Altered genome-wide hippocampal gene expression profiles following early life lead exposure and their potential for reversal by environmental enrichment.

Early life lead (Pb) exposure is detrimental to neurobehavioral development. The quality of the environment can modify negative influences from Pb exposure, impacting the developmental trajectory following Pb exposure. Little is known about the molecular underpinnings in the brain of the interaction between Pb and the quality of the environment. We examined relationships between early life Pb exposure and living in an enriched versus a non-enriched postnatal environment on genome-wide transcription profiles in hippocampus CA1. RNA-seq identified differences in the transcriptome of enriched vs. non-enriched Pb-exposed animals. Most of the gene expression changes associated with Pb exposure were reversed by enrichment. This was also true for changes in upstream regulators, splicing events and long noncoding RNAs. Non-enriched rats also had memory impairments; enriched rats had no deficits. The results demonstrate that an enriched environment has a profound impact on behavior and the Pb-modified CA1 transcriptome. These findings show the potential for interactions between Pb exposure and the environment to result in significant transcriptional changes in the brain and, to the extent that this may occur in Pb-exposed children, could influence neuropsychological/educational outcomes, underscoring the importance for early intervention and environmental enrichment for Pb-exposed children.

Cell cycle-coupled expansion of AR activity promotes cancer progression.

The androgen receptor (AR) is required for prostate cancer (PCa) survival and progression, and ablation of AR activity is the first line of therapeutic intervention for disseminated disease. While initially effective, recurrent tumors ultimately arise for which there is no durable cure. Despite the dependence of PCa on AR activity throughout the course of disease, delineation of the AR-dependent transcriptional network that governs disease progression remains elusive, and the function of AR in mitotically active cells is not well understood. Analyzing AR activity as a function of cell cycle revealed an unexpected and highly expanded repertoire of AR-regulated gene networks in actively cycling cells. New AR functions segregated into two major clusters: those that are specific to cycling cells and retained throughout the mitotic cell cycle ('Cell Cycle Common'), versus those that were specifically enriched in a subset of cell cycle phases ('Phase Restricted'). Further analyses identified previously unrecognized AR functions in major pathways associated with clinical PCa progression. Illustrating the impact of these unmasked AR-driven pathways, dihydroceramide desaturase 1 was identified as an AR-regulated gene in mitotically active cells that promoted pro-metastatic phenotypes, and in advanced PCa proved to be highly associated with development of metastases, recurrence after therapeutic intervention and reduced overall survival. Taken together, these findings delineate AR function in mitotically active tumor cells, thus providing critical insight into the molecular basis by which AR promotes development of lethal PCa and nominate new avenues for therapeutic intervention.

The retinoblastoma tumor suppressor pathway modulates the invasiveness of ErbB2-positive breast cancer.

The processes that control the progression of ductal carcinoma in situ (DCIS) to invasive breast cancer remain poorly understood. Epidermal growth factor receptor 2 (ErbB2) overexpression is common in DCIS, as is disruption of the retinoblastoma tumor suppressor (RB) pathway. Here, we examined the cooperative impact of ErbB2 and RB deregulation on facets of disease progression. Our studies demonstrate that RB deficiency altered the expression of key molecules needed for proper cellular organization and epithelial cell-cell adhesion as part of a program related to the epithelial-to-mesenchymal transition (EMT). An increase in the invasive potential of ErbB2-overexpressing cells was observed upon RB depletion. Further, stable knockdown of RB resulted in invasive lesions in orthotopic xenograft assays, compared with DCIS-like lesions developing from RB-proficient cells. Conversely, the invasive phenotype observed in ErbB2-positive cancer models was inhibited through CDK4/6 inhibition in an RB-dependent manner. Finally, in a cohort of DCIS cases, we show that, although elevated levels of ErbB2 are associated with increased risk of a subsequent DCIS recurrence, it is not associated with progression to invasive disease. In contrast, RB loss in ErbB2-positive DCIS cases was associated with increased risk for invasive breast cancer. Taken together, these data demonstrate a key role for the RB pathway in invasion associated with breast tumor progression, and shed light on the key molecular events that promote the progression of DCIS to invasive disease.

Mechanical properties of vesicles. I. Coordinated analysis of osmotic swelling and lysis.

To determine how transmembrane osmotic gradients perturb the structure and dynamics of biological membranes, we examined the effects of medium dilution on the structures of osmolyte-loaded lipid vesicles. Our preparations were characterized by dynamic light scattering (DLS) and nuclear magnetic resonance (NMR) spectroscopies. Populations of Escherichia coli phosphatidylethanolamine (PE) or dioleoylphosphatidylglycerol (DOPG) vesicles prepared by the pH jump technique were variable and polymodal in size distribution. Complex and variable structural changes occurred when PE vesicles were diluted with hypotonic buffer. Such vesicles could not be used as model systems for the analysis of membrane mechanical properties. NaCl-loaded, DOPG vesicles prepared by extrusion through 100 nm (diameter) pores were reproducible and monomodal in size distribution and unilamellar, whereas those prepared by extrusion through 200-, 400-, or 600-nm pores were variable and polymodal in size distribution and/or multilamellar. Time and pressure regimes associated with osmotic lysis of extruded vesicles were defined by monitoring release of carboxyfluorescein, a self-quenching fluorescent dye. Corresponding effects of medium dilution on vesicle structure were assessed by DLS spectroscopy. These experiments and the accompanying analysis (Hallett, F.R., J. Marsh, B.G. Nickel, and J.M. Wood. 1993. Biophys. J. 64:000-000) revealed conditions under which vesicles are expected to reside in a consistently strained state.

The differential effect of cigarette smoke on the growth of bacteria found in humans.

The effect of cigarette smoke on growth of those species of bacteria that are considered common potential human pathogens was examined in vitro. Smoke from both mentholated and nonmentholated cigarettes inhibited the growth of Gram-positive cocci to a greater degree than that of Gram-negative rods. Staphylococcus aureus, Streptococcus pneumoniae, and a variety of other streptococci were inhibited at a smoke solution dilution of 1:8. Enteric bacteria such as Klebsiella, Enterobacter, and Pseudomonas were not affected by a 1:1 dilution of the solution. As with the Gram-positive cocci, the Neisseria species and Branhamella were also inhibited at a dilution of 1:8. Culture results of the mouth of 15 smokers and 15 nonsmokers showed that the smokers have a propensity to develop heavy Gram-negative bacterial colonization.

Flexor tendon ruptures in rheumatoid arthritis.

Flexor tendon ruptures in rheumatoid arthritis are caused by either attrition on bone spurs or by direct invasion of the tendon by hypertrophic tenosynovium. All attrition ruptures occur within the carpal canal and represent the most common cause of tendon rupture. Removal of the causative bone spur is imperative in the treatment of this condition. Ruptures due to invasive tenosynovitis also are frequently found within the carpal canal. These ruptures may be unanticipated, and may be discovered as an incidental finding during flexor tenosynovectomy. Ruptures due to invasive tenosynovitis within the digit carry an unfavorable prognosis. The prognosis for restoring flexion in the event of a flexor tendon rupture is determined by the location of the rupture, the etiology, the degree of articular involvement from the rheumatoid disease, and to a lesser extent, by the number of ruptured tendons. In general, isolated or double ruptures within the carpal canal due to attrition have a better prognosis than those caused by invasive tenosynovitis since the condition of the tendons is more favorable for reconstruction; however, as the number of ruptures increases, the prognosis in both conditions worsens. Rupture of both tendons within the digital sheath is quite difficult to treat, with ruptures in zone 2 carrying the worst prognosis for the restoration of flexion. The severity of the patient's rheumatoid arthritis and articular disease has a great effect on the outcome of the reconstructive surgery. Prevention of tendon ruptures by early tenosynovectomy and the removal of bone spurs should be the goal of the surgeon.

Flexor tendon ruptures in patients with rheumatoid arthritis.

One hundred fifteen flexor tendon ruptures were reviewed in 43 hands with rheumatoid arthritis, one hand with psoriatic arthritis, and one hand with lupus erythematosis. Ninety-one tendons were ruptured at the wrist, four ruptures occurred at the palm, and 20 ruptures occurred within the digits. At the wrist level, 61 ruptures were caused by attrition on a bone spur and 30 were caused by direct invasion of the tendon by tenosynovium. All ruptures distal to the wrist were caused by invasion of the tendon by tenosynovium. Patients whose ruptures were caused by attrition regained better motion than those whose ruptures were caused by invasion by tenosynovitis; however, motion overall was poor. Patients with isolated ruptures in the palm or at the wrist had the best functional results. Those patients with multiple ruptures within the carpal canal had a worse prognosis. Ruptures of both tendons within the fibro-osseous canal had the worst prognosis. The severity of the patient's disease and the degree of articular involvement had a great effect on the outcome of surgery. Prevention of tendon ruptures by early tenosynovectomy and removal of bone spurs should be the cornerstone of treatment.

Talonavicular coalition following avascular necrosis of the tarsal navicular.

A 9-year follow-up of a case of acquired talonavicular coalition following avascular necrosis of the tarsal navicular is presented. A review of the literature suggests that this is the only reported case of acquired talonavicular coalition.

Cervical-spine instability in children with Down syndrome (trisomy 21).

Eighty-five children with Down syndrome, between sixteen months and eighteen years old, were evaluated for instability of the cervical spine at the atlanto-axial joint. The mean atlas-odontoid process interval was three millimeters in flexion and two millimeters in extension. Ten patients (12 per cent) exhibited abnormal intervals (4.5 millimeters or more) during either flexion or extension. The configuration of the odontoid process was considered normal in eighty patients and abnormal in another five patients (6 per cent). The correlation between the thickness of the interval and the degree of ligament laxity was statistically significant, as was the correlation between ligament laxity and age. Of the ten patients with an increased atlas-odontoid process interval, neurological deficit (hyperreflexia and clonus) developed in only one after a one-year follow-up.