RNA editing in response to COVID-19 vaccines: unveiling dynamic epigenetic regulation of host immunity.

Background: COVID-19 vaccines are crucial for reducing the threat and burden of the pandemic on global public health, yet the epigenetic, especially RNA editing in response to the vaccines remains unelucidated. Results: Our current study performed an epitranscriptomic analysis of RNA-Seq data of 260 blood samples from 102 healthy and SARS-CoV-2 naïve individuals receiving different doses of the COVID-19 vaccine and revealed dynamic, transcriptome-wide adenosine to inosine (A-to-I) RNA editing changes in response to COVID-19 vaccines (RNA editing in response to COVID-19 vaccines). 5592 differential RNA editing (DRE) sites in 1820 genes were identified, with most of them showing up-regulated RNA editing and correlated with increased expression of edited genes. These deferentially edited genes were primarily involved in immune- and virus-related gene functions and pathways. Differential ADAR expression probably contributed to RNA editing in response to COVID-19 vaccines. One of the most significant DRE in RNA editing in response to COVID-19 vaccines was in apolipoprotein L6 (APOL6) 3' UTR, which positively correlated with its up-regulated expression. In addition, recoded key antiviral and immune-related proteins such as IFI30 and GBP1 recoded by missense editing was observed as an essential component of RNA editing in response to COVID-19 vaccines. Furthermore, both RNA editing in response to COVID-19 vaccines and its functions dynamically depended on the number of vaccine doses. Conclusion: Our results thus underscored the potential impact of blood RNA editing in response to COVID-19 vaccines on the host's molecular immune system.

Erdafitinib in Asian patients with advanced solid tumors: an open-label, single-arm, phase IIa trial.

BACKGROUND: FGFR genomic aberrations occur in approximately 5-10% of human cancers. Erdafitinib has previously demonstrated efficacy and safety in FGFR-altered advanced solid tumors, such as gliomas, thoracic, gastrointestinal, gynecological, and other rare cancers. However, its efficacy and safety in Asian patients remain largely unknown. We conducted a multicenter, open-label, single-arm phase IIa study of erdafitinib to evaluate its efficacy in Asian patients with FGFR-altered advanced cholangiocarcinoma, non-small cell lung cancer (NSCLC), and esophageal cancer. METHODS: Patients with pathologically/cytologically confirmed, advanced, or refractory tumors who met molecular and study eligibility criteria received oral erdafitinib 8 mg once daily with an option for pharmacodynamically guided up-titration to 9 mg on a 28-day cycle, except for four NSCLC patients who received erdafitinib 10 mg (7 days on/7 days off) as they were recruited before the protocol amendment. The primary endpoint was investigator-assessed objective response rate per RECIST v1.1. Secondary endpoints included progression-free survival, duration of response, disease control rate, overall survival, safety, and pharmacokinetics. RESULTS: Thirty-five patients (cholangiocarcinoma: 22; NSCLC: 12; esophageal cancer: 1) were enrolled. At data cutoff (November 19, 2021), the objective response rate for patients with cholangiocarcinoma was 40.9% (95% CI, 20.7-63.6); the median progression-free survival was 5.6 months (95% CI, 3.6-12.7) and median overall survival was 40.2 months (95% CI, 12.4-not estimable). No patient with RET/FGFR-altered NSCLC achieved objective response and the disease control rate was 25.0% (95% CI, 5.5-57.2%), with three patients with stable disease. The single patient with esophageal cancer achieved partial response. All patients experienced treatment-emergent adverse events, and grade ≥ 3 treatment-emergent adverse events were reported in 22 (62.9%) patients. Hyperphosphatemia was the most frequently reported treatment-emergent adverse event (all-grade, 85.7%). CONCLUSIONS: Erdafitinib demonstrated efficacy in a population of Asian patients in selected advanced solid tumors, particularly in those with advanced FGFR-altered cholangiocarcinoma. Treatment was tolerable with no new safety signals. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov (NCT02699606); study registration (first posted): 04/03/2016.

Malignant atrophic papulosis treated with eculizumab and hirudin: a fatal case report and literature review.

Background: Malignant atrophic papulosis (MAP) is a rare obliterative vasculopathy whose etiology and pathophysiological mechanisms remain unknown, and the treatment is still empirical. It can involve multiple systems, especially the gastrointestinal tract and central nervous system, and has a poor prognosis. Case presentation: A 20-year-old Chinese male appeared to have Widespread atrophic papules and plaques, intermittent abdominal pain, recurrent bowel perforation, and psoas abscess. The clinical diagnosis of MAP was supported by skin biopsy. He was then treated with anticoagulants, antiplatelets, glucocorticoids, and immunosuppressants and started on eculizumab and hirudin after the first surgical interventions. Despite the aggressive immunosuppression, anticoagulant, antiplatelet, humanized monoclonal antibodies, and surgery therapy, he died five months after presentation. Conclusions: MAP is an extremely rare obliterative vasculopathy manifesting as benign cutaneous involvement or potentially malignant systemic involvement. MAP patients who exhibit any abdominal symptoms should undergo laparoscopy and evaluation in time and start on eculizumab and treprostinil as soon as possible, as the combination of them is presently the most effective treatment option for gastrointestinal MAP and hopefully reduce mortality.

Evaluating the agreement between different substance use recall periods in multiple HIV cohorts.

BACKGROUND: This study aims to evaluate the agreement in substance use on both binary and ordinal scales between 3-month and 6-month recall periods with samples from different communities, demographic backgrounds, and HIV status. METHODS: We administered the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) to 799 participants from three different North American cohorts focused on substance use and HIV. We conducted a within-person agreement analysis by calculating the agreement levels and Kappa statistic between data collected using the 3-month recall ASSIST and 6-month custom substance use surveys as well as different terminology for each substance in multiple cohorts. RESULTS: For all drugs studied, the agreement on the binary use or ordinal frequency of use metrics showed a high agreement level between 80.4% and 97.9% and an adequate adjusted kappa value between 0.61 and 0.96, suggesting substantial agreement. According to the agreement criteria we proposed, substance use data collected using different recall periods and with variation in drug names can be harmonized across cohorts. CONCLUSIONS: This study is the first to evaluate the feasibility of data harmonization of substance use by demonstrating high level of agreement between different recall periods in different cohorts. The results can inform data harmonization efforts in consortia where data are collected from cohorts using different questions and recall periods.

Establishing a common metric for physical function: Linking SARC-F and PROMIS® physical function.

INTRODUCTION: Aligned with the increasing need for standardized assessment of physical function in older individuals with cancer and other conditions, several patient-reported outcome measures (PROMs) have been developed and published. The aim of this study is to link the Strength, Assistance with walking, Rising from a chair, Climbing stairs, and Falls questionnaire (SARC-F), and the Patient-Reported Outcomes Measurement Information System® (PROMIS®) Physical Function Short Form 8c (PROMIS PF 8c), and make their scores convertible, in order to expand the use of both instruments in research and inform clinicians and researchers about the interchangeability of critical cut-off scores. MATERIALS AND METHODS: The sample included 300 participants recruited from an online panel. Participants were included if they had received a cancer diagnosis from a clinician and reported receiving anti-cancer treatment. We conducted five linking procedures and selected an optimal one to generate the crosswalk table between the two measures. RESULTS: The linked T scores of all five methods showed acceptably small mean differences from the observed T scores, and the standard deviation (SD), and root-mean-squared deviation (RMSD) of the differences were generally similar across all methods. After comparing across all statistics, the Stocking-Lord approach was considered as the optimal approach to compute the crosswalk table for converting SARC-F raw scores to PROMIS PF 8c scores. The crosswalk table shows that the SARC-F cut-off value of 4 between healthy versus symptomatic with a corresponding score of 37 fell in the range of moderate physical function limitation from 30 to 39 on the PROMI PF 8c T score metric. DISCUSSION: The linkage in this study has potential for improving clinical and research activities for people with cancer and perhaps others with a similar range of physical function. It facilitates the interpretability in scores of both measures on a common metric anchored on general population for further group-level analysis. Researchers can use this crosswalk to harmonize data collected from either instrument without requiring all cohorts to administer the same instrument for a prospective data collection or retrospective data analysis purpose or for a cross-study effectiveness study.

Patient-reported outcomes of maintenance rucaparib in patients with recurrent ovarian carcinoma in ARIEL3, a phase III, randomized, placebo-controlled trial.

PURPOSE: To compare NFOSI-18 Disease Related Symptoms - Physical (DRSP), Total score, and side effect bother between maintenance rucaparib (600 mg twice daily) vs. placebo in the phase III ARIEL3 trial. METHODS: ARIEL3 (NCT01968213) included patients with ovarian carcinoma who responded to second-line or later platinum-based chemotherapy. The NFOSI-18 DRS-P and Total scales were secondary endpoints. The NFOSI-18 contains a side effect impact item (GP5): "I am bothered by side effects of treatment." We compared treatment arms on change from baseline of DRS-P and Total scores using mixed models with repeated measures (MRMM). Time to first and confirmed deterioration of NFOSI-18 DRS-P and Total scales were analyzed using Cox regression. We also calculated the proportion of patients reporting moderate to high side effect bother on GP5. RESULTS: In the intention-to-treat (ITT) cohort, mean change from baseline favored the placebo. Compared to placebo, rucaparib was associated with higher risk of deterioration [e.g., 4-point deteriorator definition hazard ratio (HR): 1.85; 95% CI: 1.46, 2.36; median time to first deterioration on DRSP: 1.9 vs. 7.0 months]. Confirmed deterioration results resembled those for first deterioration. Proportions of patients reporting moderate/high side effect bother on GP5 fluctuated around 20% across treatment cycles. Results in BRCA mutant and homologous recombination deficient cohorts were generally similar to those from the ITT cohort. CONCLUSION: This placebo-controlled study in the maintenance therapy setting provides a unique view of the impact of PARP inhibition on the patient-reported outcomes that are commonly used in ovarian cancer clinical trials. Information regarding the adverse side effect impact of PARP inhibitors should be weighed against their clinical benefit.

Multifunctional Carbon Dots-Based Fluorescence Detection for Sudan I, Sudan IV and Tetracycline Hydrochloride in Foods.

Sudan dyes are strictly prohibited from being added to edible products as carcinogens and tetracycline hydrochloride (TC) remaining in animal-derived food may cause harm to the human body. Therefore, it is necessary to establish a high-sensitivity, simple and convenient method for the detection of Sudan dyes and TC in foods for safety purposes. In this work, multifunctional blue fluorescent carbon dots (B-CDs) were prepared by a one-step hydrothermal synthesis using glucose as the carbon source. The results show that the fluorescence intensity of B-CDs was significantly affected by the acidity of the solution and can be quenched by Sudan I, IV and TC through selective studies. Interestingly, the fluorescence quenching intensities of B-CDs have a good linear relationship with the concentration of Sudan I and IV at pH = 3-7. The wide range of pH is beneficial to broaden the application of B-CDs in a practical samples analysis. The method has been successfully applied to real food samples of tomato paste, palm oil and honey, and the detection limits are 26.3 nM, 54.2 nM and 31.1 nM for Sudan I, Sudan IV and TC, respectively. This method integrates Sudan dyes and TC into the same multifunctional B-CDs, which shows that the sensor has a great potential in food safety detection.

Linking the KOOS-PS to PROMIS Physical Function in Knee Patients Evaluated for Surgery.

INTRODUCTION: The Knee Injury and Osteoarthritis Outcome Score-Physical Function Short-form and the Patient-Reported Outcomes Measurement Information System Physical Function are widely used patient-reported outcome measures in orthopaedic practice and research. It would be helpful for clinicians and researchers to compare scores obtained on one instrument with those collected on another. To achieve this goal, this study conducted a linking analysis and computed a crosswalk table between these two scales. DATA: The data of this study were collected as part of the clinical care of total knee arthroplasty patients in a large urban and suburban health system. The sample was a mix of responses from nonsurgical (no surgery performed), preoperative (before surgical intervention), and postoperative (after surgical intervention) groups. METHODS: This study applied five linking methods: the item response theory (IRT)-based linking methods including fixed-parameter calibration, separate-parameter calibration with Stocking-Lord constants, and calibrated projection; and the equipercentile methods with log-linear smoothing and nonsmoothing approaches. Before conducting the linking analysis, we checked the linking assumptions including the similar content of the two scales, the unidimensionality of the combined scales, and the population invariance. The results of the five linking methods were evaluated by mean difference, SD, root-mean-squared deviation, intraclass correlation coefficient of the observed T scores and the crosswalk-derived T scores. RESULTS: The linking assumptions were all met. T scores generated from the Stocking-Lord crosswalk had the smallest mean difference (= -0.03) and relatively small SD (= 4.91) and root-mean-squared deviation (= 4.91) among the five linking methods. We validated this crosswalk in a larger sample with the nonsurgical, preoperative, and postoperative groups and in an external sample. DISCUSSION: This study provides clinicians and researchers a practical tool (ie, a crosswalk table) to link scores from two popular physical function measures. Given the diversity of patient-reported outcome measures in use for knee conditions, these crosswalk tables would accelerate clinical and research interpretation of aggregating functional outcomes among the patients evaluated for knee surgery each year.

The comparison of microbial communities in thyroid tissues from thyroid carcinoma patients.

Thyroid carcinoma is a common endocrine organ cancer associated with abnormal hormone secretion, leading to the disorder of metabolism. The intestinal microbiota is vital to maintain digestive and immunologic homeostasis. The relevant information of the microbial community in the gut and thyroid, including composition, structure, and relationship, is unclear in thyroid carcinoma patients. A total of 93 samples from 25 patients were included in this study. The results showed that microbial communities existed in thyroid tissue; gut and thyroid had high abundance of facultative anaerobes from the Proteobacteria phyla. The microbial metabolism from the thyroid and gut may be affected by the thyroid carcinoma cells. The cooccurrence network showed that the margins of different thyroid tissues were unique areas with more competition; the stabilization of microcommunities from tissue and stool may be maintained by several clusters of species that may execute different vital metabolism processes dominantly that are attributed to the microenvironment of cancer.

Can the Knee Outcome and Osteoarthritis Score (KOOS) Function Subscale Be Linked to the PROMIS Physical Function to Crosswalk Equivalent Scores?

BACKGROUND: An increased focus on patient-reported outcome measures (PROMs) has led to a proliferation of these measures in orthopaedic surgery. Mandating a single PROM in clinical and research orthopaedics is not feasible given the breadth of data already collected with older measures and the emergence of psychometrically superior measures. Creating crosswalk tables for scores between measures allows providers to maintain control of measure choice. Furthermore, crosswalk tables permit providers to compare scores collected with older outcome measures with newly collected ones. Given the widespread use of the newer Patient-reported Outcome Measure Information System Physical Function (PROMIS PF) and the established Knee Outcome and Osteoarthritis Score (KOOS), it would be clinically useful to link these two measures. QUESTION/PURPOSE: Can the KOOS Function in Activities of Daily Living (ADL) subscale be robustly linked to the PROMIS PF to create a crosswalk table of equivalent scores that accurately reflects a patient's reported physical function level on both scales? METHODS: We sought to establish a common standardized metric for collected responses to the PROMIS PF and the KOOS ADL to develop equations for converting a PROMIS PF score to a score for the KOOS-ADL subscale and vice versa. To do this, we performed a retrospective, observational study at two academic medical centers and two community hospitals in an urban and suburban healthcare system. Patients 18 years and older who underwent TKA were identified. Between January 2017 and July 2020, we treated 8165 patients with a TKA, 93% of whom had a diagnosis of primary osteoarthritis. Of those, we considered patients who had completed a full KOOS and PROMIS PF 10a on the same date as potentially eligible. Twenty-one percent (1708 of 8165) of patients were excluded because no PROMs were collected at any point, and another 67% (5454 of 8165) were excluded because they completed only one of the required PROMs, leaving 12% (1003 of 8165) for analysis here. PROMs were collected each time they visited the health system before and after their TKAs. Physical function was measured by the PROMIS PF version 1.0 SF 10a and KOOS ADL scale. Analyses to accurately create a crosswalk of equivalent scores between the measures were performed using the equipercentile linking method with both unsmoothed and log linear smoothed score distributions. RESULTS: Crosswalks were created, and adequate validation results supported their validity; we also created tables to allow clinicians and clinician scientists to convert individual patients' scores easily. The mean difference between the observed PROMIS PF scores and the scores converted by the crosswalk from the KOOS-ADL scores was -0.08 ± 4.82. A sensitivity analysis was conducted, confirming the effectiveness of these crosswalks to link the scores of two measures from patients both before and after surgery. CONCLUSION: The PROMIS PF 10a can be robustly linked to the KOOS ADL measure. The developed crosswalk table can be used to convert PROMIS PF scores from KOOS ADL and vice versa. CLINICAL RELEVANCE: The creation of a crosswalk table between the KOOS Function in ADL subscale and PROMIS PF allows clinicians and researchers to easily convert scores between the measures, thus permitting greater choice in PROM selection while preserving comparability between patient cohorts and PROM data collected from older outcome measures. Creating a crosswalk, or concordance table, between the two scales will facilitate this comparison, especially when pooling data for meta-analyses.

Nitrogen-doped fluorescence carbon dots as multi-mechanism detection for iodide and curcumin in biological and food samples.

Iodine ion is one of the most indispensable anions in living organisms, particularly being an important substance for the synthesis of thyroid hormones. Curcumin is a yellow-orange polyphenol compound derived from the rhizome of Curcuma longa L., which has been commonly used as a spice and natural coloring agent, food additives, cosmetics as well as Chinese medicine. However, excess curcumin may cause DNA inactivation, lead to a decrease in intracellular ATP levels, and trigger the tissue necrosis. Therefore, quantitative detection of iodine and curcumin is of great significance in the fields of food and life sciences. Herein, we develop nitrogen-doped fluorescent carbon dots (NCDs) as a multi-mechanism detection for iodide and curcumin in actual complex biological and food samples, which was prepared by a one-step solid-phase synthesis using tartaric acid and urea as precursors without adding any other reagents. An assembled NCDs-Hg2+ fluorescence-enhanced sensor for the quantitative detection of I- was established based on a fluorescence "turn-off-on" mechanism in a linear range of 0.3-15 µM with a detection limit of 69.4 nM and successfully quantified trace amounts of I- in water samples and urine sample. Meanwhile, the as-synthesized NCDs also can be used as a fluorescent quenched sensor for curcumin detection based on the synergistic internal filtration effect (IFE) and static quenching, achieving a good linear range of 0.1-20 µM with a satisfactory detection limit of 29.8 nM. These results indicate that carbon dots are potential sensing materials for iodine and curcumin detection for the good of our health.

Distinct Airway Epithelial Stem Cells Hide among Club Cells but Mobilize to Promote Alveolar Regeneration.

Lung injury activates specialized adult epithelial progenitors to regenerate the epithelium. Depending on the extent of injury, both remaining alveolar type II cells (AEC2s) and distal airway stem/progenitors mobilize to cover denuded alveoli and restore normal barriers. The major source of airway stem/progenitors other than basal-like cells remains uncertain. Here, we define a distinct subpopulation (∼5%) of club-like lineage-negative epithelial progenitors (LNEPs) marked by high H2-K1 expression critical for alveolar repair. Quiescent H2-K1high cells account for virtually all in vitro regenerative activity of airway lineages. After bleomycin injury, H2-K1 cells expand and differentiate in vivo to alveolar lineages. However, injured H2-K1 cells eventually develop impaired self-renewal with features of senescence, limiting complete repair. Normal H2-K1high cells transplanted into injured lungs differentiate into alveolar cells and rescue lung function. These findings indicate that small subpopulations of specialized stem/progenitors are required for effective lung regeneration and are a potential therapeutic adjunct after major lung injury.

Mesenchymal Stem Cell Microvesicles Attenuate Acute Lung Injury in Mice Partly Mediated by Ang-1 mRNA.

Microvesicles (MVs) derived from human mesenchymal stem cells (MSC MVs) were demonstrated to ameliorate inflammation in lungs. We have found their content of mRNA for keratinocyte growth factor was partly involved in their therapeutic effects. As MSC MVs also contained a substantial quantity of angiopoietin-1 (Ang-1) mRNA, which plays an essential role in vascular stabilization and resolving inflammation, we hypothesized that Ang-1 mRNA might similarly account for a part of their therapeutic effects. We downregulated Ang-1 mRNA expression in MVs, using a lentivirus vector carrying Ang-1 short hairpin RNA to transfect MSCs. A mouse model of lipopolysaccharide induced acute lung injury (ALI) was used in vivo. We also studied in vitro interactions between Ang-1 mRNA deficient MVs on macrophages and human lung microvascular endothelial cells. Compared with negative control, Ang-1 mRNA deficient MVs increased the influx of neutrophils and macrophage inflammatory protein-2 levels in bronchoalveolar lavage fluid by 136% and 105%, respectively, suggesting a deteriorative lung inflammation and a failure to restore pulmonary capillary permeability assessed by Evan's blue dye and bronchoalveolar lavage albumin level. In vitro, the addition of Ang-1 mRNA deficient MVs failed to maintain the integrity of endotoxin-stimulated microvascular endothelial cells and abrogated the decrease in tumor necrosis factor-α level and the increase in interleukin-10 level mediated by negative control in RAW 264.7 cells. In summary, the therapeutic effects of MVs in ALI, and their immunomodulatory properties on macrophages were partly mediated through their content of Ang-1 mRNA. Stem Cells 2017;35:1849-1859.

Antidesmone, a unique tetrahydroquinoline alkaloid, prevents acute lung injury via regulating MAPK and NF-κB activities.

Acute lung injury, characterized by inflammation, is a main cause of respiratory failure that affects patients worldwide. Antidesmone is one compound mainly isolated from Ajugade cumbens Thunb (Labiatae), an herb agent of Labiatae family. In this research, we investigated the anti-inflammation effect of antidesmone in vitro and in vivo. Antidesmone exerted none apparently cytotoxicity in vitro and toxic in vivo. In vitro results demonstrated that antidesmone suppressed the excess inflammatory cytokines production, including tumor necrosis factor-α, interleukin-6 and interleukin-1ß in lipopolysaccharide (LPS)-exposed RAW264.7 cells. In vivo results suggested that antidesmone inhibited inflammatory cytokines in the bronchoalveolar lavage fluid and lung tissue after LPS stimulation. Moreover, antidesmone attenuated the nuclear translocation of p65. Mechanism study revealed that mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways play important roles in antidesmone's action. Taken together, our data uncover a relative toxic anti-inflammatory drug, antidesmone, can inhibit inflammation on stimulated macrophages and thereby prevents acute lung injury by regulating MAPK and NF-κB signaling pathways.

The action and mechanism of myrislignan on A549 cells in vitro and in vivo.

Myrislignan is a natural compound with little pharmacological study. In our investigation, we investigated the effect of myrislignan in the induction of apoptosis in A549 cells in vitro and in vivo. Myrislignan inhibited the proliferation of A549 cells in a dose- and time-dependent manner assayed by MTT. In addition, Hoechst flow cytometry showed that myrislignan significantly induced apoptosis and cell cycle arrest in A549 cells. The apoptosis and anti-cell proliferation was mediated by the activation of mitogen-activated protein kinase and the inhibition of epidermal growth factor receptor signal pathway, change of mitochondrial membrane potential, the releasing of c-Myc, the downregulation of the level of the anti-apoptotic protein Bcl-2, and the upregulation of the level of the pro-apoptotic protein Bax. In conclusion, those results reveal a potential mechanism for the anti-cancer effect of myrislignan on human lung cancer, while suggesting that myrislignan may be a promising compound for the treatment of lung cancer.

RASSF1A gene methylation is associated with nasopharyngeal carcinoma risk in Chinese.

In order to explore the association between RASSF1A methylation and nasopharyngeal carcinoma (NPC) risk of Chinese, we carried out a meta-analysis with searches of PubMed, Web of Science, ProQest and Medline databases. Ultimately, 14 articles were identified and analysised using R Software (R version 3.1.2) including meta packages. Overall, we found a significant relationship between RASSF1A methylation and NPC risk (OR 30.7; 95 % CI, 16.71~56.23; z=11.0591; p<0.0001) in a fixed effects model and (OR 32.1; 95% CI, 14.27~72.01; z=8.3984; p<0.0001) in a random effects model pooled. In tissue and NP brushings groups , similar results were found. Hence, our study identified a strong association between RASSF1A methylation and NPC and highlighted a promising potential for RASSF1A methylation in NPC risk prediction of Chinese.

Adipose Tissue-Derived Mesenchymal Stem Cells Attenuate Pulmonary Infection Caused by Pseudomonas aeruginosa via Inhibiting Overproduction of Prostaglandin E2.

RATIONALE: New strategies for treating Pseudomonas aeruginosa pulmonary infection are urgently needed. Adipose tissue-derived mesenchymal stem cells (ASCs) may have a potential therapeutic role in P. aeruginosa-induced pulmonary infection. METHODS: The therapeutic and mechanistic effects of ASCs on P. aeruginosa pulmonary infection were evaluated in a murine model of P. aeruginosa pneumonia. RESULTS: ASCs exhibited protective effects against P. aeruginosa pulmonary infection, evidenced by reduced bacterial burdens, inhibition of alveolar neutrophil accumulation, decreased levels of myeloperoxidase, macrophage inflammatory protein-2 and total proteins in broncho-alveolar lavage fluid (BALF), and attenuated severity of lung injury. ASCs had no effects on BALF and serum levels of keratinocyte growth factor or Ang-1. ASCs had no effects on the levels of insulin growth factor 1 (IGF-1) in BALF, but increased IGF-1 levels in serum. ASCs inhibited the overproduction of prostaglandin E2 (PGE2 ) by decreasing the expression of cyclooxygenase-2 (COX2) and enhancing the expression of 15-PGDH. In addition, the addition of exogenous PGE2 with ASCs abolished many of the protective effects of ASCs, and administrating PGE2 alone exacerbated lung infection. By inhibiting production of PGE2 , ASCs improved phagocytosis and the bactericidal properties of macrophages. Furthermore suppressing PGE2 signaling by COX2 inhibition or EP2 inhibition exhibited protective effects against pulmonary infection as well. CONCLUSIONS: In a murine model of P. aeruginosa pneumonia, ASCs exhibited protective effects by inhibiting production of PGE2 , which subsequently improved phagocytosis and the bactericidal properties of macrophages. ASCs may provide a new strategy for managing pulmonary infection caused by P. aeruginosa.

Co-occurrence of driver and passenger bacteria in human colorectal cancer.

BACKGROUND: Both genetic and epigenetic alterations have been reported to act as driving forces of tumorigenesis in colorectal cancer (CRC), but a growing body of evidence suggests that intestinal microbiota may be an aetiological factor in the initiation and progression of CRC. Recently, the "driver-passenger" model for CRC has connected these different factors, but little has been done to characterize the CRC gut microbiome. FINDINGS: Building on the driver-passenger model, we used 454 pyrosequencing of bacterial 16S rRNA genes associated with 10 normal, 10 adenoma, and 8 tumor biopsy samples, and found 7 potential driver bacterial genera and 12 potential passenger bacterial genera (7 being pro-inflammatory and 5 anti-inflammatory). Further analysis also showed certain co-expression patterns among different clusters of bacteria that may potentially be related to the promotion or progression of gut cancers. CONCLUSIONS: The present findings provide preliminary experimental evidence supporting the proposition of bacterial "driver-passenger model" for CRC, and identified potentially novel microbial agents that may be connected to risk of CRC in a Han Chinese population.

Panaxatriol saponin ameliorated liver injury by acetaminophen via restoring thioredoxin-1 and pro-caspase-12.

BACKGROUND & AIMS: Acetaminophen (APAP) is widely used as an antipyretic agent which is safe at therapeutic doses. However, overdose of APAP induces fatal and non-fatal hepatic necroses. The chemical reactive metabolites of APAP initiate toxicity and inflammatory response within the liver and lead to acute liver failure. However, the mechanism underlying APAP-induced liver injury is unknown. Thioredoxin-1 (TRX-1) is an important redox regulator, which plays roles in resisting oxidative stress, regulating inflammation and inhibiting apoptosis. Panaxatriol saponin (PTS) is one of the biologically active fractions of Panax notoginseng which is a traditional Chinese medicine. The aim of this study was to investigate the mechanism on PTS protecting liver from APAP hepatotoxicity. METHODS: Mice were divided into three groups, control group, APAP group and APAP combined with PTS group. Alanine aminotransferase (ALT) and tumour necrosis factor-alpha (TNF-α) were detected by ELISA. TRX-1 and pro-caspase-12 were examined by Western blotting. RESULTS: Our results showed PTS inhibited the levels of ALT and TNF-α by APAP. Pretreatment with PTS ameliorated liver injury induced by APAP. The decrease in TRX-1 expression was restored by PTS, as well as decreased pro-caspase-12 expression was inhibited by PTS. These data suggest that PTS has roles in suppressing the hepatotoxicity by APAP. CONCLUSION: Panaxatriol saponin ameliorated liver injury by APAP through restoring the expression TRX-1 and inhibiting pro-caspase-12 decrease.

Spatial heterogeneity and co-occurrence patterns of human mucosal-associated intestinal microbiota.

Human gut microbiota shows high inter-subject variations, but the actual spatial distribution and co-occurrence patterns of gut mucosa microbiota that occur within a healthy human instestinal tract remain poorly understood. In this study, we illustrated a model of this mucosa bacterial communities' biogeography, based on the largest data set so far, obtained via 454-pyrosequencing of bacterial 16S rDNAs associated with 77 matched biopsy tissue samples taken from terminal ileum, ileocecal valve, ascending colon, transverse colon, descending colon, sigmoid colon and rectum of 11 healthy adult subjects. Borrowing from macro-ecology, we used both Taylor's power law analysis and phylogeny-based beta-diversity metrics to uncover a highly heterogeneous distribution pattern of mucosa microbial inhabitants along the length of the intestinal tract. We then developed a spatial dispersion model with an R-squared value greater than 0.950 to map out the gut mucosa-associated flora's non-linear spatial distribution pattern for 51.60% of the 188 most abundant gut bacterial species. Furthermore, spatial co-occurring network analysis of mucosa microbial inhabitants together with occupancy (that is habitat generalists, specialists and opportunist) analyses implies that ecological relationships (both oppositional and symbiotic) between mucosa microbial inhabitants may be important contributors to the observed spatial heterogeneity of mucosa microbiota along the human intestine and may even potentially be associated with mutual cooperation within and functional stability of the gut ecosystem.