Combined single cell and spatial transcriptome analysis reveals cellular heterogeneity of hedgehog pathway in gastric cancer.

Gastric cancer (GC) is one of the most common and deadly malignancies in the world. Abnormal activation of hedgehog pathway is closely related to tumor development and progression. However, potential therapeutic targets for GC based on the hedgehog pathway have not been clearly identified. In the present study, we combined single-cell sequencing data and spatial transcriptomics to deeply investigate the role of hedgehog pathway in GC. Based on a comprehensive scoring algorithm, we found that fibroblasts from GC tumor tissues were characterized by a highly enriched hedgehog pathway. By analyzing the development process of fibroblasts, we found that CCND1 plays an important role at the end stage of fibroblast development, which may be related to the formation of tumor-associated fibroblasts. Based on spatial transcriptome data, we deeply mined the role of CCND1 in fibroblasts. We found that CCND1-negative and -positive fibroblasts have distinct characteristics. Based on bulk transcriptome data, we verified that highly infiltrating CCND1 + fibroblasts are a risk factor for GC patients and can influence the immune and chemotherapeutic efficacy of GC patients. Our study provides unique insights into GC and hedgehog pathways and also new directions for cancer treatment strategies.

Reconstructing Electrically Conductive Nanofiltration Membranes with an Aniline-Functionalized Carbon Nanotubes Interlayer for Highly Effective Toxic Organic Treatment.

Conductive nanofiltration (CNF) membranes hold great promise for removing small organic pollutants from water through enhanced Donnan exclusion and electrocatalytic degradation. However, current CNF membranes face limitations in conductivity, structural stability, and nanochannel control strategies. This work addresses these challenges by introducing aniline-functionalized carbon nanotubes (NH2-CNTs) as an interlayer. NH2-CNTs enhance the dispersibility and adhesion of pristine carbon nanotubes, leading to a more conductive and stable composite nanofiltration membrane. The redesigned NH2-CNTs interlayered conductive nanofiltration (NICNF) membrane exhibits a 10-fold increase in conductivity and a high response degree (80%) with excellent cyclic stability, surpassing existing CNF membranes. The synergistic effects of enhanced Donnan exclusion, voltage switching, and electrocatalysis enable the NICNF membrane to achieve selective recovery of mixed dyes, 98.97% removal of residual wastewater toxicity, and a 5.2-fold increase in permeance compared to the commercial NF270 membrane. This research paves the way for next-generation multifunctional membranes capable of the efficient recovery and degradation of toxic organic pollutants in wastewater.

Initial indicators for the prognosis of Acinetobacter Baumannii bacteremia in children.

BACKGROUND: Risk factors related to mortality due to Acinetobacter baumannii (AB) bacteremia have been unveiled previously, but early clinical manifestations of AB bacteremia based on prognosis remain uncovered. METHODS: The demographic characteristics, clinical features, antibiotic susceptibility, and outcomes of 37 hospitalized children with laboratory-confirmed AB bacteremia from Suzhou, China, were collected and analyzed retrospectively. RESULTS: Of the 37 children with AB bacteremia included in this study, 23 were males and 14 were females, with a median age of 4.83 (0.60 to 10.15) years. Among the children, 18 died (48.65%, 18/37) and 19 survived (51.35%, 19/37). The dead group had a significantly higher incidence of respiratory failure (p = 0.008), shock (P = 0.000), MODS (p = 0.000), neutropenia (< 1.5 × 109/L) (p = 0.000) and serious neutropenia (< 0.5 × 109/L) (p = 0.000) than those in the survival group. The death group had significantly more invasive procedures (2 or more) than that in the survival group at 2 weeks before onset (p = 0.005). The proportion of MDR-AB in the death group was significantly higher than that in the survival group (p = 0.000), while the PICS score was significantly lower in the survival group than that in the death group (p = 0.000). There was no significant difference in effective antibiotic use within 24 h between these two groups (p = 0.295). Among the 37 children with bloodstream infection of AB, 56.76% (21/37) of the underlying diseases were hematological diseases and oncology. Among them, 17 (81.00%) were died in the hospital. The proportion of white blood cells (p = 0.000), neutrophils (p = 0.042), eosinophils (p = 0.029), the ANC (p = 0.000) and lymphocyte (p = 0.000), the NLR(p = 0.011), hemoglobin (p = 0.001), platelets (p = 0.000), prealbumin (P = 0.000), LDH (p = 0.017), blood gas pH (p = 0.000), and serum potassium (p = 0.002) in the death group were significantly lower than those in the survival group. However, CRP (p = 0.000) and blood glucose(p = 0.036) were significantly higher in the death group than those in the survival group. By further multivariate analysis, CRP [OR (95% CI): 1.022(1.003, 1.041), p = 0.021] and neutropenia [OR (95% CI): 21.634 (2.05, 228.313, p = 0.011] within 24 h of infection were independent risk factors for death in children with AB bacteremia. When CRP was higher than 59.02 mg/L, the sensitivity of predicting mortality was 88.9%, and the specificity was 78.9%. And the sensitivity and specificity of neutropenia for predicting mortality were 83.3% and 84.2%. CONCLUSIONS: AB bacteremia has a high mortality in children, especially in patients with hematological diseases and oncology. Many early indicators were associated with poor prognosis, while elevated CRP and neutropenia were the independent predictors for the 30-day mortality of children with laboratory-confirmed AB bacteremia.

Multiscale and local engineering of speckle morphology through disordered media.

In this Letter, we prompt a novel, to the best of our knowledge, method based on transmission matrix decomposition with wavelets to engineer the speckle morphology behind disordered media. By analyzing the speckles in multiscale spaces, we experimentally realized multiscale and localized control on the speckle size, position-dependent spatial frequency, and global morphology by operating on the decomposition coefficients using different masks. Speckles with contrasting features in different parts of the fields can be generated in one step. Our experimental results demonstrate a high degree of flexibility in manipulating light in a customizable manner. This technique has stimulating prospects in correlation control and imaging under scattering conditions.

BVES-AS1 inhibits the malignant behaviors of colon adenocarcinoma cells via regulating BVES.

The underexpression of the long noncoding RNA blood vessel epicardial substance antisense RNA 1 (BVES-AS1) has been shown in colon adenocarcinoma (COAD) patients. However, its role in COAD remains to be explored. This study aimed to investigate the function and potential mechanism of BVES-AS1 in COAD. Colony formation, Cell Counting Kit-8, JC-1 mitochondrial membrane potential assay, wound healing, transwell, and western blot analyses were used to measure cell proliferation, apoptosis, migration, invasion, and epithelial-mesenchymal transition (EMT) in COAD cells. RNA pull-down, luciferase reporter, and RNA binding protein immunoprecipitation assays were used to detect the interaction of BVES-AS1 and downstream genes. BVES-AS1 was expressed at low levels in COAD cells. Overexpressed BVES-AS1 inhibited COAD cell proliferation, migration, invasion, and EMT while elevating cell apoptosis. Mechanistically, BVES-AS1 functioned as a competing endogenous RNA sponging miR-522-3p to regulate the expression of nearby gene blood vessel epicardial substance (BVES). Besides this, BVES-AS1 recruited TATA-box binding protein associated factor 15 (TAF15) to promote BVES messenger RNA stability. Taken together, our study confirmed that BVES-AS1 inhibited COAD progression via interacting with miR-522-3p and TAF15 to regulate BVES expression, which might offer a perspective for COAD treatment.

Clinical characteristics of neonatal and infant osteomyelitis and septic arthritis: a multicenter retrospective study.

OBJECTIVE: Signs and symptoms of osteomyelitis or septic arthritis in neonates and infants are often nonspecific and early-stage bone infections in infants may often go unnoticed. The objective of this study was to analyze the clinical characteristics of newborns and infants with osteomyelitis and septic arthritis to improve understanding of the disorder and to assist clinicians with diagnosis. METHODS: A retrospective multicenter study was conducted on neonates (0-28 days old, n = 94) and infants (1-12 months old, n = 415) with osteoarticular infections. Data consisting of clinical characteristics, complications, laboratory outcomes, and the pathogenic microorganisms causing osteomyelitis were tabulated. The statistics were further broken down into two regions and the significant differences between neonates and infants were evaluated and compared to the literature. RESULTS: Compared to infants, neonates had significantly lower incidences of fever (p < 0.0001), higher incidences of localized swelling (p = 0.0021), higher rate of infection at the humerus (p = 0.0016), higher percentage of Escherichia coli (p < 0.0001) and Klebsiella pneumoniae (p = 0.0039) infections, lower percentage of Staphylococcus aureus infections (p < 0.0001) and were more likely to develop septic arthritis (p < 0.0001). CONCLUSION: Distinct differences were found between neonatal and infants with osteoarticular infections. Future studies should focus on improving diagnosis and subsequent treatment regimens for younger age groups.

Microporous membrane with ionized sub-nanochannels enabling highly selective monovalent and divalent anion separation.

Membranes tailored for selective ion transport represent a promising avenue toward enhancing sustainability across various fields including water treatment, resource recovery, and energy conversion and storage. While nanochannels formed by polymers of intrinsic microporosity (PIM) offer a compelling solution with their uniform and durable nanometer-sized pores, their effectiveness is hindered by limited interactions between ions and nanochannel. Herein, we introduce the randomly twisted V-shaped structure of Tröger's Base unit and quaternary ammonium groups to construct ionized sub-nanochannel with a window size of 5.89-6.54 Å between anion hydration and Stokes diameter, which enhanced the dehydrated monovalent ion transport. Combining the size sieving and electrostatic interaction effects, sub-nanochannel membranes achieved exceptional ion selectivity of 106 for Cl-/CO32- and 82 for Cl-/SO42-, significantly surpassing the state-of-the-art membranes. This work provides an efficient template for creating functionalized sub-nanometer channels in PIM membranes, and paves the way for the development of precise ion separation applications.

LaenNet: Learning robust GCNs by propagating labels.

Graph Convolutional Networks (GCNs) can be acknowledged as one of the most significant methodologies for graph representation learning, and the family of GCNs has recently achieved great success in the community. However, in real-world scenarios, the graph data may be imperfect, e.g., with noisy and sparse features or labels, which poses a great challenge to the robustness of GCNs. To meet this challenge, we propose a simple-yet-effective LAbel-ENhanced Networks (LaenNet) architecture for GCNs, where the basic spirit is to propagate labels together with features. Specifically, we add an extra LaenNet module at one hidden layer of GCNs, which propagates labels along the graph and then integrates them with the hidden representations as the inputs to the deeper layer. The proposed LaenNet can be directly generalized to the variants of GCNs. We conduct extensive experiments to verify LaenNet on semi-supervised node classification tasks under four noisy and sparse graph data scenarios, including the graphs with noisy features, sparse features, noisy labels, and sparse labels. Empirical results indicate the superiority and robustness of LaenNet compared to the state-of-the-art baseline models. The implementation code is available to ease reproducibility1.

ShuffleTrans: Patch-wise weight shuffle for transparent object segmentation.

Transparent objects widely exist in the world. The task of transparent object segmentation is challenging as the object lacks its own texture. The cue of shape information therefore gets more critical. Most existing methods, however, rely on the mechanism of simple convolution, which is good at local cues and performs weakly on global cues like shape. To solve this problem, an operation named Patch-wise Weight Shuffle is proposed to bring in the global context cue by being combined with the dynamic convolution. A network ShuffleTrans that recognizes shape better is then designed based on this operation. Besides, fitter for this task, two auxiliary modules are presented in ShuffleTrans: a Boundary and Direction Refinement Module which collects two additional information, and a Channel Attention Enhancement Module that assists the above operation. Experiments on four texture-less object segmentation datasets and two normal datasets verify the effectiveness and generality of the method. Especially, the ShuffleTrans achieved 74.93% mIoU on the Trans10k v2 test set, which is more accurate than existing methods.

Propensity Score Analysis of Outcomes Following Laparoscopic or Open Radical Resection for Gallbladder Cancer in T2 and T3 Stages.

BACKGROUND: Although laparoscopic radical resection (LRR) has long been contraindicated in gallbladder cancer (GBC), recent studies have demonstrated laparoscopic surgery did not adversely affect the perioperative and survival outcomes of GBC patients. However, these literatures are mainly focused on GBC of relatively early stages or incidental GBC. This study aimed to investigate the perioperative and long-term outcomes of LRR versus open radical resection (ORR) for GBCs in T2 and T3 stages. METHODS: A retrospective study was conducted on 99 patients with GBC of T2 and T3 stages who underwent radical resection at Zhejiang Provincial People's Hospital from January 2010 to December 2020. A 1:1 propensity score matching (PSM), which is widely used to reduce selection bias, was performed to compare the surgical outcomes and long-term prognosis between LRR and ORR. A logistic regression analysis was implemented to identify the predictive risk factors of postoperative overall survival. RESULTS: By using PSM, the baseline characteristics of two groups (with 30 patients in each group) were generally well balanced. In the LRR group, the length of operation was significantly longer than the ORR group, but the intraoperative bleeding and postoperative days of hospital stay were significantly decreased compared to the ORR group. The two groups showed comparable outcomes regarding the incidence of biliary reconstruction, lymph node yield, the incidence of postoperative morbidities, the incidence of Clavien-Dindo (C-D) grades III-IV, the days of drainage tubes indwelling, mortality at 30 postoperative days and 90 postoperative days, and the incidence of port-site metastasis. The 1-, 2-, and 3-year overall survival rates were 61.2, 40.1, and 30.1%, respectively, in the LRR group, and 53.3, 40.1, and 40.1%, respectively, in the OLR group (P = 0.644). On multivariate analysis, T stage, vascular invasion, and tumor differentiation were found to be the independent risk factors for overall survival of GBC in T2 and T3 stages. CONCLUSIONS: For GBC in T2 and T3 stages, LRR can achieve comparable perioperative outcomes and similar long-term survival benefit compared to ORR. LRR tends to show advantages over ORR regarding intraoperative bleeding and postoperative days of hospital stay.

Investigating the association between P wave duration and atrial fibrillation recurrence after radiofrequency ablation in early persistent atrial fibrillation patients.

BACKGROUND: In the present study, we aimed to explore the association between P wave duration, as the measured time from the start point of the P wave to the end point, and atrial fibrillation recurrence after transcatheter radiofrequency ablation in patients with early persistent atrial fibrillation. METHODS: Patients with early persistent atrial fibrillation who underwent the first radiofrequency ablation procedure were retrospectively analyzed. The electrocardiographic, echocardiographic and clinical data of the enrolled patients before and after operation were collected and recorded. After adjusting confounding factors and performing stratified analysis, the association between the P wave duration and the atrial fibrillation recurrence of patients with early persistent atrial fibrillation after radiofrequency ablation was explored. RESULTS: The proportions of atrial fibrillation recurrence of the low, medium, and high P wave duration groups were 6.4%, 19.7%, and 47.0%, respectively. After potential confounding factors were adjusted, the risk of atrial fibrillation recurrence gradually increased with the increase of P wave duration (odds ratio: 1.093, 95% confidence interval: 1.063-1.124, p < 0.001). This trend was statistically significant (odds ratio: 1.099, 95% confidence interval: 1.052-1.149, p < 0.001), especially in comparison of high vs. low (odds ratio: 16.99, 95% confidence interval: 4.75-60.78, p < 0.001). Curve fitting showed that there was a linear and positive association between the P wave duration and the risk of atrial fibrillation recurrence. This association was consistent in different subgroups based on gender, drinking, history of smoking, hypertension, diabetes mellitus, peripheral artery disease, stroke or transient ischemia attack, hyperlipidemia, heart failure, and heart rate, suggesting that there was no significant interaction between different grouping parameters and the association (p for interaction range = 0.217-0.965). CONCLUSIONS: In patients with early persistent atrial fibrillation who underwent radiofrequency ablation procedure for the first time and converted to sinus rhythm, the P wave duration within 72 h after the procedure was independently associated with the risk of atrial fibrillation recurrence, and such association was linear and positive.

Removing miscellaneous heavy metals by all-in-one ion exchange-nanofiltration membrane.

The composition of wastewater containing heavy metal mixtures is often complex and poses a serious threat to human and environmental health. Effective removal of a variety of heavy metal ions with a single technology is challenging, and the conventional split integrated technologies require multi-step processing and a massive footprint. For the first time, we achieve hierarchically integrating ion exchange and nanofiltration into all-in-one "iNF" membranes. The iNF membrane has a hierarchical structure with an interfacial polymerization layer and an ion exchange layer, which can achieve highly efficient indiscriminate heavy metal ion removal, overcoming the defect that traditional nanofiltration membranes can only remove single metal cations or oxyanions. The ion exchange layer can remove heavy metal ions through sulfonic acid groups and quaternary amine groups. In addition, the ion exchange layer can be regenerated by electro-deionization, which is meaningful for sustainable membrane usage. This facile, scalable, and compact integrated process shows outstanding potential and universal applicability in complex wastewater treatment.

MRI recovery of the Achilles tendon after percutaneous tenotomy in older children.

BACKGROUND: An observational study was conducted to evaluate the recovery of older children with relapsed congenital clubfoot who underwent an Achilles tenotomy for the second time as part of the Ponseti treatment. METHODS: Thirteen patients (19 feet) with congenital clubfoot underwent Achilles tenotomy where magnetic resonance images of the severed tendons were taken after 1, 3, and 6 weeks post-procedure. The participants were categorized into older children who underwent tenotomy for the first time (group A: mean, 4.9±1.8, and range, 2.8-7 years old) and older children who underwent tenotomy for a second time (group B: mean, 4.9±1.5, and range, 3-6.8 years old). The area of high signal intensity between the severed tendons on MRI scans was computed using Python programming language and compared with clinical assessment. RESULTS: Three weeks after Achilles tenotomy, groups A and B had clinically intact tendons in 9 out of 11 and 2 out of 8 feet, respectively, according to both clinical and MRI assessment. From week 1 to week 3 post-tenotomy, computational analysis showed that the mean high signal intensity area of group A decreased by 88.5±15.2%, which was significantly different (P .048 < .05) than the percent reduction of high signal intensity area of group B (69.0±24.9%). CONCLUSION: Children who underwent Achilles tenotomy for the second time showed slower tendon recovery on the third week post-procedure. A possible reason for slower healing times may be due to the location of tenotomy in being further away from the musculotendinous junction where extrinsic healing mechanisms take place.

An echocardiographic model for predicting the recurrence of paroxysmal atrial fibrillation after circumferential pulmonary vein ablation.

BACKGROUND: Atrial fibrillation (AF) is a highly prevalent arrhythmia, with substantial associated morbidity and mortality. Circumferential pulmonary vein ablation (CPVA) is an effective rhythm control strategy, however, recurrence is an important factor influencing treatment decisions. HYPOTHESIS: To develop a predictive model based on left atrial (LA) structure and function, and evaluate its efficiency in predicting the recurrence of AF after CPVA. METHODS: Patients with paroxysmal AF who underwent CPVA were enrolled in this study and randomly divided into a development set and a validation set. The clinical and echocardiographic data of each patient were collected. In the development set, a least absolute shrinkage and selection operator (LASSO) regression was used to establish a LA ultrasound feature. By combining that LA ultrasound feature with independent clinical risk factors, we established an echocardiographic model using multivariate logistic regression and plotted the corresponding nomogram. RESULTS: The LA ultrasound feature established by LASSO regression included nine echocardiographic indicators related to LA structure and function. It also exhibited good predictive ability in both the development set and the validation set (AUC:0.944, 95%CI: 0.910-0.978; AUC:0.878, 95%CI: 0.816-0.942). Logistic regression analysis indicated that LA ultrasound feature and AF duration were independent predictors for AF recurrence. The combined model including LA ultrasound feature and AF duration also showed good discriminability in both the development set (AUC: 0.950, 95% CI:0.914-0.985) and the validation set (AUC: 0.890, 95% CI: 0.831-0.949). The calibration curve showed good agreement between the predicted value and observed value. CONCLUSIONS: Our model that is based on LA structure and function measured by echocardiography is a useful non-invasive preoperative tool, which exhibits good accuracy in predicting the recurrence of AF after CPVA.

Metabolomic Approach for Characterization of Polyphenolic Compounds in Laminaria japonica, Undaria pinnatifida, Sargassum fusiforme and Ascophyllum nodosum.

Profiling of polyphenolics in four types of brown macroalgae, namely Laminaria japonica (L. japonica), Undaria pinnatifida (U. pinnatifida), Sargassum fusiforme (S. fusiforme), and Ascophyllum nodosum (A. nodosum), and their effect on oxidation resistance were investigated for the first time. Polyphenolic extracts from marine brown macroalgae were shown to effectively remove oxidants from cells and cellular systems. A. nodosum showed the highest antioxidant activity among evaluated brown macroalgae, showing a better scavenging effect on 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical and alleviating oxidative damage caused by hydrogen peroxide to human keratinocytes (HaCaT) cells. Through Q-Exactive HF-X mass spectrometry analysis, 12 polyphenolic compounds were preliminarily identified, including phlorotannins, phenolic acids, and flavonoids. Significant differences in content and variety of polyphenolics were found in evaluated brown macroalgae, which could be related to differences in antioxidant activity in vivo and in vitro. Moreover, the antioxidant activity might be related to the total phenolic content and the types of polyphenolics, especially phlorotannins. The findings presented in this study indicate that A. nodosum could be used as an important substitute for functional ingredients in foods and pharmaceutical preparations, as well as a raw material for phlorotannins research.

Metabotropic Glutamate Receptor 8 Is Regulated by miR-33a-5p and Functions as an Oncogene in Breast Cancer.

It has been reported that glutamate metabotropic receptor 8 (GRM8) is closely implicated in the progression of human neuroblastoma, lung cancer, and glioma, but its role in breast cancer remains unknown. Thus, the present study was performed to uncover it. Immunohistochemistry, real-time PCR (RT-PCR), and western blotting experiments were performed to test GRM8 expression levels in tissues and cells. Cell functions were assessed by Cell Count Kit 8 (CCK-8), flow cytometry, wound healing, transwell chambers, and in vivo xenotransplantation experiments. The relationship between miR-33a-5p and GRM8 was evaluated by luciferase gene reporter and western blotting assay. The results showed that GRM8 expression was increased in breast cancer tissues and cells, which was closely associated with lower overall survival rate. Ectopic expression of GRM8 significantly enhanced cell growth, migration, and invasion and tumorigenesis and repressed cell apoptosis. In addition, GRM8 was under the negative regulation of miR-33a-5p, which was downregulated in breast cancer tissues and served as a tumor suppressor. Moreover, overexpression of GRM8 abrogated the inhibitive role of miR-33a-5p played in breast cancer. Collectively, this study reveals that GRM8 functions as an oncogene in breast cancer and is regulated by miR-33a-5p.

Symptom Clusters and Influencing Factors in Children With Acute Leukemia During Chemotherapy.

BACKGROUND: Acute leukemia is the most common malignancy in childhood. Identification of symptom clusters and their influencing factors in children with acute leukemia may improve the management of symptoms. OBJECTIVE: The aims of this study were to investigate symptom clusters in children with acute leukemia during chemotherapy and analyze the factors influencing their severity. METHODS: A cross-sectional survey was administered to 159 Chinese children with acute leukemia during chemotherapy. A demographic questionnaire and the Memorial Symptom Assessment Scale 10-18 were completed by the patients and their parents. Exploratory factor analysis was used to identify symptom clusters. Univariate analyses and multiple linear regression analyses were performed to analyze the factors affecting symptom clusters. RESULTS: Six clusters were identified, including gastrointestinal cluster, emotional cluster, head-related cluster, self-image disorder cluster, skin itching/irritation cluster, and somatic cluster. Factors influencing the severity of symptom clusters included age, gender, stage of chemotherapy, and medical reimbursement. CONCLUSIONS: There are multiple symptom clusters in children with acute leukemia during chemotherapy. Medical care staff should manage symptoms from the perspective of symptom cluster and carry out personalized interventions according to factors influencing these clusters. IMPLICATIONS FOR PRACTICE: The ability to predict symptom clusters in children with acute leukemia undergoing chemotherapy may assist with optimal clinical decision making in order to alleviate the symptom burden and improve children's quality of life.

Atypical features and de novo heterozygous mutations in two siblings with Cockayne syndrome.

BACKGROUND: Cockayne syndrome (CS) is a rare autosomal recessive disorder which displays multiorgan dysfunction, especially within the nervous system including psychomotor retardation, cerebral atrophy, microcephaly, cognitive dysfunction, mental retardation, and seizures. Many genetic variations reported were related to this syndrome, but splicing mutations with cardiac anomalies have not been found in previous studies. METHODS: Herein, we described a pair of brothers and sisters who present essential manifestations of CS including premature feature, developmental delay, growth failure, microcephaly, and characteristic facial features, such as sunken eyes and a beaked nose. Interestingly, the brother also presented with atypical features which included cardiac anomalies such as left atrioventricular enlargement and cardiac dysfunction such as dilated cardiomyopathy. In addition, whole exome sequencing and RNA sequencing were employed to analyze their genetic landscape. RESULTS: WES analysis showed that these two cases carried double unreported heterozygous spliced mutations in the excision repair cross-complementing group 8 (ERCC8, also known as CSA, NM_000082) gene, which were c.78-2 (IVS1) A>T and c.1042-1 (IVS10) G>A, respectively. Moreover, transcript sequencing analysis validated these mutation sites. In this study, Gene Ontology enrichment and KEGG pathway analyses from RNA sequencing demonstrated similarities but some differences when compared with previous studies. CONCLUSION: For patients with Cockayne syndrome, cardiac changes need to be monitored carefully, especially for cases with splicing mutations of the ERCC8 gene.

RNAi targeting urokinase-type plasminogen activator receptor inhibits metastasis and progression of oral squamous cell carcinoma in vivo.

It has been admitted that urokinase-type plasminogen activator receptor (u-PAR) is overexpressed in many human malignant tumors including oral squamous cell carcinoma (OSCC) and plays an important role in a variety of cancer key cellular events as a versatile signaling orchestrator. In our study, a retroviral vector expressing u-PAR-specific siRNA was injected into OSCC xenografts of nude mice to observe its inhibitory effects on OSCC. Our data demonstrate that siRNA targeting u-PAR markedly suppressed tumor growth, reduced the expression of proliferation-related gene, Ki-67 and increased cell apoptosis, accompanying with the efficient and specific inhibition of endogenous u-PAR expression in OSCC. More importantly, the mRNA and protein expression of MMP-2, MMP-9, VEGF-C, VEGF-D and VEGFR-3 that are intimately involved in oral cancer invasion and metastasis, was simultaneously downregulated significantly as determined by quantitative real-time RT-PCR, Western blot and immunohistochemistry; and Gelatin and fibrin zymography showed that MMP-9, MMP-2 and u-PA enzymatic activities were significantly reduced in u-PAR-specific siRNA group, compared to those in control groups. In addition, the expression of MDR-1 gene related to drug resistance was obviously inhibited by silencing of u-PAR. These findings suggest that RNAi targeting u-PAR could effectively inhibit the metastasis and progression of OSCC in vivo. Thus, it may be used as a potent and specific therapy for oral cancer, especially in inhibiting and preventing cancer cell invasion and metastasis.

PRR11 and SKA2 gene pair is overexpressed and regulated by p53 in breast cancer.

Our previous study found that two novel cancer-related genes, PRR11 and SKA2, constituted a classic gene pair that was regulated by p53 and NF-Y in lung cancer. However, their role and regulatory mechanism in breast cancer remain elusive. In this study, we found that the expression levels of PRR11 and SKA2 were upregulated and have a negative prognotic value in breast cancer. Loss-of-function experiments showed that RNAi-mediated knockdown of PRR11 and/or SKA2 inhibited proliferation, migration, and invasion of breast cancer cells. Mechanistic experiments revealed that knockdown of PRR11 and/or SKA2 caused dysregulation of several downstream genes, including CDK6, TPM3, and USP12, etc. Luciferase reporter assays demonstrated that wild type p53 significantly repressed the PRR11-SKA2 bidirectional promoter activity, but not NF-Y. Interestingly, NF-Y was only essential for and correlated with the expression of PRR11, but not SKA2. Consistently, adriamycin-induced (ADR) activation of endogenous p53 also caused significant repression of the PRR11 and SKA2 gene pair expression. Notably, breast cancer patients with lower expression levels of either PRR11 or SKA2, along with wild type p53, exhibited better disease-free survival compared to others with p53 mutations and/or higher expression levels of either PRR11 or SKA2. Collectively, our study indicates that the PRR11 and SKA2 transcription unit might be an oncogenic contributor and might serve as a novel diagnostic and therapeutic target in breast cancer. [BMB Reports 2019; 52(2): 157-162].