Signal enhancement ratio of multi-phase contrast-enhanced MRI: an imaging biomarker for survival in pancreatic adenocarcinoma.

OBJECTIVES: To evaluate signal enhancement ratio (SER) for tissue characterization and prognosis stratification in pancreatic adenocarcinoma (PDAC), with quantitative histopathological analysis (QHA) as the reference standard. METHODS: This retrospective study included 277 PDAC patients who underwent multi-phase contrast-enhanced (CE) MRI and whole-slide imaging (WSI) from three centers (2015-2021). SER is defined as (SIlt - SIpre)/(SIea - SIpre), where SIpre, SIea, and SIlt represent the signal intensity of the tumor in pre-contrast, early-, and late post-contrast images, respectively. Deep-learning algorithms were implemented to quantify the stroma, epithelium, and lumen of PDAC on WSIs. Correlation, regression, and Bland-Altman analyses were utilized to investigate the associations between SER and QHA. The prognostic significance of SER on overall survival (OS) was evaluated using Cox regression analysis and Kaplan-Meier curves. RESULTS: The internal dataset comprised 159 patients, which was further divided into training, validation, and internal test datasets (n = 60, 41, and 58, respectively). Sixty-five and 53 patients were included in two external test datasets. Excluding lumen, SER demonstrated significant correlations with stroma (r = 0.29-0.74, all p < 0.001) and epithelium (r = -0.23 to -0.71, all p < 0.001) across a wide post-injection time window (range, 25-300 s). Bland-Altman analysis revealed a small bias between SER and QHA for quantifying stroma/epithelium in individual training, validation (all within ± 2%), and three test datasets (all within ± 4%). Moreover, SER-predicted low stromal proportion was independently associated with worse OS (HR = 1.84 (1.17-2.91), p = 0.009) in training and validation datasets, which remained significant across three combined test datasets (HR = 1.73 (1.25-2.41), p = 0.001). CONCLUSION: SER of multi-phase CE-MRI allows for tissue characterization and prognosis stratification in PDAC. CLINICAL RELEVANCE STATEMENT: The signal enhancement ratio of multi-phase CE-MRI can serve as a novel imaging biomarker for characterizing tissue composition and holds the potential for improving patient stratification and therapy in PDAC. KEY POINTS: Imaging biomarkers are needed to better characterize tumor tissue in pancreatic adenocarcinoma. Signal enhancement ratio (SER)-predicted stromal/epithelial proportion showed good agreement with histopathology measurements across three distinct centers. Signal enhancement ratio (SER)-predicted stromal proportion was demonstrated to be an independent prognostic factor for OS in PDAC.

Bulk and single-cell transcriptome profiling identify potential cellular targets of the long noncoding RNA Gas5 in renal fibrosis.

The long noncoding RNA growth arrest-specific 5 (lncRNA Gas5) is implicated in various kidney diseases. In this study, we investigated the lncRNA Gas5 expression profile and its critical role as a potential biomarker in the progression of chronic kidney disease. Subsequently, we assessed the effect of lncRNA Gas5 deletion on renal fibrosis induced by unilateral ureteral obstruction (UUO). The results indicated that loss of lncRNA Gas5 exacerbates UUO-induced renal injury and extracellular matrix deposition. Notably, the deletion of lncRNA Gas5 had a similar effect on control mice. The fibrogenic phenotype observed in mice lacking lncRNA Gas5 correlates with peroxisome proliferator-activated receptor (PPAR) signaling pathway activation and aberrant cytokine and chemokine reprogramming. Single-cell RNA sequencing analysis revealed key transcriptomic features of fibroblasts after Gas5 deletion, revealing heterogeneous cellular states suggestive of a propensity for renal fibrosis. Our findings indicate that lncRNA Gas5 regulates the differentiation and activation of immune cells and the transcription of key genes in the PPAR signaling pathway. These data offer novel insights into the involvement of lncRNA Gas5 in renal fibrosis, potentially paving the way for innovative diagnostic and therapeutic targets.

Nomogram for predicting the surgical difficulty of laparoscopic total mesorectal excision and exploring the technical advantages of robotic surgery.

Background: Total mesorectal excision (TME), represents a key technique in radical surgery for rectal cancer. This study aimed to construct a preoperative nomogram for predicting the surgical difficulty of laparoscopic total mesorectal excision (L-TME) and to investigate whether there were potential benefits of robotic TME (R-TME) for patients with technically challenging rectal cancer. Methods: Consecutive mid-low rectal cancer patients receiving total mesorectal excision were included. A preoperative nomogram to predict the surgical difficulty of L-TME was established and validated. Patients with technically challenging rectal cancer were screened by calculating the prediction score of the nomogram. Then patients with technically challenging rectal cancer who underwent different types of surgery, R-TME or L-TME, were analyzed for comparison. Results: A total of 533 consecutive patients with mid-low rectal cancer who underwent TME at a single tertiary medical center between January 2018 and January 2021 were retrospectively enrolled. Multivariable analysis demonstrated that mesorectal fat area, intertuberous distance, tumor size, and tumor height were independent risk factors for surgical difficulty. Subsequently, these variables were used to construct the nomogram model to predict the surgical difficulty of L-TME. The area under the receiver operating characteristic curve of the nomogram was 0.827 (95% CI 0.745 - 0.909) and 0.809 (95% CI 0.674- 0.944) in the training and validation cohort, respectively. For patients with technically challenging rectal cancer, R-TME was associated with a lower diverting ileostomy rate (p = 0.003), less estimated blood loss (p < 0.043), shorter procedure time (p = 0.009) and shorter postoperative hospital stay (p = 0.037). Conclusion: In this study, we established a preoperative nomogram to predict the surgical difficulty of L-TME. Furthermore, this study also indicated that R-TME has potential technical advantages for patients with technically challenging rectal cancer.

Single cell multi-omics of fibrotic kidney reveal epigenetic regulation of antioxidation and apoptosis within proximal tubule.

BACKGROUND: Until now, there has been no particularly effective treatment for chronic kidney disease (CKD). Fibrosis is a common pathological change that exist in CKD. METHODS: To better understand the transcriptional dynamics in fibrotic kidney, we make use of single-nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq) and single-cell RNA sequencing (scRNA-seq) from GEO datasets and perform scRNA-seq of human biopsy to seek possible transcription factors (TFs) regulating target genes in the progress of kidney fibrosis across mouse and human kidneys. RESULTS: Our analysis has displayed chromatin accessibility, gene expression pattern and cell-cell communications at single-cell level in kidneys suffering from unilateral ureteral obstruction (UUO) or chronic interstitial nephritis (CIN). Using multimodal data, there exists epigenetic regulation producing less Sod1 and Sod2 mRNA within the proximal tubule which is hard to withstand oxidative stress during fibrosis. Meanwhile, a transcription factor Nfix promoting the apoptosis-related gene Ifi27 expression found by multimodal data was validated by an in vitro study. And the gene Ifi27 upregulated by in situ AAV injection within the kidney cortex aggravates kidney fibrosis. CONCLUSIONS: In conclusion, as we know oxidation and apoptosis are traumatic factors during fibrosis, thus enhancing antioxidation and inhibiting the Nfix-Ifi27 pathway to inhibit apoptosis could be a potential treatment for kidney fibrosis.

Development of a radiomics-based model to predict occult liver metastases of pancreatic ductal adenocarcinoma: a multicenter study.

BACKGROUND: Undetectable occult liver metastases block the long-term survival of pancreatic ductal adenocarcinoma (PDAC). This study aimed to develop a radiomics-based model to predict occult liver metastases and assess its prognostic capacity for survival. MATERIALS AND METHODS: Patients who underwent surgical resection and were pathologically proven with PDAC were recruited retrospectively from five tertiary hospitals between January 2015 and December 2020. Radiomics features were extracted from tumors, and the radiomics-based model was developed in the training cohort using LASSO-logistic regression. The model's performance was assessed in the internal and external validation cohorts using the area under the receiver operating curve (AUC). Subsequently, the association of the model's risk stratification with progression-free survival (PFS) and overall survival (OS) was then statistically examined using Cox regression analysis and the log-rank test. RESULTS: A total of 438 patients [mean (SD) age, 62.0 (10.0) years; 255 (58.2%) male] were divided into the training cohort ( n =235), internal validation cohort ( n =100), and external validation cohort ( n =103). The radiomics-based model yielded an AUC of 0.73 (95% CI: 0.66-0.80), 0.72 (95% CI: 0.62-0.80), and 0.71 (95% CI: 0.61-0.80) in the training, internal validation, and external validation cohorts, respectively, which were higher than the preoperative clinical model. The model's risk stratification was an independent predictor of PFS (all P <0.05) and OS (all P <0.05). Furthermore, patients in the high-risk group stratified by the model consistently had a significantly shorter PFS and OS at each TNM stage (all P <0.05). CONCLUSION: The proposed radiomics-based model provided a promising tool to predict occult liver metastases and had a great significance in prognosis.

TRIOBP modulates ß-catenin signaling by regulation of miR-29b in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fatal and devastating lung disease of unknown etiology, described as the result of multiple cycles of epithelial cell injury and fibroblast activation. Despite this impressive increase in understanding, a therapy that reverses this form of fibrosis remains elusive. In our previous study, we found that miR-29b has a therapeutic effect on pulmonary fibrosis. However, its anti-fibrotic mechanism is not yet clear. Recently, our study identified that F-Actin Binding Protein (TRIOBP) is one of the target genes of miR-29b and found that deficiency of TRIOBP increases resistance to lung fibrosis in vivo. TRIOBP knockdown inhibited the proliferation of epithelial cells and attenuated the activation of fibroblasts. In addition, deficiency of Trio Rho Guanine Nucleotide Exchange Factor (TRIO) in epithelial cells and fibroblasts decreases susceptibility to lung fibrosis. TRIOBP interacting with TRIO promoted abnormal epithelial-mesenchymal crosstalk and modulated the nucleocytoplasmic translocation of ß-catenin. We concluded that the miR-29b‒TRIOBP-TRIO-ß-catenin axis might be a key anti-fibrotic axis in IPF to regulate lung regeneration and fibrosis, which may provide a promising treatment strategy for lung fibrosis.

Anxiety, Depression, Quality of Life, and Family Support Among Family Caregivers of Children with Disabilities.

Purpose: To investigate the family support, anxiety, depression, health-related quality of life (HRQoL), and their associations among parents and grandparents of children with disabilities. Methods: This is a cross-sectional study and a total of 327 family caregivers were included. Chi-square test, Mann-Whitney U-test, and two independent t-test were used to identify the intergenerational differences in sociodemographic characteristics, received family support, anxiety, depression, and HRQoL. Eight generalized linear models were developed to examine the associations in both generations. Results: Parents and grandparents were most in need of rehabilitation and financial support, but both populations received the least amount of financial support. 33.6% and 36.1% of family caregivers had the risk of anxiety and depression and found no significant intergenerational differences. As for HRQoL, intergenerational differences were found in the physical component score, but not found in the mental component score. Among parents, childcare support of respite care and household tasks assistance was negatively associated with their depression (p<0.05), professional support of appropriate surgery for children (p<0.05) and psychological support from professional psychologists (p<0.01) were negatively associated with their anxiety and depression, psychological support from relatives and friends was negatively associated with their depression (p<0.05) whereas was positively associated with their mental HRQoL (p<0.01). As for grandparents, financial support for daily living expenses was negatively associated with depression (p<0.05), and psychological support from families was negatively associated with depression (p<0.05) whereas was positively associated with mental HRQoL (p<0.05). However, no relationship was found between family support and anxiety among grandparents. Notably, no association was found between family support and physical HRQoL among both populations. Conclusion: Both parents and grandparents had high risks of anxiety, depression and low levels of mental HRQoL. To efficiently improve psychological health, care providers and policymakers may consider intergenerational differences and provide targeted family support.

Biology and function of exosomes in tumor immunotherapy.

Exosomes are nano-scale extracellular vesicles that are found widely in various biological fluids. As messengers, exosomes deliver characteristic biological information from donor cells, facilitating their accumulation and subsequent transfer of information to tumor immune cells. Immunotherapy is a cutting-edge strategy for cancer therapy, but it has not yet reached its full potential owing to severe side effects and limited efficacy. Exosomes possess antigens and immunostimulatory molecules and can serve as cell-free vaccines to induce antitumor immunity. In addition, given their stability, low immunogenicity, and targeting ability, exosomes represent ideal drug delivery systems in tumor immunotherapy by delivering cargoes, including non-coding ribonucleic acids (RNAs), membrane proteins, chemotherapeutic agents, and immune cell death inducers. Exosomes can also be engineered to precisely target tumor cells. However, as a rising star in tumor immunotherapy, exosomes are also impeded by some challenges, including the lack of uniform technical standards for their isolation and purification, the need to improve exosomal cargo loading for efficient exosome delivery, and the expansion of clinical trials, which are currently in their infancy. Long-term, multi-center, and large-scale clinical trials are needed to evaluate the performance of exosomes in the future. Nonetheless, exosomes have demonstrated encouraging performance in tumor immunotherapy. In this review, we summarize the potential and challenges of exosomes in tumor immunotherapy, with the aim to shed light on exosomes as new-era tumor immunotherapy tools.

Depression and Associated Factors among Family Caregivers of Children with Disabilities: Analysis of Intergenerational Differences.

Family caregivers of children with disabilities might face high risks of depression, whereas the existing literature focused more on parents neglecting grandparents. This study investigated 380 parents and 108 grandparents of children with disabilities to identify depression and associated factors. Descriptive statistics, Chi-square test, Mann-Whitney U test, and multivariable logistic regression were performed to describe the participants' characteristics and risks of depression and identify significant factors. Results showed that parents (35.5%) had higher risks of depression than grandparents (32.4%), but statistical differences were not found. Children's sleep problems (AOR = 1.751, 95%CI = 1.019, 3.008), harmonious family relationships (AOR = 0.694, 95%CI = 0.569, 0.846), and better barrier-free construction (AOR = 0.742, 95%CI = 0.568, 0.970) were significantly associated with depression among parents. As for grandparents, higher education (AOR = 4.108, 95%CI = 1.526, 11.057) and caring for children who experience frequent mood swings (AOR = 2.242, 95%CI = 1.161, 4.329) were associated with higher risks of depression. Further, house ownership (AOR = 0.167, 95%CI = 0.031, 0.887), higher family cohesion (AOR = 0.545, 95%CI = 0.297, 1.000), and better barrier-free construction (AOR = 0.401, 95%CI = 0.185, 0.869) were associated with lower odds of depression. Therefore, both parents and grandparents of children with disabilities had high risks of depression and thus required urgent attention. Healthcare providers and policymakers should develop and implement interventions considering intergenerational differences to reach optimal efficiency.

High expression of NOLC1 as an independent prognostic factor for survival in patients with colorectal cancer.

BACKGROUND: As a phosphorylated protein, NOLC1 is mainly located in the nucleus and is highly expressed in a variety of tumors, participating in the regulation of cell proliferation and aging. This study further investigated the role of NOLC1 in colorectal cancer tumors, aiming to provide sufficient scientific evidence for the clinical treatment of colorectal cancer. METHODS: We used TCGA, GEO, TNMplot, GEPIA, and other databases to explore the expression level of NOLC1 in colorectal cancer patients, as well as the correlation between the clinical characteristics of colorectal cancer patients and their expression, and conducted the prognostic analysis. Immunohistofluorescence (IHF) staining verified the analytical results. Subsequently, KEGG and GO enrichment analysis was used to identify the potential molecular mechanism of NOLC1 promoting the occurrence and development of colorectal cancer. The influence of NOLC1 expression on the immune microenvironment of colorectal cancer patients was further investigated using the TIMER database. GDSC database analysis was used to screen out possible anti-colorectal cancer drugs against NOLC1. Finally, we demonstrated the effect of NOLC1 on the activity and migration of colorectal cancer cells by Edu Cell proliferation assay and Wound Healing assay in vitro. RESULTS: Our results suggest that NOLC1 is overexpressed in colorectal cancer, and that overexpression of NOLC1 is associated with relevant clinical features. NOLC1, as an independent risk factor affecting the prognosis of colorectal cancer patients, can lead to a poor prognosis of colorectal cancer. In addition, NOLC1 may be associated with MCM10, HELLS, NOC3L, and other genes through participating in Wnt signaling pathways and jointly regulate the occurrence and development of colorectal cancer under the influence of the tumor microenvironment and many other influencing factors. Related to NOLC1: Selumetinib, Imatinib, and targeted drugs such as Lapatinib have potential value in the clinical application of colorectal cancer. NOLC1 enhances the proliferation and migration of colorectal cancer cells. CONCLUSIONS: High expression of NOLC1 as an independent prognostic factor for survival in patients with colorectal cancer. NOLC1 enhances the proliferation and migration of colorectal cancer cells. Further studies and clinical trials are needed to confirm the role of NOLC1 in the development and progression of colorectal cancer.

The role of gut microbiota and drug interactions in the development of colorectal cancer.

The human gut microbiota is a complex ecosystem regulating the host's environmental interaction. The same functional food or drug may have varying bioavailability and distinct effects on different individuals. Drugs such as antibiotics can alter the intestinal flora, thus affecting health. However, the relationship between intestinal flora and non-antibiotic drugs is bidirectional: it is not only affected by drugs; nevertheless, it can alter the drug structure through enzymes and change the bioavailability, biological activity, or toxicity of drugs to improve their efficacy and safety. This review summarizes the roles and mechanisms of antibiotics, antihypertensive drugs, nonsteroidal anti-inflammatory drugs, lipid-lowering drugs, hypoglycemic drugs, virus-associated therapies, metabolites, and dietary in modulating the colorectal cancer gut microbiota. It provides a reference for future antitumor therapy targeting intestinal microorganisms.

Pharmacological activities and therapeutic potential of galangin, a promising natural flavone, in age-related diseases.

BACKGROUND: The extension of average life expectancy and the aggravation of population aging have become the inevitable trend of human development. In an aging society, various problems related to medical care for the elderly have become increasingly prominent. However, most of the age-related diseases have the characteristics of multiple diseases at the same time, prone to complications, and atypical clinical manifestations, which bring great difficulties to its treatment. Galangin (3,5,7-trihydroxyflavone) is a natural active compound extracted from the root of Alpinia officinarum Hance (Zingiberaceae). Recently, many studies have shown that galangin has potential advantages in the treatment of neurodegenerative diseases and cardiovascular and cerebrovascular diseases, which are common in the elderly. In addition, it also showed that galangin had prospective activities in the treatment of tumor, diabetes, liver injury, asthma and arthritis. PURPOSE: This review aims to systematically summarize and discuss the effects and the underlying mechanism of galangin in the treatment of age-related diseases. METHODS: We searched PubMed, SciFinder, Web of Science and CNKI literature database resources, combined with the keywords "galangin", "neurodegenerative disease", "tumor", "diabetes", "pharmacological activity", "drug combination", "pharmacokinetics", "drug delivery system" and "safety", and comprehensively reviewed the pharmacological activities and mechanism of galangin in treating age-related diseases. RESULTS: According to the previous studies on galangin, the anti-neurodegenerative activity, cardiovascular and cerebrovascular protective activity, anti-tumor activity, anti-diabetes activity, anti-arthritis activity, hepatoprotective activity and antiasthmatic activity of galangin were discussed, and the related mechanisms were classified and summarized in detail. In addition, the drug combination, pharmacokinetics, drug delivery system and safety of galangin were furtherly discussed. CONCLUSIONS: This review will provide reference for galangin in the treatment of age-related diseases. Meanwhile, further experimental research and long-term clinical trials are needed to determine the therapeutic safety and efficacy of galangin.

Predicting post-resection recurrence by integrating imaging-based surrogates of distinct vascular patterns of hepatocellular carcinoma.

Background & Aims: Distinct vascular patterns, including microvascular invasion (MVI) and vessels encapsulating tumour clusters (VETC), are associated with poor outcomes of hepatocellular carcinoma (HCC). Imaging surrogates of these vascular patterns potentially help to predict post-resection recurrence. Herein, a prognostic model integrating imaging-based surrogates of these distinct vascular patterns was developed to predict postoperative recurrence-free survival (RFS) in patients with HCC. Methods: Clinico-radiological data of 1,285 patients with HCC from China undergoing surgical resection were retrospectively enrolled from seven medical centres between 2014 and 2020. A prognostic model using clinical data and imaging-based surrogates of MVI and VETC patterns was developed (n = 297) and externally validated (n = 373) to predict RFS. The surrogates (i.e. MVI and VETC scores) were individually built from preoperative computed tomography using two independent cohorts (n = 360 and 255). Whether the model's stratification was associated with postoperative recurrence following anatomic resection was also evaluated. Results: The MVI and VETC scores demonstrated effective performance in their respective training and validation cohorts (AUC: 0.851-0.883 for MVI and 0.834-0.844 for VETC). The prognostic model incorporating serum alpha-foetoprotein, tumour multiplicity, MVI score, and VETC score achieved a C-index of 0.748-0.764 for the developing and external validation cohorts and generated three prognostically distinct strata. For patients at model-predicted medium risk, anatomic resection was associated with improved RFS (p <0.05). By contrast, anatomic resection had no impact on RFS in patients at model-predicted low or high risk (both p >0.05). Conclusions: The proposed model integrating imaging-based surrogates of distinct vascular patterns enabled accurate prediction for RFS. It can potentially be used to identify HCC surgical candidates who may benefit from anatomic resection. Impact and implications: MVI and VETC are distinct vascular patterns of HCC associated with aggressive biological behaviour and poor outcomes. Our multicentre study provided a model incorporating imaging-based surrogates of these patterns for preoperatively predicting RFS. The proposed model, which uses imaging detection to estimate the risk of MVI and VETC, offers an opportunity to help shed light on the association between tumour aggressiveness and prognosis and to support the selection of the appropriate type of surgical resection.

An imaging-based machine learning model outperforms clinical risk scores for prognosis of cirrhotic variceal bleeding.

OBJECTIVES: To develop and validate a machine learning model based on contrast-enhanced CT to predict the risk of occurrence of the composite clinical endpoint (hospital-based intervention or death) in cirrhotic patients with acute variceal bleeding (AVB). METHODS: This retrospective study enrolled 330 cirrhotic patients with AVB between January 2017 and December 2020 from three clinical centers. Contrast-enhanced CT and clinical data were collected. Centers A and B were divided 7:3 into a training set and an internal test set, and center C served as a separate external test set. A well-trained deep learning model was applied to segment the liver and spleen. Then, we extracted 106 original features of the liver and spleen separately based on the Image Biomarker Standardization Initiative (IBSI). We constructed the Liver-Spleen (LS) model based on the selected radiomics features. The performance of LS model was evaluated by receiver operating characteristics and calibration curves. The clinical utility of models was analyzed using decision curve analyses (DCA). RESULTS: The LS model demonstrated the best diagnostic performance in predicting the composite clinical endpoint of AVB in patients with cirrhosis, with an AUC of 0.782 (95% CI 0.650-0.882) and 0.789 (95% CI 0.674-0.878) in the internal test and external test groups, respectively. Calibration curves and DCA indicated the LS model had better performance than traditional clinical scores. CONCLUSION: A novel machine learning model outperforms previously known clinical risk scores in assessing the prognosis of cirrhotic patients with AVB CLINICAL RELEVANCE STATEMENT: The Liver-Spleen model based on contrast-enhanced CT has proven to be a promising tool to predict the prognosis of cirrhotic patients with acute variceal bleeding, which can facilitate decision-making and personalized therapy in clinical practice. KEY POINTS: • The Liver-Spleen machine learning model (LS model) showed good performance in assessing the clinical composite endpoint of cirrhotic patients with AVB (AUC ≥ 0.782, sensitivity ≥ 80%). • The LS model outperformed the clinical scores (AUC ≤ 0.730, sensitivity ≤ 70%) in both internal and external test cohorts.

Urokinase-based lock solutions for catheter salvage: A case of an upcoming kidney transplant recipient.

Catheter-related bloodstream infection (CRBSI) is a significant complication among patients on haemodialysis (HD) who are dependent on a central venous catheter (CVC) for an extended period. Catheter removal as first-line treatment can induce accelerated venous access site depletion in patients on HD who rely on it to survive. It is possible to retain the catheter in stable patients without septic syndrome while administering systemic antibiotics and antibiotic lock therapy. Herein, we report the case of a patient on HD with CRBSI who was successfully treated with intravenous levofloxacin- and urokinase-based antibiotic lock, without catheter removal prior to kidney transplantation. The use of urokinase in combination with antibiotics in lock solutions for treating catheter infections is rare. We verified the physical compatibility of levofloxacin and urokinase by visual inspection, turbidimetric measurements, and particle count. To our knowledge, this was a rare case demonstrating the effective use of urokinase and levofloxacin in a catheter lock for CRBSI in a patient on HD. Considering the need for highly concentrated antimicrobials and the availability of various antibiotics, the compatibility and stability of the lock solution is a matter of concern. Further studies are warranted to assess the stability and compatibility of various antibiotics in combination with urokinase.

Potassium channels, tumorigenesis and targeted drugs.

Potassium channels play an important role in human physiological function. Recently, various molecular mechanisms have implicated abnormal functioning of potassium channels in the proliferation, migration, invasion, apoptosis, and cancer stem cell phenotype formation. Potassium channels also mediate the association of tumor cells with the tumor microenvironment. Meanwhile, potassium channels are important targets for cancer chemotherapy. A variety of drugs exert anti-cancer effects by modulating potassium channels in tumor cells. Therefore, there is a need to understand how potassium channels participate in tumor development and progression, which could reveal new, novel targets for cancer diagnosis and treatment. This review summarizes the roles of voltage-gated potassium channels, calcium-activated potassium channels, inwardly rectifying potassium channels, and two-pore domain potassium channels in tumorigenesis and the underlying mechanism of potassium channel-targeted drugs. Therefore, the study lays the foundation for rational and effective drug design and individualized clinical therapeutics.

Survival Nomogram for Patients With Locally Advanced Breast Cancer Undergoing Immediate Breast Reconstruction: A SEER Population-Based Study.

INTRODUCTION/BACKGROUND: This study aimed to construct a nomogram to provide prognostic references for patients with locally advanced breast cancer (LABC) to receive immediate breast reconstruction (IBR). MATERIALS AND METHODS: All data were obtained from the Surveillance, Epidemiology and End Results (SEER) database. Univariate Cox regression, least absolute shrinkage and selection operator (LASSO) and best subset regression (BSR), separately followed by backward stepwise multivariable Cox, were used to construct the nomogram. Risk stratification was established after validation. RESULTS: A total of 6,285 patients were enrolled to generate the training group (n = 3,466) and the test group (n = 2,819) by geographical split. Age, marital status, grade, T staging, N staging, radiotherapy, chemotherapy, estrogen receptor status (ER), progesterone receptor status (PR) and human epidermal growth factor receptor type 2 status (HER2) were used to fit the nomogram. The overall Harrell's concordance index (C-index) was 0.772 in the training group and 0.762 in the test group. The area under the receiver operator characteristic curves (AUC) at 3-year and 5-year were respectively 0.824 and 0.720 in the training group, 0.792 and 0.733 in the test group. The calibration curves showed great consistency in both groups. A dynamic nomogram (https://dcpanfromsh.shinyapps.io/NomforLABCafterIBR/) was developed. CONCLUSION: A nomogram was developed and validated that predicts prognosis more accurately than the AJCC 7th stage and can be used as a reference for decision-making in LABC patients receiving IBR.

Endothelial cell-derived MMP19 promotes pulmonary fibrosis by inducing E(nd)MT and monocyte infiltration.

BACKGROUND: Matrix metalloproteinases (MMPs) play important roles in remodeling the extracellular matrix and in the pathogenesis of idiopathic pulmonary fibrosis (IPF). MMP19, which is an MMP, was significantly upregulated in hyperplastic alveolar epithelial cells in IPF lung tissues and promoted epithelial-mesenchymal transition (EMT). Recent studies have demonstrated that endothelial-to-mesenchymal transition (E(nd)MT) contributes to pulmonary fibrosis. However, the role of MMP19 in pulmonary vascular injury and repair and E(nd)MT remains unclear. METHODS: To determine the role of MMP19 in E(nd)MT and pulmonary fibrosis. MMP19 expressions were determined in the lung endothelial cells of IPF patients and bleomycin (BLM)-induced mice. The roles of MMP19 in E(nd)MT and endothelial barrier permeability were studied in the MMP19 cDNA-transfected primary human pulmonary microvascular endothelial cells (HPMECs) and MMP19 adenoassociated virus (MMP19-AAV)-infected mice. The regulatory mechanism of MMP19 in pulmonary fibrosis was elucidated by blocking its interacting proteins SDF1 and ET1 with AMD3100 and Bosentan, respectively. RESULTS: In this study, we found that MMP19 expression was significantly increased in the lung endothelial cells of IPF patients and BLM-induced mice compared to the control groups. MMP19 promoted E(nd)MT and the migration and permeability of HPMECs in vitro, stimulated monocyte infiltration into the alveolus, and aggravated BLM-induced pulmonary fibrosis in vivo. SDF1 and Endothelin-1 (ET1) were physically associated with MMP19 in HPMECs and colocalized with MMP19 in endothelial cells in IPF patient lung tissues. AMD3100 and bosentan alleviated the fibrosis induced by MMP19 in the BLM mouse model. CONCLUSION: MMP19 promoted E(nd)MT by interacting with ET1 and stimulated monocyte infiltration into lung tissues via the SDF1/CXCR4 axis, thus aggravating BLM-induced pulmonary fibrosis. Vascular integrity regulated by MMP19 could be a promising therapeutic target for suppressing pulmonary fibrosis. Video abstract.

Gap junction is essential for the antidepressant effects of fluoxetine.

OBJECTIVES: Fluoxetine has been used as the first line for the therapy of depression. However, lack of therapeutic efficacy and time lag still limit the application of fluoxetine. Gap junction dysfunction is a potentially novel pathogenic mechanism for depression. To clarify the mechanism underlying these limitations, we investigated whether gap junction was related to the antidepressant effects of fluoxetine. METHODS AND KEY FINDINGS: After chronic unpredictable stress (CUS), animals showed decreases in gap junction intracellular communication (GJIC). Treatment with fluoxetine 10 mg/kg significantly improved GJIC and anhedonia of rats until six days. These results indicated that fluoxetine improved gap junction indirectly. Furthermore, to test the role of gap junction on antidepressant effects of fluoxetine, we blocked gap junction using carbenoxolone (CBX) infusion in the prefrontal cortex. CBX dampened fluoxetine-induced decrease in immobility time of mice in tail suspension test (TST). CONCLUSIONS: Our study suggested that gap junction dysfunction blocks antidepressant effects of fluoxetine, contributing to understanding the mechanism underlying the time lag of fluoxetine.