corresponding normal tissues, and Cdc2-like kinases 1 (CLK1) was identified as a significantly upregulated alternative splicing related gene. Real-time quantitative PCR (qPCR) and western blotting were applied to determine the CLK1 levels. The prognostic value of CLK1 was elucidated by Immunohistochemistry (IHC) analyses in two independent PDAC cohorts. The functional characterizations and mechanistic insights of CLK1 in PDAC growth and metastasis were evaluated with PDAC cell lines and nude mice. SR-like splicing factors5250-Ser (SRSF5250-Ser) was identified as an important target phosphorylation site by phosphorylation mass spectrometry. Through transcriptome sequencing, Methyltransferase-like 14exon10 (METTL14exon10) and Cyclin L2exon6.3 skipping were identified as key alternative splicing events regulated by the CLK1-SRSF5 axis. RIP assays, RNA-pulldown and CLIP-qPCR were performed to confirm molecular interactions and the precise binding sites. The roles of the shift of METTL14exon 10 and Cyclin L2exon6.3 skipping were surveyed. RESULTS: CLK1 expression was significantly increased in PDAC tissues at both the mRNA and protein levels. High CLK1 expression was associated with poor prognosis. Elevated CLK1 expression promoted growth and metastasis of PC cells in vitro and in vivo. Mechanistically, CLK1 enhanced phosphorylation on SRSF5250-Ser, which inhibited METTL14exon10 skipping while promoted Cyclin L2exon6.3 skipping. In addition, aberrant METTL14exon 10 skipping enhanced the N6-methyladenosine modification level and metastasis, while aberrant Cyclin L2exon6.3 promoted proliferation of PDAC cells. CONCLUSIONS: The CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2, which promotes growth and metastasis and regulates m6A methylation of PDAC cells. This study suggests the potential prognostic value and therapeutic targeting of this pathway in PDAC patients.

Migration of mineral oil hydrocarbons from food contact papers into food simulants and extraction from their raw materials.

To determine the occurrence of mineral oil hydrocarbons (MOH) in food contact papers in China, and to investigate the potential sources of MOH contamination, a total of 159 food contact papers and raw materials were analysed by off-line solid-phase extraction-gas chromatography flame ionisation detection (SPE-GC-FID) and a GC-MS method. The migration of MOH from food contact papers into Tenax, olive oil or 50% ethanol under the worst foreseeable conditions of use was determined. The results indicated that the occurrence of MOH in China is of a potential health risk concerning the migration of mineral oil saturated hydrocarbons (MOSH) and mineral oil aromatic hydrocarbons (MOAH) which were detected in 82.6% and 50.4% of samples, respectively. Migration of MOSH from 47.9% of samples was higher than 2 mg/kg and migration of MOAH from 32.2% samples exceeded 0.5 mg/kg in case of the worst foreseeable condition of use. The highest mean migration of MOSH and MOAH were found in packaging papers for long-term storage (more than 6 months), with mean migration of 91.2 mg/kg and 1.4 mg/kg, respectively. Migration of MOH from printed paper was considerably higher than that of unprinted paper, validating previous findings that the printing ink is the predominant source of MOH contamination in food contact papers. Migration of MOH from paper bowls used for packing instant noodles was relatively low, suggesting the internal hollow layer may be acting as a functional barrier that could block the transfer of MOH (up to C28) through the gas phrase, even though the outer layer was made from recycled paper. High concentrations of MOSH and MOAH were also detected in de-foamers, adhesives and rosin sizing agents, indicating that the MOH contamination caused by the use of raw materials and additives should also be taken into consideration.

SHCBP1 interacting with EOGT enhances O-GlcNAcylation of NOTCH1 and promotes the development of pancreatic cancer.

O-GlcNAcylation is important in the development and progression of pancreatic ductal adenocarcinoma (PDAC). The glycosyltransferase EGF domain-specific O-linked GlcNAc transferase (EOGT) acts as a key participant in glycosylating NOTCH1. High-throughput sequencing of specimens from 30 advanced PDAC patients identified SHCBP1 and EOGT as factors of poor prognosis. We hypothesized that they could mediate PDAC progression by influencing NOTCH1 O-GlcNAcylation. Thus, 186 PDAC tissue specimens were immunostained for EOGT and SHCBP1. Pancreatic cancer cell lines and nude mouse models were used for in vitro and in vivo experiments. Respectively, The protein expression of EOGT and SHCBP1 was significantly elevated and correlated with worse prognosis in PDAC patients. In vitro, SHCBP1 overexpression promoted pancreatic cancer cell proliferation, migration and invasion, while knocking down SHCBP1 and EOGT inhibited these malignant processes. In vivo data showed that SHCBP1 overexpression promoted xenograft growth and lung metastasis and shortened survival in mice, whereas knocking down either EOGT or SHCBP1 expression suppressed xenograft growth and metastasis and prolonged survival. We further clarified the molecular mechanisms by which EOGT and SHCBP1 enhance the O-GlcNAcylation of NOTCH1, Subsequently promoting the nuclear localization of the Notch intracellular domain (NICD) and inhibiting the transcription of E-cadherin and P21 in pancreatic cancer cells.