Modular Edge Analysis Reveals Chemotherapy-induced Brain Network Changes in Lung Cancer Patients.

BACKGROUND: Lung cancer patients with post-chemotherapy may have disconnected or weakened function connections within brain networks. OBJECTIVE: This study aimed to explore the abnormality of brain functional networks in lung cancer patients with post-chemotherapy by modular edge analysis. METHODS: Resting-state functional magnetic resonance imaging (rs-fMRI) scans were performed on 40 patients after chemotherapy, 40 patients before chemotherapy and 40 normal controls. Patients in all three groups were age and sex well-matched. Then, modular edge analysis was applied to assess brain functional network alterations. RESULTS: Post-chemotherapy patients had the worst MoCA scores among the three groups (p < 0.001). In intra-modular connections, compared with normal controls, the patients after chemotherapy had decreased connection strengths in the occipital lobe module (p < 0.05). Compared with the nonchemotherapy group, the patients after chemotherapy had decreased connection strengths in the subcortical module (p < 0.05). In inter-modular connections, compared with normal controls, the patients after chemotherapy had decreased connection strength in the frontal-temporal lobe modules (p < 0.05). Compared with the non-chemotherapy group, the patients after chemotherapy had decreased connection strength in the subcortical-temporal lobe modules (p < 0.05). CONCLUSION: The results reveal that chemotherapy can disrupt connections in brain functional networks. As far as we know, the use of modular edge analysis to report changes in brain functional brain networks associated with chemotherapy was rarely reported. Modular edge analysis may play a crucial part in predicting the clinical outcome for the patients after chemotherapy.

Humanized mouse models for inherited thrombocytopenia studies.

Inherited thrombocytopenia (IT) is a group of hereditary disorders characterized by a reduced platelet count as the main clinical manifestation, and often with abnormal platelet function, which can subsequently lead to impaired hemostasis. In the past decades, humanized mouse models (HMMs), that are mice engrafted with human cells or genes, have been widely used in different research areas including immunology, oncology, and virology. With advances of the development of immunodeficient mice, the engraftment, and reconstitution of functional human platelets in HMM permit studies of occurrence and development of platelet disorders including IT and treatment strategies. This article mainly reviews the development of humanized mice models, the construction methods, research status, and problems of using humanized mice for the in vivo study of human thrombopoiesis.

Humanized mouse models (HMMs) refer to immunodeficient mice that have been used for the investigation of human hematopoiesis and immunity for years. With engrafted human hematopoietic stem cells (HSCs), the differentiation process of HSCs and re-construction of platelets can be monitored in the mice. Until now, several strains of HMMs have been used in the studies of inherited thrombocytopenia (IT), a genetic disorder associated with low platelet count in the blood. In this study, we reviewed the development of these HMMs in IT studies, compared the different sources of HSCs transplanted into HMMs and summarize the strategies of HSC transplantation in HMMs. The Kit^−/− immunodeficient mice showed effectively long-term and stable implantation of human HSC without irradiation and higher implantation levels, and they also support multilinear differentiation of human HSC, such as platelets and red blood cells. The source and count of HSCs and the transplantation strategy may also impact the result. This study provides a basis information for HMMs used in IT and will help other investigators in this field choosing the right research plan.

SKA2-mediated transcriptional downregulation of the key enzyme of CoQ10 biosynthesis PDSS2 in lung cancer cells.

Lung cancer is the leading cause of cancer-associated mortality worldwide. SKA2 is a novel cancer-associated gene that plays critical roles in both cell cycle and tumorigenesis including lung cancer. However, the molecular mechanisms underlying its implication in lung cancer remains elusive. In this study, we first analyzed the gene expression profiling after SKA2 knockdown, and identified several candidate downstream target genes of SKA2, including PDSS2, the first key enzyme in CoQ10 biosynthesis pathway. Further experiments verified that SKA2 remarkably repressed PDSS2 gene expression at both mRNA and protein levels. Luciferase reporter assay showed that SKA2 repressed PDSS2 promoter activity through its Sp1-binding sites. Co-immunoprecipitation assay demonstrated that SKA2 associated with Sp1. Functional analysis revealed that PDSS2 remarkably suppressed lung cancer cell growth and motility. Furthermore, SKA2-induced malignant features can be also significantly attenuated by PDSS2 overexpression. However, CoQ10 treatment showed no obvious effects on lung cancer cell growth and motility. Of note, PDSS2 mutants with no catalytic activity exhibited comparable inhibitory effects on the malignant features of lung cancer cells and could also abrogate SKA2-promoted malignant phenotypes in lung cancer cells, highly suggesting a non-enzymatic tumor-suppressing activity of PDSS2 in lung cancer cells. The levels of PDSS2 expression were significantly decreased in lung cancer samples, and lung cancer patients with high expression of SKA2 and low expression of PDSS2 displayed remarkable poor prognosis. Collectively, our results demonstrated that PDSS2 is a novel downstream target gene of SKA2 in lung cancer cells, and the SKA2-PDSS2 transcriptional regulatory axis functionally contributes to human lung cancer cell malignant phenotypes and prognosis.

Development and validation of a nomogram for predicting intraoperative hypotension in cardiac valve replacement.

Background: Cardiac valve replacement risks include intraoperative hypotension, endangering organ perfusion. Our nomogram predicted hypotension risk in valve surgery, guiding early intervention. Methods: Analyzing 561 patients from July to November 2022, we developed a nomogram to predict hypotension in valve replacement patients, validated using data from December 2022 to January 2023 on 241 patients, with robust statistical confirmation. Results: Our study identified age, hypertension, left ventricular ejection fraction and serum creatinine as hypotension predictors. The resulting nomogram, validated with high concordance index and area under the curve scores, provided a clinically useful tool for managing intraoperative risk. Conclusion: For valve replacement patients, factors like age, hypertension, low left ventricular ejection fraction and high serum creatinine predicted hypotension risk. Our nomogram enabled clinicians to quantify this risk and proactively manage it.

Platelet-promoting drug delivery efficiency for inhibition of tumor growth, metastasis, and recurrence.

Nanomedicines are considered one of the promising strategies for anticancer therapy; however, the low targeting efficiency of nanomedicines in vivo is a great obstacle to their clinical applications. Camouflaging nanomedicines with either platelet membrane (PM) or platelet would significantly prolong the retention time of nanomedicines in the bloodstream, enhance the targeting ability of nanomedicines to tumor cells, and reduce the off-target effect of nanomedicines in major organs during the anticancer treatment. In the current review, the advantages of using PM or platelet as smart carriers for delivering nanomedicines to inhibit tumor growth, metastasis, and recurrence were summarized. The opportunities and challenges of this camouflaging strategy for anticancer treatment were also discussed.

Platelet detection as a new liquid biopsy tool for human cancers.

Cancer is still a leading cause of death worldwide and liquid biopsy is a powerful tool that can be applied to different stages of cancer screening and treatment. However, as the second most abundant cell type in the bloodstream, platelets are isolated through well-established and fast methods in clinic but their value as a BioSource of cancer biomarkers is relatively recent. Many studies demonstrated the bidirectional interaction between cancer cells and platelets. Platelets transfer various proteins (e.g., growth factors, cytokine, chemokines) and RNAs (e.g., mRNA, lncRNA, miRNA, circRNA) into the tumor cells and microenvironment, leading the stimulation of tumor growth and metastasis. In turn, the platelet clinical characteristics (e.g., count and volume) and contents (e.g., RNA and protein) are altered by the interactions with cancer cells and this enables the early cancer detection using these features of platelets. In addition, platelet-derived microparticles also demonstrate the prediction power of being cancer biomarkers. In this review, we focus on the clinical applications of platelet detection using the platelet count, mean platelet volume, platelet RNA and protein profiles for human cancers and discuss the gap in bringing these implementations into the clinic.

Cerebral Blood Flow and its Connectivity Deficits in Patients With Lung Cancer After Chemotherapy.

Purpose: This study was performed to investigate the regional cerebral blood flow (CBF) and CBF connectivity in the chemotherapy-induced cognitive impairment of patients with lung cancer by using arterial spin labeling. Methods: Pseudocontinuous arterial spin labeling perfusion magnetic resonance imaging and neuropsychological tests were performed for 21 patients with non-small cell lung cancer who had received chemotherapy CT (+) and 25 non-small cell lung cancer patients who need chemotherapy but did not yet received CT (-). The CT (+) group previously received platinum-based therapy for 3 months to 6 months (the time from their first chemotherapy to the MRI scan). Group comparisons were performed in the regional normalized CBF and CBF connectivity, and the relationship between the regional normalized CBF and cognitive impairment were detected. Results: The CT (+) group exhibited higher CBF in the left insula, right caudate, right superior occipital gyrus, left superior temporal gyrus (STG), and right middle frontal gyrus (MFG). MoCA scores as well as the memory scores were negatively correlated with the increased CBF in the right MFG (r = -0.492, p = 0.023; r = -0.497, p = 0.022). Alterations in the CBF connectivity were detected only in the CT (+) group between the following: right MFG and the right precentral gyrus; the right caudate and the right lingual gyrus; right caudate and right precuneus; left STG and the bilateral MFG; and the left STG and the right middle cingulum. Conclusion: These findings indicated that chemotherapy is associated with abnormalities in the CBF and connectivity alterations, which may contribute to the cognitive impairment in patients with lung cancer.

Dynamic functional network connectivity reveals the brain functional alterations in lung cancer patients after chemotherapy.

This study aimed to investigate alterations of brain functional network connectivity (FNC) in lung cancer patients after chemotherapy and explore links between these FNC differences and cognitive impairment. Twenty-two lung cancer patients receiving chemotherapy and 26 healthy controls (HCs) underwent resting-state functional MRI (rs-fMRI) and neuropsychological testing. Group independent component analysis (GICA) was applied to rs-fMRI data to extract whole-brain resting state networks (RSNs). Static and dynamic FNC (dFNC) were constructed to reveal RSNs connectivity alterations between lung cancer patients and HCs group, and the correlations between the group differences in RSNs and cognitive performance were analyzed. Our findings revealed that chemotherapeutics can produce widespread connectivity abnormalities in RSNs, mainly focused on default mode network (DMN) and executive control network. Furthermore, the dFNC analysis help identify network configurations of each state and capture more chemotherapy-induced disorders of interactions between and within RSNs, which mainly includes sensorimotor network, attentional network and auditory network. In addition, after chemotherapy, the lung cancer patients spend shorter mean dwell time (MDT) in state 2. The decreased dFNC between DMN [independent component 5 (IC5)] and DMN (IC6) in the lung cancer patients after chemotherapy in state 4 was negatively correlated with Montreal Cognitive Assessment (MoCA) scores (r=-0.447, p=0.042). The dFNC analysis enrich our understanding of the neural mechanisms underlying the chemobrain, and suggested that the temporal dynamics of FNC could be a potential effective method to detect cognitive changes in lung cancer patients receiving chemotherapy.

EloA promotes HEL polyploidization upon PMA stimulation through enhanced ERK1/2 activity.

Megakaryocytes (MKs) are the unique non-pathological cells that undergo polyploidization in mammals. The polyploid formation is critical for understanding the MK biology, and transcriptional regulation is involved in the differentiation and maturation of MKs. However, little is known about the functions of transcriptional elongation factors in the MK polyploidization. In this study, we investigated the role of transcription elongation factor EloA in the polyploidy formation during the MK differentiation. We found that EloA was highly expressed in the erythroleukemia cell lines HEL and K562. Knockdown of EloA in HEL cell line was shown to impair the phorbol myristate acetate (PMA) induced polyploidization process, which was used extensively to model megakaryocytic differentiation. Selective over-expression of EloA mutants with Pol II elongation activity partially restored the polyploidization. RNA-sequencing revealed that knockdown of EloA decelerated the transcription of genes enriched in the ERK1/2 cascade pathway. The phosphorylation activity of ERK1/2 decreased upon the EloA inhibition, and the polyploidization process of HEL was hindered when ERK1/2 phosphorylation was inhibited by PD0325901 or SCH772984. This study evidenced a positive role of EloA in HEL polyploidization upon PMA stimulation through enhanced ERK1/2 activity.

Potential biomarkers for inherited thrombocytopenia 2 identified by plasma proteomics.

Inherited thrombocytopenia 2 (THC2) is difficult to diagnose due to the lack of specific clinical characteristics and diagnostic methods. To identify potential plasma protein biomarkers for THC2, we collected the plasma samples from a THC2 family (9 THC2 and 15 non-THC2 members), enriched the medium and low abundant proteins using Proteominer and analyzed the protein profiles using the liquid chromatography-mass spectrometry in data independent acquisition mode. Initially, we detected 784 proteins in the plasma samples of this family and identified 27 up-regulated and 36 down-regulated in the THC2 group compared to the non-THC2 group (|log2 ratio| >1 and p-value <0.05). To improve the predictive power, top eight dysregulated proteins (B7Z2B4, LTF, HP, ERN1, IGHV1-8, A0A0X9V9C4, VH6DJ, and D3JV41) were selected by an area under the curve-based random forest process to construct a clinical model. Multivariate analysis with random forest and support vector machine showed that the prediction model provided high discrimination ability for THC2 diagnosis (AUC: 1.000 and 0.967, respectively). The potential plasma protein biomarkers will be tested in more THC2 patients and other thrombocytopenia patients to further validate their specificity and sensitivity.

Altered Brain Functional Network Topology in Lung Cancer Patients After Chemotherapy.

Purpose: This study aimed to explore the topological features of brain functional network in lung cancer patients before and after chemotherapy using graph theory. Methods: Resting-state functional magnetic resonance imaging scans were obtained from 44 post-chemotherapy and 46 non-chemotherapy patients as well as 49 healthy controls (HCs). All groups were age- and gender-matched. Then, the topological features of brain functional network were assessed using graph theory analysis. Results: At the global level, compared with the HCs, both the non-chemotherapy group and the post-chemotherapy group showed significantly increased values in sigma (p < 0.05), gamma (p < 0.05), and local efficiency, E loc (p < 0.05). The post-chemotherapy group and the non-chemotherapy group did not differ significantly in the above-mentioned parameters. At the nodal level, when non-chemotherapy or post-chemotherapy patients were compared with the HCs, abnormal nodal centralities were mainly observed in widespread brain regions. However, when the post-chemotherapy group was compared with the non-chemotherapy group, significantly decreased nodal centralities were observed primarily in the prefrontal-subcortical regions. Conclusions: These results indicate that lung cancer and chemotherapy can disrupt the topological features of functional networks, and chemotherapy may cause a pattern of prefrontal-subcortical brain network abnormality. As far as we know, this is the first study to report that altered functional brain networks are related to lung cancer and chemotherapy.

Disrupted functional network connectivity predicts cognitive impairment after acute mild traumatic brain injury.

AIMS: This study aimed to detect alterations of brain functional connectivity (FC) in acute mild traumatic brain injury (mTBI) and to estimate the extent to which these FC differences predicted the characteristics of posttraumatic cognitive impairment. METHODS: Resting-state fMRI data were acquired from acute mTBI patients (n = 50) and healthy controls (HCs) (n = 43). Resting-state networks (RSNs) were established based on independent component analysis (ICA), and functional network connectivity (FNC) analysis was performed. Subsequently, we analyzed the correlations between FNC abnormalities and cognitive impairment outcomes. RESULTS: Altered FC within the salience network (SN), sensorimotor network (SMN), default mode network (DMN), executive control network (ECN), visual network (VN), and cerebellum network (CN) was found in the mTBI group relative to the HC group. Moreover, different patterns of altered network interactions were found between the mTBI patients and HCs, including the SN-CN, VN-SMN, and ECN-DMN connections. Correlations between functional disconnection and cognitive impairment measurements in acute mTBI patients were also found. CONCLUSION: This study indicated that widespread FNC impairment and altered integration existed in mTBI patients at acute stage, suggesting that FNC disruption as a biomarker may be applied for the early diagnosis and prediction of cognitive impairment in mTBI.

Aberrant static and dynamic functional connectivity of the executive control network in lung cancer patients after chemotherapy: a longitudinal fMRI study.

OBJECTIVE: The purpose of the current study was to investigate chemotherapy-related variations in the intrinsic static and dynamic functional connectivity (sFC and dFC, respectively) of the executive control network (ECN) in lung cancer patients. MATERIALS AND METHODS: In this study, we evaluated 18 lung cancer patients scanned before and after adjuvant chemotherapy treatment and compared the patients with 21 healthy controls (HCs). All subjects underwent resting-state functional MRI (rs-fMRI). We constructed the sFC and dFC of the bilateral dorsolateral prefrontal cortex (DLPFC) using a sliding-window approach, and the correlations between the changed sFC or dFC and cognitive performance were analyzed. RESULTS: Whole-brain sFC analysis showed that the lung cancer patients showed significant FC pattern changes in the bilateral DLPFC, mainly in the bilateral superior frontal gyrus (SFG), bilateral middle frontal gyrus, left superior temporal gyrus, left inferior parietal lobe and the right insula. Furthermore, after chemotherapy, the lung cancer patients showed significantly reduced dFC variability between the right DLPFC and right precuneus compared with HCs. In addition, the decreased dFC between the right DLPFC and left SFG in the lung cancer patients after chemotherapy in state 1 and between the right DLPFC and left insula in the lung cancer patients before chemotherapy in state 2 were negatively correlated with MoCA scores ((r = -0.520, p = 0.039; r = -0.548, p = 0.028, respectively). CONCLUSIONS: Our results reveal that dynamic connectivity analysis is more effective and sensitive than methods that assume static brain states for linking brain FC patterns and chemotherapy.

BTG4 is A Novel p53 Target Gene That Inhibits Cell Growth and Induces Apoptosis.

BTG4 is the last cloned and poorly studied member of BTG/Tob family. Studies have suggested that BTG4 is critical for the degradation of maternal mRNAs in mice during the process of maternal-to-zygotic transition, and downregulated in cancers, such as gastric cancer. However, the regulatory mechanism of BTG4 and its function in cancers remain elusive. In this study, we have for the first time identified the promoter region of the human BTG4 gene. Serial luciferase reporter assay demonstrated that the core promoter of BTG4 is mainly located within the 388 bp region near its transcription initiation site. Transcription factor binding site analysis revealed that the BTG4 promoter contains binding sites for canonical transcription factors, such as Sp1, whereas its first intron contains two overlapped consensus p53 binding sites. However, overexpression of Sp1 has negligible effects on BTG4 promoter activity, and site-directed mutagenesis assay further suggested that Sp1 is not a critical transcription factor for the transcriptional regulation of BTG4. Of note, luciferase assay revealed that one of the intronic p53 binding sites is highly responsive to p53. Both exogenous p53 overexpression and adriamycin-mediated endogenous p53 activation result in the transcriptional upregulation of BTG4. In addition, BTG4 is downregulated in lung and colorectal cancers, and overexpression of BTG4 inhibits cell growth and induces apoptosis in cancer cells. Taken together, our results strongly suggest that BTG4 is a novel p53-regulated gene and probably functions as a tumor suppressor in lung and colorectal cancers.

Altered Dynamic Neural Activity in the Default Mode Network in Lung Cancer Patients After Chemotherapy.

BACKGROUND Few studies have examined functional brain changes specifically associated with chemotherapy (CTx) in patients with lung cancer. This prospective longitudinal research aimed to explore the change in intrinsic brain activity by investigating patients with lung cancer after CTx. MATERIAL AND METHODS Sixteen patients and 20 healthy individuals were enrolled in this study. The amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo), dynamic amplitude of low-frequency fluctuation (dALFF), and dynamic regional homogeneity (dReHo) were computed. The group differences in resting state functional magnetic resonance imaging (rs-fMRI) parameters were compared. Alterations in the rs-fMRI parameters from before CTx to after CTx were assessed using the paired t-test. We performed correlation analyses between rs-fMRI parameters and Montreal Cognitive Assessment (MoCA) scores. RESULTS We found statistically significant differences in MoCA scores before CTx and after CTx. Compared to the healthy group, rs-fMRI values decreased in the frontal regions as well as parietal regions compared to values before CTx. In addition, we found significantly decreased rs-fMRI values in the default-mode network (DMN) region of the brain before CTx compared to after CTx. We found no significant correlations between altered intrinsic activity values and MoCA scores. CONCLUSIONS The current study indicated that patients with lung cancer after CTx had decreased dynamic brain activity in the DMN region, and the DMN is vulnerable when patients undergoing CTx.

Chemotherapy-induced functional changes of the default mode network in patients with lung cancer.

Previous studies have demonstrated that cognitive impairment is associated with neurophysiological changes in lung cancer following chemotherapy. This study aimed to investigate the intrinsic functional connectivity (FC) pattern within the default mode network (DMN) and its associations with cognitive impairment in patients with lung cancer revealed by resting-state functional magnetic resonance imaging (fMRI). Resting-state fMRI scans were acquired from 21 post-chemotherapy and 27 non-chemotherapy lung cancer patients and 30 healthy controls. All groups were age, gender and education-matched. The posterior cingulate cortex (PCC) was chosen as the seed region to detect the FC patterns and then determine whether these changes were related with specific cognitive performance. Compared with non-chemotherapy lung cancer patients, chemotherapy patients revealed decreased FC between the PCC and the right anterior cingulate cortex (ACC), left inferior parietal lobule (IPL), and left medial prefrontal cortex (mPFC), as well as increased FC with the left postcentral gyrus (PoCG). Relative to healthy controls, post-chemotherapy patients exhibited reduced FC between the PCC and the left ACC and left temporal lobe, as well as increased FC with the right PoCG. Moreover, the decreased FC of the PCC to bilateral ACC in post-chemotherapy patients was positively associated with reduced MoCA scores (left: r = 0.529, p = 0.029; right: r = 0.577, p = 0.015). The current study mainly demonstrated reduced resting-state FC pattern within the DMN regions that was linked with impaired cognitive function in lung cancer patients after chemotherapy. These findings illustrated the potential role of the DMN in lung cancer patients that will provide novel insight into the underlying neuropathological mechanisms in chemotherapy-induced cognitive impairment.

Identification and characterization of the promoter of cancer-related gene LOXL2.

Lysyl oxidase like 2, LOXL2, as a member of the lysyl oxidase (LOX) family, has been shown to function similarly to LOX in the extracellular matrix (ECM) by promoting crosslinking of collagen and elastin. LOXL2 is also engaged to transcription regulation, cell signaling transduction and cell adhesion regulation. It has been reported that LOXL2 is highly expressed in several types of tumors and promotes cell proliferation and migration in various cancer cells. However, the regulatory mechanism of LOXL2 expression remains largely unknown. To further investigate its transcriptional regulatory mechanism, LOXL2 promoter region has been cloned and identified in the present study. Chromatin state analysis revealed that LOXL2 gene locus contained an active promoter near its first exon. We then constructed five different LOXL2 gene promoter luciferase reporter constructs covering 1.7 kb upstream of LOXL2 gene transcription initiation site. Series luciferase reporter assay demonstrated that all the five constructs showed notable promoter activity, and LOXL2 core promoter was located in a region of 185 bp near the transcription initiation site. Transcriptional factor binding analysis indicated that, LOXL2 promoter lacked classical TATA box, but contained putative binding sites for classic transcriptional factors such as Sp1 and NF-κB. Ectopic overexpression of Sp1 significantly enhanced LOXL2 promoter activity as well as its endogenous expression in cells. In contrast, mithramycin A (a selective Sp1 inhibitor) treatment repressed LOXL2 promoter as well as its endogenous transcription. Site directed mutagenesis assay further confirmed that the Sp1 binding sites were essential for proximal prompter activity of LOXL2 gene. Chromatin immunoprecipitation (ChIP) assay revealed that Sp1 bound LOXL2 promoter in vivo. Of note, the expression of Sp1 and LOXL2 are positively correlated, and the higher expression of LOXL2 is associated with poor prognosis in colorectal cancer, strongly suggesting the implication of Sp1-mediated LOXL2 transactivation in the pathogenesis of colorectal cancer.

Sp1 Mediates the Constitutive Expression and Repression of the PDSS2 Gene in Lung Cancer Cells.

Prenyl diphosphate synthase subunit 2 (PDSS2) is the first key enzyme in the CoQ10 biosynthesis pathway, and contributes to various metabolic and nephritic diseases. It has been reported that PDSS2 is downregulated in several types of tumors and acts as a potential tumor suppressor gene to inhibit the proliferation and migration of cancer cells. However, the regulatory mechanism of PDSS2 expression remains elusive. In the present study, we first identified and characterized the PDSS2 promoter region. We established four different luciferase reporter constructs which mainly cover the 2 kb region upstream of the PDSS2 gene transcription initiation site. Series luciferase reporter assay demonstrated that all four constructs have prominent promoter activity, and the core promoter of PDSS2 is mainly located within the 202 bp region near its transcription initiation site. Transcription factor binding site analysis revealed that the PDSS2 promoter contains binding sites for canonical transcription factors such as Sp1 and GATA-1. Overexpression of Sp1 significantly inhibited PDSS2 promoter activity, as well as its endogenous expression, at both mRNA and protein levels in lung cancer cells. Site-directed mutagenesis assay further confirmed that the Sp1 binding sites are essential for proximal prompter activity of PDSS2. Consistently, a selective Sp1 inhibitor, mithramycin A, treatment repressed the PDSS2 promoter activity, as well as its endogenous expression. Chromatin immunoprecipitation (ChIP) assay revealed that Sp1 binds to the PDSS2 promoter in vivo. Of note, the expression of Sp1 and PDSS2 are negatively correlated, and higher Sp1 expression with low PDSS2 expression is significantly associated with poor prognosis in lung cancer. Taken together, our results strongly suggest the essential role of Sp1 in maintaining the basic constitutive expression of PDSS2, and the pathogenic implication of Sp1-mediated PDSS2 transcriptional repression in lung cancer cells.

Swine Model of Thrombotic Caval Occlusion Created by Autologous Thrombus Injection with Assistance of Intra-caval Net Knitting.

To evaluate the feasibility of a swine model of thrombotic inferior vena cava (IVC) occlusion (IVCO) created by autologous thrombus injection with assistance of intra-caval net knitting. Sixteen pigs were included and divided into two groups: Group A (n = 10), IVCO model created by knitting a caval net followed by autologous thrombus injection; Group B (n = 6), control model created by knitting a net and normal saline injection. Venography was performed to assess each model and the associated thrombotic occlusion. The vessels were examined histologically to analyse the pathological changes postoperatively. IVCO model was successfully created in 10 animals in Group A (100%). Immediate venography showed extensive clot burden in the IVC. Postoperative venography revealed partial caval occlusion at 7 days, and complete occlusion coupled with collateral vessels at 14 days. Histologically, Group A animals had significantly greater venous wall thickening, with CD163-positive and CD3-positive cell infiltration. Recanalization channels were observed at the margins of the thrombus. By contrast, no thrombotic occlusion of the IVC was observed in Group B. The thrombotic IVCO model can be reliably established in swine. The inflammatory reaction may contribute to the caval thrombus propagation following occlusion.

Two swine models of iliac vein occlusion: Which form most contributes to venous thrombosis?

OBJECTIVES: In the present study, we establish two swine models of iliac vein occlusion (IVO) with spontaneous thrombosis to understand the mechanisms linking IVO and thrombosis. METHODS: Two IVO models were established in 12 swine either by ligating the common iliac vein (CIVO) or both the common and external iliac veins (CEIVO). Venography was performed to assess each model and the associated thrombosis. Invasive blood pressure was also measured, and the vessels were examined histologically to analyse the pathological changes after ligation. RESULTS: On venography, the CIVO model showed common iliac vein (CIV) occlusion and reflux in the collateral veins whereas the CEIVO model showed occlusion in the CIV and external iliac vein (EIV), stasis in the EIV, and decreased collateral vasculature on venography. Thrombosis was only observed in the CEIVO model, which was with significantly higher venous blood pressure in the EIV and with significantly more thickened venous wall with lymphocytic infiltration histologically. CONCLUSIONS: Two IVO models can be feasibly and reliably established in swine. The CEIVO model had a higher prevalence of thrombosis than the CIVO model. This CEIVO model produces comparatively less collateral drainage and greater inflammation that can contribute to the thrombosis prone to this type of model.