Identifying Significantly Perturbed Subnetworks in Cancer Using Multiple Protein-Protein Interaction Networks.

BACKGROUND: The identification of cancer driver genes and key molecular pathways has been the focus of large-scale cancer genome studies. Network-based methods detect significantly perturbed subnetworks as putative cancer pathways by incorporating genomics data with the topological information of PPI networks. However, commonly used PPI networks have distinct topological structures, making the results of the same method vary widely when applied to different networks. Furthermore, emerging context-specific PPI networks often have incomplete topological structures, which pose serious challenges for existing subnetwork detection algorithms. METHODS: In this paper, we propose a novel method, referred to as MultiFDRnet, to address the above issues. The basic idea is to model a set of PPI networks as a multiplex network to preserve the topological structure of individual networks, while introducing dependencies among them, and, then, to detect significantly perturbed subnetworks on the modeled multiplex network using all the structural information simultaneously. RESULTS: To illustrate the effectiveness of the proposed approach, an extensive benchmark analysis was conducted on both simulated and real cancer data. The experimental results showed that the proposed method is able to detect significantly perturbed subnetworks jointly supported by multiple PPI networks and to identify novel modular structures in context-specific PPI networks.

Design, synthesis and evaluation of dihydro-1H-indene derivatives as novel tubulin polymerisation inhibitors with anti-angiogenic and antitumor potency.

Angiogenesis plays an important role in tumour generation and progression, which is used to supply nutrients and metastasis. Herein, a series of novel dihydro-1H-indene derivatives were designed and evaluated as tubulin polymerisation inhibitors by binding to colchicine site, exhibiting anti-angiogenic activities against new vessel forming. Through structure-activity relationships study, compound 12d was found to be the most potent derivative possessing the antiproliferative activity against four cancer lines with IC50 values among 0.028-0.087 µM. Compound 12d bound to colchicine site on tubulin and inhibited tubulin polymerisation in vitro. In addition, compound 12d induced cell cycle arrest at G2/M phase, stimulated cell apoptosis, inhibited tumour metastasis and angiogenesis. Finally, the results of in vivo assay suggested that compound 12d could prevent tumour generation, inhibit tumour proliferation and angiogenesis without obvious toxicity. Collectively, all these findings suggested that compound 12d is a novel tubulin polymerisation inhibitor deserving further research.

A systematic review and bibliometric study of Bertolotti's syndrome: clinical characteristics and global trends.

PURPOSE: Bertolotti's syndrome is a prevalent congenital deformity. However, many physicians fail to include it in their differential diagnosis for low back pain (LBP), which results in missed diagnosis or misdiagnosis. There is still a lack of standardized treatment and management strategies for Bertolotti's syndrome. This study aimed to review the clinical characteristics and management of Bertolotti's syndrome and reports bibliometric insights in advancements in Bertolotti's syndrome research. METHODS: Studies published until 30 September 2022 were systematically reviewed according to the PRISMA guidelines. Three independent reviewers extracted the data and assessed the quality and risk of bias of the studies based on the methodological index of non-randomized studies (MINORS). SPSS, VOS viewer, and the Citespace software were used for the systematic review, visual analysis, data mining, mapping, and clustering of the retrieved articles, which presented clear and visual presentations of the structural patterns of published research in graphs. RESULT: A total of 118 articles, describing a total of 419 patients with Bertolotti's syndrome, were included. There was an upward trend with a steady increase in the number of publications. The world map distribution showed that most publications were predominantly from North America and Asia. The most cited articles were published in the following journals: Spine, J Bone Joint Surg, and Radiology. The mean age of the patients was 47.7 years, and 49.6% of them were male. A total of 159 (96.4%) patients had LBP symptoms. The mean symptom duration was 41.4 months (74.8%), and most of the patients had Castellvi type II. Disc degeneration was the most reported comorbid spinal diseases. The mean methodological index of non-randomized studies score was 4.16±3.95 points (range, 1-21). A total of 265 (68.3%) patients underwent surgical treatments. Minimally invasive surgical techniques, prevalence, image classification, and disc degeneration were the current main research areas of Bertolotti's syndrome. CONCLUSIONS: The steady increase in the number of publications demonstrated the increased attention of researchers on this topic. Our results showed a significant prevalence of Bertolotti's syndrome in patients with LBP and a long symptom duration before the initiation of treatment. Surgical treatments were commonly used to treat patients with Bertolotti's syndrome after a non-effective conservative treatment. Minimally invasive surgical techniques, prevalence, image classification, and disc degeneration are the major research areas of Bertolotti's syndrome.

[Analysis of continuous polysomnography in children with recurrent vertigo].

Objective:To explore the relationship between sleep status and the disease in children with recurrent vertigo（RVC） by analyzing the objective sleep condition of children with recurrent vertigo. Methods:According to the diagnostic criteria of RVC, 50 children with RVC and 20 normal controls without RVC were selected. According to the vertigo questionnaire score, the RVC group was divided into mild, moderate and severe groups according to severity. Continuous polysomnography（PSG） was performed for all participants, and SPSS 25.0 statistical software was used to analyze the monitoring results. Results:①There were significant differences in sleep time of each period, total sleep time and sleep efficiency between RVC group and control group（P<0.05）, but there was no significant difference in sleep latency（P>0.05）. The specific manifestations were that the proportion of sleep time in N1 and N2 phases increased, the proportion of sleep time in N3 and REM phases decreased, the total sleep time and sleep efficiency decreased in RVC group. ②The abnormal rate of sleep apnea hypopnea index, that is, the proportion of AHI≥5 times/h and the abnormal rate of lowest blood oxygen saturation in RVC group were higher than those in normal control group. There was significant difference between the two groups（P<0.05）. ③There were significant differences in the proportion of AHI≥5 times/h and lowest SpO2 among mild group, moderate group and severe group（P<0.05）. ④There was no significant correlation between the degree of vertigo and the abnormal rate of AHI in children with RVC, but there was a negative correlation between the degree of vertigo and the abnormal rate of lowest SpO2 in children with RVC. Conclusion:Children with RVC are often accompanied by sleep disorders, clinicians should pay attention to both the symptoms of vertigo and sleep condition in children. Polysomnography is non-invasive and operable, providing a new idea to the auxiliary examination of RVC in children. It is of certain clinical significance for the comprehensive treatment of children with RVC to actively improve vertigo symptoms and pay attention to improving sleep quality.

Periodontal disease is associated with increased gut colonization of pathogenic Haemophilus parainfluenzae in patients with Crohn's disease.

Intestinal colonization of the oral bacterium Haemophilus parainfluenzae has been associated with Crohn's disease (CD) severity and progression. This study examines the role of periodontal disease (PD) as a modifier for colonization of H. parainfluenzae in patients with CD and explores the mechanisms behind H. parainfluenzae-mediated intestinal inflammation. Fifty subjects with and without CD were evaluated for the presence of PD, and their oral and fecal microbiomes were characterized. PD is associated with increased levels of H. parainfluenzae strains in subjects with CD. Oral inoculation of H. parainfluenzae elicits strain-dependent intestinal inflammation in murine models of inflammatory bowel disease, which is associated with increased intestinal interferon-γ (IFN-γ)+ CD4+ T cells and disruption of the host hypusination pathway. In summary, this study establishes a strain-specific pathogenic role of H. parainfluenzae in intestinal inflammation and highlights the potential effect of PD on intestinal colonization by pathogenic H. parainfluenzae strains in patients with CD.

Association between visceral adiposity index and heart failure: A cross-sectional study.

BACKGROUND: Obesity is an important risk factor for heart failure (HF). HYPOTHESIS: Visceral adiposity index (VAI) is a simple metric for assessing obesity; however, the association between VAI and risk for HF has not been studied. METHODS: A cross-sectional study involving 28 764 participants ≥18 years of age from the National Health and Nutrition Examination Survey (NHANES), 2009-2018, in the United States was performed. VAI was calculated using body mass index (BMI), waist circumference (WC), triglycerides (TG), and high-density lipoprotein cholesterol. VAI was analyzed as a continuous and categorical variable to examine its association with HF. Subgroup analysis was also performed. RESULTS: The highest VAI (fourth quartile [Q4]) was found among males, BMI, systolic and diastolic blood pressure, WC, hypertension, diabetes, liver disease, coronary heart disease, smoking, total cholesterol, and TG. More participants in Q4 took ß-receptor blockers, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers/angiotensin receptor-neprilysin inhibitor, calcium channel blockers, and antidiabetic and antihyperlipidemic medications. Participants with HF exhibited greater VAI. A per-unit increase in VAI resulted in a 4% increased risk for HF (odds ratio [OR] 1.04 [95% confidence interval (CI) 1.02-1.05]). After multivariable adjustment, compared with the lowest quartile, the OR for Q3 was 1.55 (95% CI 1.24-1.94). Subgroup analysis revealed no significant interactions between VAI and specific subgroups. CONCLUSION: VAI was independently associated with the risk for HF. As a noninvasive index of visceral adiposity, VAI could be used for a "one shot" assessment of HF risk and may serve as a novel marker.

[The value of high intensity stimulation training of semicircular canal of SRM-â £ vertigo diagnosis and treatment system in the rehabilitation of vestibular neuritis].

Objective:To evaluate the value of high intensity stimulation training of semicircular canal of SRM-Ⅳ vertigo diagnosis and treatment system in the rehabilitation of vestibular neuritis. Methods:To analyze 68 patients with vestibular neuritis treated in Department of Otorhinolaryngology Head and Neck Surgery, Shijiazhuang People's Hospital from January 2020 to January 2021, conduct spontaneous nystagmus and head toss test, and perform spontaneous nystagmus and rotation test of SRM-Ⅳvertigo system, compare the positive rate of the side of disease was between the two. To randomly divide 68 patients into treatment group 1, 2 and control group, the control group with drugs, treatment group 1 with drugs and vestibular rehabilitation training exercise, treatment group 2 with additional high intensity stimulation training of semicircular canal at one week after onset, on the basis of drug therapy and vestibular rehabilitation training exercise. At 2 weeks and 1 month, through swivel chair test negative rate, DHI score, compare the efficacy of the three groups. Results:Spontaneous nystagmus combined with head toss test confirmed 80.9% of the side of the disease, spontaneous nystagmus and rotation test of SRM-Ⅳ vertigo system confirmed 100%, the difference is statistically significant（P<0.05）. Compared with the control group and the treatment group 1, the negative conversion rate of the rotation test in the treatment group 2 at the second week and the first month of treatment, the difference is statistically significant（P<0.05, the second week χ²=6.474, the first month χ²=6.245）; the DHI score of treatment group 2 was statistically significant compared with that of control group and treatment group 1 at the second week and first month of treatment（P<0.05, the second week F=13.578, the first month F=28.599）. Conclusion:SRM-Ⅳ vertigo diagnosis and treatment system semicircular canal high intensity stimulation training has a certain role in the rehabilitation treatment of vestibular neuritis. It is simple to operate, patient tolerance and compliance are good, and it is worth promoting.

Computational approach to modeling microbiome landscapes associated with chronic human disease progression.

A microbial community is a dynamic system undergoing constant change in response to internal and external stimuli. These changes can have significant implications for human health. However, due to the difficulty in obtaining longitudinal samples, the study of the dynamic relationship between the microbiome and human health remains a challenge. Here, we introduce a novel computational strategy that uses massive cross-sectional sample data to model microbiome landscapes associated with chronic disease development. The strategy is based on the rationale that each static sample provides a snapshot of the disease process, and if the number of samples is sufficiently large, the footprints of individual samples populate progression trajectories, which enables us to recover disease progression paths along a microbiome landscape by using computational approaches. To demonstrate the validity of the proposed strategy, we developed a bioinformatics pipeline and applied it to a gut microbiome dataset available from a Crohn's disease study. Our analysis resulted in one of the first working models of microbial progression for Crohn's disease. We performed a series of interrogations to validate the constructed model. Our analysis suggested that the model recapitulated the longitudinal progression of microbial dysbiosis during the known clinical trajectory of Crohn's disease. By overcoming restrictions associated with complex longitudinal sampling, the proposed strategy can provide valuable insights into the role of the microbiome in the pathogenesis of chronic disease and facilitate the shift of the field from descriptive research to mechanistic studies.

A Diagnostic Gene Expression Signature for Bladder Cancer Can Stratify Cases into Prescribed Molecular Subtypes and Predict Outcome.

Bladder cancer is a biologically heterogeneous disease with variable clinical presentations, outcomes and responses to therapy. Thus, the clinical utility of single biomarkers for the detection and prediction of biological behavior of bladder cancer is limited. We have previously identified and validated a bladder cancer diagnostic signature composed of 10 biomarkers, which has been incorporated into a multiplex immunoassay bladder cancer test, Oncuria™. In this study, we evaluate whether these 10 biomarkers can assist in the prediction of bladder cancer clinical outcomes. Tumor gene expression and patient survival data from bladder cancer cases from The Cancer Genome Atlas (TCGA) were analyzed. Alignment between the mRNA expression of 10 biomarkers and the TCGA 2017 subtype classification was assessed. Kaplan-Meier analysis of multiple gene expression datasets indicated that high expression of the combined 10 biomarkers correlated with a significant reduction in overall survival. The analysis of three independent, publicly available gene expression datasets confirmed that multiplex prognostic models outperformed single biomarkers. In total, 8 of the 10 biomarkers from the Oncuria™ test were significantly associated with either luminal or basal molecular subtypes, and thus, the test has the potential to assist in the prediction of clinical outcome.

PAI-1 is a potential transcriptional silencer that supports bladder cancer cell activity.

The extracellular activity of Plasminogen activator inhibitor-1 (PAI-1) is well described, acting as an inhibitor of tissue plasminogen activator and urokinase-type plasminogen activator, impacting fibrinolysis. Recent studies have revealed a pro-tumorigenic role of PAI-1 in human cancers, via the regulation of angiogenesis and tumor cell survival. In this study, immunohistochemical staining of 939 human bladder cancer specimens showed that PAI-1 expression levels correlated with tumor grade, tumor stage and overall survival. The typical subcellular localization of PAI-1 is cytoplasmic, but in approximately a quarter of the cases, PAI-1 was observed to be localized to both the tumor cell cytoplasm and the nucleus. To investigate the potential function of nuclear PAI-1 in tumor biology we applied chromatin immunoprecipitation (ChIP)-sequencing, gene expression profiling, and rapid immunoprecipitation mass spectrometry to a pair of bladder cancer cell lines. ChIP-sequencing revealed that PAI-1 can bind DNA at distal intergenic regions, suggesting a role as a transcriptional coregulator. The downregulation of PAI-1 in bladder cancer cell lines caused the upregulation of numerous genes, and the integration of ChIP-sequence and RNA-sequence data identified 57 candidate genes subject to PAI-1 regulation. Taken together, the data suggest that nuclear PAI-1 can influence gene expression programs and support malignancy.

The Relationship Between the Utilization of Arterial Blood Gas Analysis and Rehospitalization in Heart Failure: A Retrospective Cohort Study.

Background: The most common presentation of decompensated HF is dyspnea, and arterial blood gas analysis is an excellent tool for the decision-making process for most dyspneic patients. However, data on the prognostic value of ABG in HF patients are limited. Herein, a retrospective cohort study was conducted to investigate whether the utilization of arterial blood gas analysis was independently associated with re-hospitalization in patients with heart failure. Methods: As a retrospective cohort study, the relevant clinical data of hospitalized patients admitted to Zigong Fourth People's Hospital, Sichuan, China from December 2016 to June 2019 with a diagnosis of HF were analyzed. The re-hospitalization within 6 months and the use of intravenous diuretic, nitrates, inotropes, or vasopressors were compared between patients with and without arterial blood gas analysis. We used a multivariable logistic regression model, propensity score analysis, and an inverse probability-weighting model to ensure the robustness of our findings. Results: We included 1,605 patients with heart failure. The overall re-hospitalization rate within 6 months was 38.2%; it was 34.8% and 41.8% for heart failure patients with or without arterial blood gas analysis, respectively. In the inverse probability-weighting model, the use of arterial blood gas analysis was associated with a 26% lower re-hospitalization rate within 6 months. Conclusion: The performance of arterial blood gas analysis is associated with a 6-month rehospitalization rate benefit in a general population of heart failure patients. This association warrants further investigation.

Global Trends of Researches on Lumbar Spinal Stenosis: A Bibliometric and Visualization Study.

STUDY DESIGN: Bibliometric and visualization analysis. OBJECTIVE: Lumbar spinal stenosis (LSS) has become a common health problem and the most frequent indication for spinal surgery. This study aimed to illustrate the overall knowledge structure, and development trends of LSS, using a bibliometric analysis and newly developed visualization tools. MATERIALS AND METHODS: Research data sets were acquired from the Web of Science. The time span was defined as "2000-2019". VOS viewer and Citespace software was provided to analyze the data and generate visualization knowledge maps. Annual trend of publications, distribution, H-index status, co-authorship status and research hotspots were analyzed. RESULTS: A total of 1934 publications met the requirement. The United States published most papers (521, 26.9%), both total citations (17,626) and H-index (61) ranked first of all the countries. The most productive organizations on LSS is Seoul National University (50). Spine (43) published the most papers on LSS. Quality of life, risk factor, disability, double blind trials, and decompression surgery are the research hotspots in the recent years. CONCLUSION: The number of publications showed an upward trend with a stable rise in recent years. The United States is a country with the highest productivity, not only in quality, but also in quantity. Seoul National University has been the largest contributor in this field. Spine is the best journal related to LSS. Quality of life, risk factor, disability, and decompression surgery are the research hotspots in the recent years. Indeed, this study provides a new insight to the growth and development of LSS. Moreover, it will contribute to the growth of the international frontier of LSS.

Application of a multiplex urinalysis test for the prediction of intravesical BCG treatment response: A pilot study.

BACKGROUND: Intravesical Bacillus Calmette-Guerin (BCG), a live attenuated tuberculosis vaccine that acts as a non-specific immune system stimulant, is the most effective adjuvant treatment for patients with intermediate or high-risk non-muscle-invasive bladder cancer (NMIBC). However, to date, there are no reliable tests that are predictive of BCG treatment response. In this study, we evaluated the performance of OncuriaTM, a bladder cancer detection test, to predict response to intravesical BCG. METHODS: OncuriaTM data was evaluated in voided urine samples obtained from a prospectively collected cohort of 64 subjects with intermediate or high risk NMIBC prior to treatment with intravesical BCG. The OncuriaTM test, which measures 10 cancer-associated biomarkers was performed in an independent clinical laboratory. The ability of the test to identify those patients in whom BCG is ineffective against tumor recurrence was tested. Predictive models were derived using supervised learning and cross-validation analyses. Model performance was assessed using ROC curves. RESULTS: Pre-treatment urinary concentrations of MMP9, VEGFA, CA9, SDC1, PAI1, APOE, A1AT, ANG and MMP10 were increased in patients who developed disease recurrence. A combinatorial predictive model of treatment outcome achieved an AUROC 0.89 [95% CI: 0.80-0.99], outperforming any single biomarker, with a test sensitivity of 81.8% and a specificity of 84.9%. Hazard ratio analysis revealed that patients with higher urinary levels of ANG, CA9 and MMP10 had a significantly higher risk of disease recurrence. CONCLUSIONS: Monitoring the urinary levels of a cancer-associated biomarker panel enabled the discrimination of patients who did not respond to intravesical BCG therapy. With further study, the multiplex OncuriaTM test may be applicable for the clinical evaluation of bladder cancer patients considering intravesical BCG treatment.

Monolithic integration of nanorod arrays on microfluidic chips for fast and sensitive one-step immunoassays.

Here, we present integrated nanorod arrays on microfluidic chips for fast and sensitive flow-through immunoassays of physiologically relevant macromolecules. Dense arrays of Au nanorods are easily fabricated through one-step oblique angle deposition, which eliminates the requirement of advanced lithography methods. We report the utility of this plasmonic structure to improve the detection limit of the cardiac troponin I (cTnI) assay by over 6 × 105-fold, reaching down to 33.9 fg mL-1 (~1.4 fM), compared with an identical assay on glass substrates. Through monolithic integration with microfluidic elements, the device enables a flow-through assay for quantitative detection of cTnI in the serum with a detection sensitivity of 6.9 pg mL-1 (~0.3 pM) in <6 min, which was 4000 times lower than conventional glass devices. This ultrasensitive detection arises from the large surface area for antibody conjugation and metal-enhanced fluorescent signals through plasmonic nanostructures. Moreover, due to the parallel arrangement of flow paths, simultaneous detection of multiple cancer biomarkers, including prostate-specific antigen and carcinoembryonic antigen, has been fulfilled with increased signal-to-background ratios. Given the high performance of this assay, together with its simple fabrication process that is compatible with standard mass manufacturing techniques, we expect that the prepared integrated nanorod device can bring on-site point-of-care diagnosis closer to reality.

Influencing Factors on the Oncuria™ Urinalysis Assay: An Experimental Model.

BACKGROUND: The Oncuria™ urine test for the detection of bladder cancer measures a multiplex protein signature. In this study, we investigated the influence of urinary cellularity, protein, and hematuria on the performance of the Oncuria™ test in an ex vivo experimental model. MATERIALS AND METHODS: Pooled urine from healthy subjects was spiked with cultured benign (UROtsa) or malignant cells (T24), cellular proteins, or whole blood. The resulting samples were analyzed using the Oncuria™ test following the manufacturer's instructions. RESULTS: Urine samples obtained from healthy subjects were negative for bladder cancer by Oncuria™ test criteria. The majority of the manipulated conditions did not result in a false-positive test. The addition of whole blood (high concentration) did result in a false-positive result, but this was abrogated by sample centrifugation prior to analysis. The addition of cellular proteins (high concentration) resulted in a positive Oncuria™ test, and this was unaffected by pre-analysis sample centrifugation. CONCLUSIONS: The Oncuria™ multiplex test performed well in the ex vivo experimental model and shows promise for clinical application. The identification of patients who require additional clinical evaluation could reduce the need to subject patients who do not have bladder cancer to frequent, uncomfortable and expensive cystoscopic examinations, thus benefiting both patients and the healthcare system.

Diagnostic performance of Oncuria™, a urinalysis test for bladder cancer.

BACKGROUND: Due to insufficient accuracy, urine-based assays currently have a limited role in the management of patients with bladder cancer. The identification of multiplex molecular signatures associated with disease has the potential to address this deficiency and to assist with accurate, non-invasive diagnosis and monitoring. METHODS: To evaluate the performance of Oncuria™, a multiplex immunoassay for bladder detection in voided urine samples. The test was evaluated in a multi-institutional cohort of 362 prospectively collected subjects presenting for bladder cancer evaluation. The parallel measurement of 10 biomarkers (A1AT, APOE, ANG, CA9, IL8, MMP9, MMP10, PAI1, SDC1 and VEGFA) was performed in an independent clinical laboratory. The ability of the test to identify patients harboring bladder cancer was assessed. Bladder cancer status was confirmed by cystoscopy and tissue biopsy. The association of biomarkers and demographic factors was evaluated using linear discriminant analysis (LDA) and predictive models were derived using supervised learning and cross-validation analyses. Diagnostic performance was assessed using ROC curves. RESULTS: The combination of the 10 biomarkers provided an AUROC 0.93 [95% CI 0.87-0.98], outperforming any single biomarker. The addition of demographic data (age, sex, and race) into a hybrid signature improved the diagnostic performance AUROC 0.95 [95% CI 0.90-1.00]. The hybrid signature achieved an overall sensitivity of 0.93, specificity of 0.93, PPV of 0.65 and NPV of 0.99 for bladder cancer classification. Sensitivity values of the diagnostic panel for high-grade bladder cancer, low-grade bladder cancer, MIBC and NMIBC were 0.94, 0.89, 0.97 and 0.93, respectively. CONCLUSIONS: Urinary levels of a biomarker panel enabled the accurate discrimination of bladder cancer patients and controls. The multiplex Oncuria™ test can achieve the efficient and accurate detection and monitoring of bladder cancer in a non-invasive patient setting.

An efficient and effective method to identify significantly perturbed subnetworks in cancer.

The identification of key functional biological networks from high-dimensional genomics data is pivotal for cancer research. Here, we introduce FDRnet, a method for the detection of molecular subnetworks in cancer, which addresses several challenges in pathway analysis. FDRnet detects key subnetworks by solving a mixed-integer linear programming problem, using a given upper bound of false discovery rate (FDR) as a budget constraint, and minimizing a conductance score to find dense subgraphs around seed genes. A large-scale benchmark study was performed on both simulation and cancer genomics data. FDRnet outperformed other methods in the ability to detect functionally homogeneous subnetworks in a scale-free biological network, to control FDRs of the genes in detected subnetworks, to improve computational efficiency and to integrate multi-omics data. By overcoming the limitations of existing approaches, FDRnet can facilitate the detection of key functional pathways in cancer and other genetic diseases.

Subgingival microbiome is associated with alveolar bone loss measured 5 years later in postmenopausal women.

BACKGROUND: The aim of this study was to quantify the association between subgingival microbiota and periodontal disease progression in older women, for which limited published data exist. METHODS: A total of 1016 postmenopausal women, aged 53 to 81 years, completed baseline (1997 to 2001) and 5-year (2002 to 2006) dental exams that included probing depth, clinical attachment level, gingival bleeding, and radiographic alveolar crestal height (ACH). Baseline microbiota were measured in subgingival plaque using 16S rRNA sequencing. Associations between 52 microbiota we previously found statistically significantly associated with clinical periodontal disease at baseline, were examined with disease progression. The traditional Socransky microbiota complexes also were evaluated. Side-by-side radiograph comparisons were used to define progression as ≥2 teeth with ≥1 mm ACH loss or ≥1 new tooth loss to periodontitis. The association between baseline centered log(2) ratio transformed microbial relative abundances and 5-year periodontal disease progression was measured with generalized linear models. RESULTS: Of 36 microbiota we previously showed were elevated in moderate/severe disease at baseline, 24 had statistically significantly higher baseline mean relative abundance in progressing compared with non-progressing women (P < .05, all); which included all Socransky red bacteria (P. gingivalis, T. forsythia, T. denticola). Of 16 microbiota elevated in none/mild disease at baseline, five had statistically significantly lower baseline abundance in non-progressing compared with progressing women (P < 0.05, all), including one Socransky yellow bacteria (S. oralis). When adjusted for baseline age, socioeconomic status, and self-rated general health status, odds ratios for 5-year progression ranged from 1.18 to 1.51 (per 1-standard deviation increment in relative abundance) for microbiota statistically significantly (P < 0.05) positively associated with progression, and from 0.77 to 0.82 for those statistically significantly (P < 0.05) inversely associated with progression. These associations were similar when stratified on baseline levels of pocket depth, gingival bleeding, ACH, and smoking status. CONCLUSIONS: These prospective results affirm clearly that subgingival microbiota are measurably elevated several years prior to progression of alveolar bone loss, and include antecedent elevations in previously undocumented taxa additional to known Socransky pathogenic complexes.

Plasminogen activator inhibitor-2 (PAI-2) overexpression supports bladder cancer development in PAI-1 knockout mice in N-butyl-N- (4-hydroxybutyl)-nitrosamine- induced bladder cancer mouse model.

BACKGROUND: Accumulating evidence suggests that plasminogen activator inhibitor-1 (PAI-1) plays an important role in bladder tumorigenesis by regulating cell cycle. However, it remains unclear whether and how inhibition of PAI-1 suppresses bladder tumorigenesis. METHODS: To elucidate the therapeutic effect of PAI-1 inhibition, we tested its tumorigenicity in PAI-1 knockout (KO) mice exposed to a known bladder carcinogen. RESULTS: PAI-1 deficiency did not inhibit carcinogen-induced bladder cancer in mice although carcinogen-exposed wild type mice significantly increased PAI-1 levels in bladder tissue, plasma and urine. We found that PAI-1 KO mice exposed to carcinogen tended to upregulate protein C inhibitor (PAI-3), urokinase-type plasminogen activator (uPA) and tissue-type PA (tPA), and significantly increased PAI-2, suggesting a potential compensatory function of these molecules when PAI-1 is abrogated. Subsequent studies employing gene expression microarray using mouse bladder tissues followed by post hoc bioinformatics analysis and validation experiments by qPCR and IHC demonstrated that SERPING1 is further downregulated in PAI-1 KO mice exposed to BBN, suggesting that SERPING1 as a potential missing factor that regulate PAI-2 overexpression (compensation pathway). CONCLUSIONS: These results indicate that serpin compensation pathway, specifically PAI-2 overexpression in this model, supports bladder cancer development when oncoprotein PAI-1 is deleted. Further investigations into PAI-1 are necessary in order to identify true potential targets for bladder cancer therapy.