Capillary Electrophoretic Analysis of Exhaled Breath Condensate in the Diagnosis of Gastroesophageal Reflux Disease

In this work, capillary electrophoresis with contactless conductometric detection (CCD) was used for the analysis of the ionic content of exhaled breath condensate (EBC) to differentiate between healthy individuals and patients with gastroesophageal reflux disease (GERD). The exhaled breath condensate was collected using a miniature sample collection device and the content analyzed using a separation electrolyte composed of 20 mM 2-(N-morpholino)ethanesulfonic acid, 20 mM L-histidine, 2 mM 18-Crown-6 and 30 M cetyltrimethylammonium bromide. The separation of anions took less than 2.5 minutes, while the cations were separated in less than 1.5 minutes. The most significantly elevated ions in the group of patients suffering from gastroesophageal reflux disease were chloride, nitrate, propionate and butyrate. Although the number of subjects was too small to draw definite conclusions with regard to the discriminatory power of these ions, the pilot data are promising for EBC as a useful non-invasive alternative for other methods used in the diagnosis of gastroesophageal reflux diseas

Mycobacterium tuberculosis transmission in a country with low tuberculosis incidence: role of immigration and HIV infection.

Immigrants from high-burden countries and HIV-coinfected individuals are risk groups for tuberculosis (TB) in countries with low TB incidence. Therefore, we studied their role in transmission of Mycobacterium tuberculosis in Switzerland. We included all TB patients from the Swiss HIV Cohort and a sample of patients from the national TB registry. We identified molecular clusters by spoligotyping and mycobacterial interspersed repetitive-unit-variable-number tandem-repeat (MIRU-VNTR) analysis and used weighted logistic regression adjusted for age and sex to identify risk factors for clustering, taking sampling proportions into account. In total, we analyzed 520 TB cases diagnosed between 2000 and 2008; 401 were foreign born, and 113 were HIV coinfected. The Euro-American M. tuberculosis lineage dominated throughout the study period (378 strains; 72.7%), with no evidence for another lineage, such as the Beijing genotype, emerging. We identified 35 molecular clusters with 90 patients, indicating recent transmission; 31 clusters involved foreign-born patients, and 15 involved HIV-infected patients. Birth origin was not associated with clustering (adjusted odds ratio [aOR], 1.58; 95% confidence interval [CI], 0.73 to 3.43; P = 0.25, comparing Swiss-born with foreign-born patients), but clustering was reduced in HIV-infected patients (aOR, 0.49; 95% CI, 0.26 to 0.93; P = 0.030). Cavitary disease, male sex, and younger age were all associated with molecular clustering. In conclusion, most TB patients in Switzerland were foreign born, but transmission of M. tuberculosis was not more common among immigrants and was reduced in HIV-infected patients followed up in the national HIV cohort study. Continued access to health services and clinical follow-up will be essential to control TB in this population

Association between the degree of immunodeficiency and tuberculosis with an allopatric <i>Mycobacterium tuberculosis</i> strain among European patients (n = 233).

<p>Model was adjusted for age, sex, Swiss-born, frequent travelling, contact with foreign-born population, and immunosuppression other than HIV infection (see <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003318#pgen-1003318-g002" target="_blank">Figure 2</a> for a graphical overview).</p><p><i>P</i> values of linear tests for trend are shown.</p

HIV status in tuberculosis (TB) patients with an allopatric compared to patients with a sympatric <i>Mycobacterium tuberculosis</i> strain among European patients in a second panel.

<p>Patient isolates were obtained from a population-based TB study (n = 1,642) in the Canton of Bern, Switzerland, diagnosed between 1991 and 2011.</p><p>Sympatric was defined as a strain belonging to Lineage 4 (Euro-American lineage), allopatric as a strain belonging to a lineage other than Lineage 4.</p>1<p>Fisher's exact test.</p><p>95% CI, 95% confidence interval.</p

Patient characteristics of tuberculosis (TB) patients born in Europe, by presence of allopatric and sympatric <i>Mycobacterium tuberculosis</i> strains.

1<p>Fisher's exact test.</p>2<p>Use of TNF-alpha inhibitors, malignancy, organ transplantation, use of steroids, or methotrexate.</p>3<p>Among HIV–infected patients (n = 36).</p><p>95% CI, 95% confidence interval; IQR, interquartile range.</p

Phylogeography of the six main <i>Mycobacterium tuberculosis</i> lineages.

<p>A: Phylogenetic tree of the main <i>M. tuberculosis</i> lineages described in our study based on the neighbor-joining phylogeny across 23 <i>M. tuberculosis</i> complex whole-genome sequences (from Ref. <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003318#pgen.1003318-Bentley1" target="_blank">[72]</a>). Numbers on branches refer to the corresponding number of single nucleotide polymorphisms inferred. B: Distribution of the main phylogenetic <i>M. tuberculosis</i> lineages among Swiss tuberculosis cases included in the study (n = 518), by geographic origin of the patients. In (A) <i>Mycobacterium canettii</i> was used as the outgroup. SNPs, single nucleotide polymorphisms. In (B) the sizes of the pie charts correspond to the number of patients included in the study: European region (233 patients), Middle-East/North Africa (27), Indian subcontinent (36), Western Pacific (19), Central/South America (24), South-East Asia (48), and Eastern (55), Western (46) and Southern region (30) of sub-Saharan Africa. Lineage 1: Indo-Oceanic lineage; Lineage 2: East-Asian lineage (includes Beijing strains); Lineage 3: Delhi/CAS; Lineage 4: Euro-American lineage; Lineages 5 and 6: West African lineages.</p

HIV infection disrupts the sympatric host-pathogen relationship in human tuberculosis

The phylogeographic population structure of Mycobacterium tuberculosis suggests local adaptation to sympatric human populations. We hypothesized that HIV infection, which induces immunodeficiency, will alter the sympatric relationship between M. tuberculosis and its human host. To test this hypothesis, we performed a nine-year nation-wide molecular-epidemiological study of HIV-infected and HIV-negative patients with tuberculosis (TB) between 2000 and 2008 in Switzerland. We analyzed 518 TB patients of whom 112 (21.6%) were HIV-infected and 233 (45.0%) were born in Europe. We found that among European-born TB patients, recent transmission was more likely to occur in sympatric compared to allopatric host-pathogen combinations (adjusted odds ratio [OR] 7.5, 95% confidence interval [95% CI] 1.21-infinity, p = 0.03). HIV infection was significantly associated with TB caused by an allopatric (as opposed to sympatric) M. tuberculosis lineage (OR 7.0, 95% CI 2.5-19.1, p<0.0001). This association remained when adjusting for frequent travelling, contact with foreigners, age, sex, and country of birth (adjusted OR 5.6, 95% CI 1.5-20.8, p = 0.01). Moreover, it became stronger with greater immunosuppression as defined by CD4 T-cell depletion and was not the result of increased social mixing in HIV-infected patients. Our observation was replicated in a second independent panel of 440 M. tuberculosis strains collected during a population-based study in the Canton of Bern between 1991 and 2011. In summary, these findings support a model for TB in which the stable relationship between the human host and its locally adapted M. tuberculosis is disrupted by HIV infection

Comprehensive genomic characterization of squamous cell lung cancers

Lung squamous cell carcinoma is a common type of lung cancer, causing approximately 400,000 deaths per year worldwide. Genomic alterations in squamous cell lung cancers have not been comprehensively characterized, and no molecularly targeted agents have been specifically developed for its treatment. As part of The Cancer Genome Atlas, here we profile 178 lung squamous cell carcinomas to provide a comprehensive landscape of genomic and epigenomic alterations. We show that the tumour type is characterized by complex genomic alterations, with a mean of 360 exonic mutations, 165 genomic rearrangements, and 323 segments of copy number alteration per tumour. We find statistically recurrent mutations in 11 genes, including mutation of TP53 in nearly all specimens. Previously unreported loss-of-function mutations are seen in the HLA-A class I major histocompatibility gene. Significantly altered pathways included NFE2L2 and KEAP1 in 34%, squamous differentiation genes in 44%, phosphatidylinositol-3-OH kinase pathway genes in 47%, and CDKN2A and RB1 in 72% of tumours. We identified a potential therapeutic target in most tumours, offering new avenues of investigation for the treatment of squamous cell lung cancers.National Institutes of Health (U.S.) (Grant U24 CA126561)National Institutes of Health (U.S.) (Grant U24 CA126551)National Institutes of Health (U.S.) (Grant U24 CA126554)National Institutes of Health (U.S.) (Grant U24 CA126543)National Institutes of Health (U.S.) (Grant U24 CA126546)National Institutes of Health (U.S.) (Grant U24 CA126563)National Institutes of Health (U.S.) (Grant U24 CA126544)National Institutes of Health (U.S.) (Grant U24 CA143845)National Institutes of Health (U.S.) (Grant U24 CA143858)National Institutes of Health (U.S.) (Grant U24 CA144025)National Institutes of Health (U.S.) (Grant U24 CA143882)National Institutes of Health (U.S.) (Grant U24 CA143866)National Institutes of Health (U.S.) (Grant U24 CA143867)National Institutes of Health (U.S.) (Grant U24 CA143848)National Institutes of Health (U.S.) (Grant U24 CA143840)National Institutes of Health (U.S.) (Grant U24 CA143835)National Institutes of Health (U.S.) (Grant U24 CA143799)National Institutes of Health (U.S.) (Grant U24 CA143883)National Institutes of Health (U.S.) (Grant U24 CA143843)National Institutes of Health (U.S.) (Grant U54 HG003067)National Institutes of Health (U.S.) (Grant U54 HG003079)National Institutes of Health (U.S.) (Grant U54 HG003273

Comprehensive molecular characterization of human colon and rectal cancer

To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total, 16% of colorectal carcinomas were found to be hypermutated: three-quarters of these had the expected high microsatellite instability, usually with hypermethylation and MLH1 silencing, and one-quarter had somatic mismatch-repair gene and polymerase ε (POLE) mutations. Excluding the hypermutated cancers, colon and rectum cancers were found to have considerably similar patterns of genomic alteration. Twenty-four genes were significantly mutated, and in addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include the fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression.National Institutes of Health (U.S.) (Grant U24CA143799)National Institutes of Health (U.S.) (Grant U24CA143835)National Institutes of Health (U.S.) (Grant U24CA143840)National Institutes of Health (U.S.) (Grant U24CA143843)National Institutes of Health (U.S.) (Grant U24CA143845)National Institutes of Health (U.S.) (Grant U24CA143848)National Institutes of Health (U.S.) (Grant U24CA143858)National Institutes of Health (U.S.) (Grant U24CA143866)National Institutes of Health (U.S.) (Grant U24CA143867)National Institutes of Health (U.S.) (Grant U24CA143882)National Institutes of Health (U.S.) (Grant U24CA143883)National Institutes of Health (U.S.) (Grant U24CA144025)National Institutes of Health (U.S.) (Grant U54HG003067)National Institutes of Health (U.S.) (Grant U54HG003079)National Institutes of Health (U.S.) (Grant U54HG003273