Strains of human immunodeficiency virus type 1 differ in their abilities to infect and replicate in primary human macrophages. Chimeric clones were constructed from a provirus unable to infect macrophages (NLHX) and envelope sequences (V3 loop) of viruses derived without cultivation from brain (YU2 and wl-lcl) or spleen (w2-1b4) tissues. The substituted V3 loop sequences in each case were sufficient to confer upon NLHX the ability to infect macrophages. Furthermore, an envelope domain immediately N terminal to the V3 loop also was found to modulate the level of replication in macrophages. These results demonstrate that an envelope determinant derived directly from patients with AIDS confers HIV-1 tropism for macrophages.

SUMMARY The esophagogastric junction contractile integral (EGJ-CI), designed similar to distal contractile integral (DCI), has been proposed as a metric to evaluate EGJ barrier function. We determined normative values and evaluated EGJ-CI in predicting esophageal acid exposure time (AET) and symptomatic outcome in this observational cohort study. High-resolution manometry (HRM) studies were reviewed in 188 patients (55.2 ± 0.9 years, 64% female) undergoing ambulatory pH monitoring off therapy. Dominant symptoms and global symptom severity (GSS) were determined on questionnaires initially and upon follow-up. EGJ-CI was measured using the DCI tool placed across the EGJ and compared to normal controls (n = 21, 27.6 ± 0.6 years, 52% female). EGJ-CI was calculated both for a single respiratory cycle (SRC, in mmHg.cm.s) and corrected for respiratory cycle (CRC, mmHg.cm). Univariate and multivariate analyses determined the predictive potential of EGJ-CI in terms of AET and post-therapy GSS at follow-up, controlling for medical versus surgical therapy. Mean EGJ-CI values were significantly lower when AET was abnormal; EGJ-CI/SRC and EGJ-CI/CRC were 86% concordant (r = 0.84). Using receiver operating characteristic analysis, values below 121.8 mmHg.cm.s (EGJ-CI/SRC) and 39.3 mmHg.cm (EGJ-CI/CRC) predicted abnormal AET best (sensitivity 0.61 and 0.65, specificity 0.61 and 0.57, respectively). On univariate and multivariate analysis, the EGJ-CI discriminated normal from abnormal AET better than conventional LES parameters (P ≤ 0.02). After 2.7 ± 0.1 years follow-up, EGJ-CI below identified thresholds predicted better symptom response to antireflux surgery compared to medical therapy (P = 0.009). EGJ-CI is a novel HRM metric that has potential to complement or replace currently used basal LES and EGJ parameters.

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Although Wnt signaling activation is frequently observed in human breast cancer, mutations in the genes encoding intracellular components of the Wnt signaling pathway are rare. We found that expression of Wnt signaling co-receptor LRP6 is up-regulated in a subset of human breast cancer tissues and cell lines. To examine whether overexpression of LRP6 in mammary epithelial cells is sufficient to activate Wnt signaling and promote cell proliferation, we generated transgenic mice overexpressing LRP6 in mammary epithelial cells driven by the mouse mammary tumor virus (MMTV) promoter. We found that mammary glands from MMTV-LRP6 mice exhibit significant Wnt activation evidenced by the translocation of β-catenin from membrane to cytoplasmic/nuclear fractions. Expression of several Wnt-target genes including Axin2, Cyclin D1 and c-Myc was also increased in MMTV-LRP6 mice. More importantly, mammary glands from virgin MMTV-LRP6 mice exhibit significant hyperplasia, a precursor to breast cancer, when compared to wild-type littermate controls. Several matrix metalloproteinases are up-regulated in MMTV-LRP6 mice that could contribute to the hyperplasia phenotype. Our results suggest that Wnt signaling activation at the cell surface receptor level can contribute to breast cancer tumorigenesis.