Analysis of Factors Driving Incident and Ascending Infection and the Role of Serum Antibody in Chlamydia trachomatis Genital Tract Infection

Background. Chlamydia trachomatis genital tract infection is a major cause of female reproductive morbidity. Risk factors for ascending infection are unknown, and the role for antibody in protection is not well established

A 43-GHz Survey in the ELAIS N2 Area

We describe a survey in the ELAIS N2 region with the VLA at 43.4 GHz, carried out with 1627 independent snapshot observations in D-configuration and covering about 0.5 square degrees. One certain source is detected, a previously-catalogued flat-spectrum QSO at z=2.2. A few (<5) other sources may be present at about the 3sigma level, as determined from positions of source-like deflections coinciding with blue stellar objects, or with sources from lower-frequency surveys. Independently we show how all the source-like detections identified in the data can be used with a maximum-likelihood technique to constrain the 43-GHz source counts at a level of ~7 mJy. Previous estimates of the counts at 43 GHz, based on lower-frequency counts and spectral measurements, are consistent with these constraints, although the present results are suggestive of somewhat higher surface densities at the 7 mJy level. They do not provide direct evidence of intrusion of a previously unknown source population, although the several candidate sources need examination before such a population can be ruled out.Comment: 13 pages, 11 figures, 1 table; accepted for publication in Mon. Not R. Astr. So

Identification of Chlamydia trachomatis Antigens Recognized by T Cells From Highly Exposed Women Who Limit or Resist Genital Tract Infection

Background. Natural infection induces partial immunity to Chlamydia trachomatis. Identification of chlamydial antigens that induce interferon γ (IFN-) secretion by T cells from immune women could advance vaccine development

Gene Expression Signatures Can Aid Diagnosis of Sexually Transmitted Infection-Induced Endometritis in Women

Sexually transmitted infection (STI) of the upper reproductive tract can result in inflammation and infertility. A biomarker of STI-induced upper tract inflammation would be significant as many women are asymptomatic and delayed treatment increases risk of sequelae. Blood mRNA from 111 women from three cohorts was profiled using microarray. Unsupervised analysis revealed a transcriptional profile that distinguished 9 cases of STI-induced endometritis from 18 with cervical STI or uninfected controls. Using a hybrid feature selection algorithm we identified 21 genes that yielded maximal classification accuracy within our training dataset. Predictive accuracy was evaluated using an independent testing dataset of 5 cases and 10 controls. Sensitivity was evaluated in a separate test set of 12 women with asymptomatic STI-induced endometritis in whom cervical burden was determined by PCR; and specificity in an additional test set of 15 uninfected women with pelvic pain due to unknown cause. Disease module preservation was assessed in 42 women with a clinical diagnosis of pelvic inflammatory disease (PID). We also tested the ability of the biomarker to discriminate STI-induced endometritis from other diseases. The biomarker was 86.7% (13/15) accurate in correctly distinguishing cases from controls in the testing dataset. Sensitivity was 83.3% (5/6) in women with high cervical Chlamydia trachomatis burden and asymptomatic endometritis, but 0% (0/6) in women with low burden. Specificity in patients with non-STI-induced pelvic pain was 86.7% (13/15). Disease modules were preserved in all 8 biomarker predicted cases. The 21-gene biomarker was highly discriminatory for systemic infections, lupus, and appendicitis, but wrongly predicted tuberculosis as STI-induced endometritis in 52.4%. A 21-gene biomarker can identify asymptomatic women with STI-induced endometritis that places them at risk for chronic disease development and discriminate STI-induced endometritis from non-STI pelvic pain and other diseases

Epithelial Expressed B7-H4 Drives Differential Immunotherapy Response in Murine and Human Breast Cancer

Combinations of immune checkpoint inhibitors (ICI, including anti-PD-1/PD-L1) and chemotherapy have been FDA approved for metastatic and early-stage triple-negative breast cancer (TNBC), but most patients do not benefit. B7-H4 is a B7 family ligand with proposed immunosuppressive functions being explored as a cancer immunotherapy target and may be associated with anti-PD-L1 resistance. However, little is known about its regulation and effect on immune cell function in breast cancers. We assessed murine and human breast cancer cells to identify regulation mechanisms of B7-H4 in vitro. We used an immunocompetent anti-PD-L1-sensitive orthotopic mammary cancer model and induced ectopic expression of B7-H4. We assessed therapy response and transcriptional changes at baseline and under treatment with anti-PD-L1. We observed B7-H4 was highly associated with epithelial cell status and transcription factors and found to be regulated by PI3K activity. EMT6 tumors with cell-surface B7-H4 expression were more resistant to immunotherapy. In addition, tumor-infiltrating immune cells had reduced immune activation signaling based on transcriptomic analysis. Paradoxically, in human breast cancer, B7-H4 expression was associated with survival benefit for patients with metastatic TNBC treated with carboplatin plus anti-PD-L1 and was associated with no change in response or survival for patients with early breast cancer receiving chemotherapy plus anti-PD-1. While B7-H4 induces tumor resistance to anti-PD-L1 in murine models, there are alternative mechanisms of signaling and function in human cancers. In addition, the strong correlation of B7-H4 to epithelial cell markers suggests a potential regulatory mechanism of B7-H4 independent of PD-L1. SIGNIFICANCE: This translational study confirms the association of B7-H4 expression with a cold immune microenvironment in breast cancer and offers preclinical studies demonstrating a potential role for B7-H4 in suppressing response to checkpoint therapy. However, analysis of two clinical trials with checkpoint inhibitors in the early and metastatic settings argue against B7-H4 as being a mechanism of clinical resistance to checkpoints, with clear implications for its candidacy as a therapeutic target

Bacterial Signatures of Paediatric Respiratory Disease : An Individual Participant Data Meta-Analysis

Introduction: The airway microbiota has been linked to specific paediatric respiratory diseases, but studies are often small. It remains unclear whether particular bacteria are associated with a given disease, or if a more general, non-specific microbiota association with disease exists, as suggested for the gut. We investigated overarching patterns of bacterial association with acute and chronic paediatric respiratory disease in an individual participant data (IPD) meta-analysis of 16S rRNA gene sequences from published respiratory microbiota studies.Methods: We obtained raw microbiota data from public repositories or via communication with corresponding authors. Cross-sectional analyses of the paediatric (10 case subjects were included. Sequence data were processed using a uniform bioinformatics pipeline, removing a potentially substantial source of variation. Microbiota differences across diagnoses were assessed using alpha- and beta-diversity approaches, machine learning, and biomarker analyses.Results: We ultimately included 20 studies containing individual data from 2624 children. Disease was associated with lower bacterial diversity in nasal and lower airway samples and higher relative abundances of specific nasal taxa including Streptococcus and Haemophilus. Machine learning success in assigning samples to diagnostic groupings varied with anatomical site, with positive predictive value and sensitivity ranging from 43 to 100 and 8 to 99%, respectively.Conclusion: IPD meta-analysis of the respiratory microbiota across multiple diseases allowed identification of a non-specific disease association which cannot be recognised by studying a single disease. Whilst imperfect, machine learning offers promise as a potential additional tool to aid clinical diagnosis.Peer reviewe

Application of Two-Part Statistics for Comparison of Sequence Variant Counts

Investigation of microbial communities, particularly human associated communities, is significantly enhanced by the vast amounts of sequence data produced by high throughput sequencing technologies. However, these data create high-dimensional complex data sets that consist of a large proportion of zeros, non-negative skewed counts, and frequently, limited number of samples. These features distinguish sequence data from other forms of high-dimensional data, and are not adequately addressed by statistical approaches in common use. Ultimately, medical studies may identify targeted interventions or treatments, but lack of analytic tools for feature selection and identification of taxa responsible for differences between groups, is hindering advancement. The objective of this paper is to examine the application of a two-part statistic to identify taxa that differ between two groups. The advantages of the two-part statistic over common statistical tests applied to sequence count datasets are discussed. Results from the t-test, the Wilcoxon test, and the two-part test are compared using sequence counts from microbial ecology studies in cystic fibrosis and from cenote samples. We show superior performance of the two-part statistic for analysis of sequence data. The improved performance in microbial ecology studies was independent of study type and sequence technology used

Leptin Reduces the Expression and Increases the Phosphorylation of the Negative Regulators of GLUT4 Traffic TBC1D1 and TBC1D4 in Muscle of ob/ob Mice

Leptin improves insulin sensitivity in skeletal muscle. Our goal was to determine whether proteins controlling GLUT4 traffic are altered by leptin deficiency and in vivo leptin administration in skeletal muscle of wild type and ob/ob mice. Leptin-deficient ob/ob mice were divided in three groups: control, leptin-treated (1 mg/kg/d) and leptin pair-fed ob/ob mice. Microarray analysis revealed that 1,546 and 1,127 genes were regulated by leptin deficiency and leptin treatment, respectively. Among these, we identified 24 genes involved in intracellular vesicle-mediated transport in ob/ob mice. TBC1 domain family, member 1 (Tbc1d1), a negative regulator of GLUT4 translocation, was up-regulated (P = 0.001) in ob/ob mice as compared to wild types. Importantly, leptin treatment reduced the transcript levels of Tbc1d1 (P<0.001) and Tbc1d4 (P = 0.004) in the leptin-treated ob/ob as compared to pair-fed ob/ob animals. In addition, phosphorylation levels of TBC1D1 and TBC1D4 were enhanced in leptin-treated ob/ob as compared to control ob/ob (P = 0.015 and P = 0.023, respectively) and pair-fed ob/ob (P = 0.036 and P = 0.034, respectively) mice. Despite similar GLUT4 protein expression in wild type and ob/ob groups a different immunolocalization of this protein was evidenced in muscle sections. Leptin treatment increased GLUT4 immunoreactivity in gastrocnemius and extensor digitorum longus sections of leptin-treated ob/ob mice. Moreover, GLUT4 protein detected in immunoprecipitates from TBC1D4 was reduced by leptin replacement compared to control ob/ob (P = 0.013) and pair-fed ob/ob (P = 0.037) mice. Our findings suggest that leptin enhances the intracellular GLUT4 transport in skeletal muscle of ob/ob animals by reducing the expression and activity of the negative regulators of GLUT4 traffic TBC1D1 and TBC1D4

Current opinion on the role of testosterone in the development of prostate cancer: a dynamic model

Background: Since the landmark study conducted by Huggins and Hodges in 1941, a failure to distinguish between the role of testosterone in prostate cancer development and progression has led to the prevailing opinion that high levels of testosterone increase the risk of prostate cancer. To date, this claim remains unproven. Presentation of the Hypothesis: We present a novel dynamic mode of the relationship between testosterone and prostate cancer by hypothesizing that the magnitude of age-related declines in testosterone, rather than a static level of testosterone measured at a single point, may trigger and promote the development of prostate cancer. Testing of the Hypothesis: Although not easily testable currently, prospective cohort studies with population-representative samples and repeated measurements of testosterone or retrospective cohorts with stored blood samples from different ages are warranted in future to test the hypothesis. Implications of the Hypothesis: Our dynamic model can satisfactorily explain the observed age patterns of prostate cancer incidence, the apparent conflicts in epidemiological findings on testosterone and risk of prostate cancer, racial disparities in prostate cancer incidence, risk factors associated with prostate cancer, and the role of testosterone in prostate cancer progression. Our dynamic model may also have implications for testosterone replacement therapy