Response of Laryngeal and Tracheo-Bronchial Surface Lining to Inhaled Cigarette Smoke in Normal and Vitamin A-Deficient Rats: A Scanning Electron Microscopic Study.

The effects on surface morphology of airway epithelium of cigarette smoke (CS) inhalation alone (experiments one and two) or of CS in combination with hypovitaminosis A (experiment two) was investigated using specific pathogen free rats. Eight morphologically distinct cell types were distinguished overall. Apart from atypical squamous lesions each of the other cell types could be found in varying proportions in all experimental groups. CS alone caused an increase in the frequency with which intra-lumenal mucus was seen and an increase in the occurrence of secretory cells of types IV (i.e.,\u27merocrine\u27) and V (i.e.,\u27apocrine\u27). In experiment one, the area of trachea covered by cilia as determined by point counting increased significantly (P\u3c0.01). Hypovitaminosis A was induced by lowering the dietary intake of vitamin A to a minimum, defined level. Rats showed an approximately 75% decrease in plasma retinol levels and a 95-100% decrease in hepatic stores of vitamin A. At this level, hypovitaminosis A alone had no significant effect on airway epithelial morphology. Foci of squamous metaplasia (squamous cells of type VIIIa) were found in all groups but extensive squamous metaplasia of the larynx and squamous lesions of atypical appearance (type VIIIb) were found only in the vitamin deficient group exposed to CS. The results suggest the synergistic effects of reduced vitamin A and CS may be important in the induction of atypical squamous changes which may predispose the airway to the development of squamous carcinoma

On the origin of aurorae on Mars

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95268/1/grl20829.pd

Common Era sea-level budgets along the U.S. Atlantic coast

Sea-level budgets account for the contributions of processes driving sea-level change, but are predominantly focused on global-mean sea level and limited to the 20th and 21st centuries. Here we estimate site-specific sea-level budgets along the U.S. Atlantic coast during the Common Era (0-2000 CE) by separating relative sea-level (RSL) records into process-related signals on different spatial scales. Regional-scale, temporally linear processes driven by glacial isostatic adjustment dominate RSL change and exhibit a spatial gradient, with fastest rates of rise in southern New Jersey (1.6 ± 0.02 mm yr-1). Regional and local, temporally non-linear processes, such as ocean/atmosphere dynamics and groundwater withdrawal, contributed between -0.3 and 0.4 mm yr-1 over centennial timescales. The most significant change in the budgets is the increasing influence of the common global signal due to ice melt and thermal expansion since 1800 CE, which became a dominant contributor to RSL with a 20th century rate of 1.3 ± 0.1 mm yr-1

Trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer and brain metastases: exploratory final analysis of cohort 1 from KAMILLA, a single-arm phase IIIb clinical trial

Background: Patients with brain metastases (BM) from human epidermal growth factor receptor 2 (HER2)-positive breast cancer represent a difficult-to-treat population. Trastuzumab emtansine (T-DM1) has shown potential activity in this subset of patients in small clinical series. Patients and methods: KAMILLA is an ongoing, phase IIIb study of T-DM1 in patients with HER2-positive locally advanced/metastatic breast cancer with prior HER2-targeted therapy and chemotherapy. Patients received T-DM1 3.6 mg/kg every 3 weeks (intravenously) until unacceptable toxicity, withdrawal of consent, or disease progression. Tumor response and clinical outcomes in patients with baseline BM were evaluated in this post hoc, exploratory analysis. The main outcome measures were best overall response rate (complete response + partial response) and clinical benefit rate (complete response + partial response + stable disease lasting =6 months) by RECIST v1.1 criteria, progression-free survival, overall survival, and safety. Results: Of 2002 treated patients, 398 had baseline BM. In 126 patients with measurable BM, the best overall response rate and clinical benefit rate were 21.4% [95% confidence interval (CI) 14.6–29.6] and 42.9% (95% CI 34.1–52.0), respectively. A reduction in the sum of the major diameters of BM =30% occurred in 42.9% (95% CI 34.1–52.0), including 49.3% (95% CI 36.9–61.8) of 67 patients without prior radiotherapy to BM. In the 398 patients with baseline BM, median progression-free survival and overall survival were 5.5 (95% CI 5.3–5.6) months and 18.9 (95% CI 17.1–21.3) months, respectively. The adverse event profile was broadly similar in patients with and without baseline BM, although nervous system adverse events were more common in patients with [208 (52.3%)] versus without [701 (43.7%)] baseline BM. Conclusion: This exploratory analysis of patients with HER2-positive metastatic breast cancer and BM enrolled in a prospective clinical trial shows that T-DM1 is active and well-tolerated in this population. T-DM1 should be explored further in this setting

Molecular Gas in Quasar Hosts

The study of molecular gas in quasar host galaxies addresses a number of interesting questions pertaining to the hosts' ISM, to unified schemes relating quasars and IR galaxies, and to the processes fueling nuclear activity. In this contribution I review observations of molecular gas in quasar hosts from z=0.06 to z=4.7. The Cloverleaf quasar at z=2.5 is featured as a case where there are now enough detected transitions (four in CO, and one each in CI and HCN) to allow detailed modeling of physical conditions in the molecular ISM. We find that the CO-emitting gas is warmer, denser, and less optically thick than that found in typical Galactic molecular clouds. These differences are probably due to the presence of the luminous quasar in the nucleus of the Cloverleaf's host galaxy

The read-across hypothesis and environmental risk assessment of pharmaceuticals

This article is made available through the Brunel Open Access Publishing Fund. Copyright © 2013 American Chemical Society.Pharmaceuticals in the environment have received increased attention over the past decade, as they are ubiquitous in rivers and waterways. Concentrations are in sub-ng to low μg/L, well below acute toxic levels, but there are uncertainties regarding the effects of chronic exposures and there is a need to prioritise which pharmaceuticals may be of concern. The read-across hypothesis stipulates that a drug will have an effect in non-target organisms only if the molecular targets such as receptors and enzymes have been conserved, resulting in a (specific) pharmacological effect only if plasma concentrations are similar to human therapeutic concentrations. If this holds true for different classes of pharmaceuticals, it should be possible to predict the potential environmental impact from information obtained during the drug development process. This paper critically reviews the evidence for read-across, and finds that few studies include plasma concentrations and mode of action based effects. Thus, despite a large number of apparently relevant papers and a general acceptance of the hypothesis, there is an absence of documented evidence. There is a need for large-scale studies to generate robust data for testing the read-across hypothesis and developing predictive models, the only feasible approach to protecting the environment.BBSRC Industrial Partnership Award BB/ I00646X/1 and BBSRC Industrial CASE Partnership Studentship BB/I53257X/1 with AstraZeneca Safety Health and Environment Research Programme

Trimetric Imaging of the Martian Ionosphere Using a CubeSat Constellation

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/143020/1/6.2017-5252.pd