The age-dependent association of risk factors with pancreatic cancer.

BACKGROUND: Pancreatic cancer presents as advanced disease in >80% of patients; yet, appropriate ages to consider prevention and early detection strategies are poorly defined. We investigated age-specific associations and attributable risks of pancreatic cancer for established modifiable and non-modifiable risk factors. PATIENTS AND METHODS: We included 167 483 participants from two prospective US cohort studies with 1190 incident cases of pancreatic cancer during >30 years of follow-up; 5107 pancreatic cancer cases and 8845 control participants of European ancestry from a completed multicenter genome-wide association study (GWAS); and 248 893 pancreatic cancer cases documented in the US Surveillance, Epidemiology, and End Results (SEER) Program. Across different age categories, we investigated cigarette smoking, obesity, diabetes, height, and non-O blood group in the prospective cohorts; weighted polygenic risk score of 22 previously identified single nucleotide polymorphisms in the GWAS; and male sex and black race in the SEER Program. RESULTS: In the prospective cohorts, all five risk factors were more strongly associated with pancreatic cancer risk among younger participants, with associations attenuated among those aged >70 years. The hazard ratios comparing participants with three to five risk factors with those with no risk factors were 9.24 [95% confidence interval (CI) 4.11-20.77] among those aged ≤60 years, 3.00 (95% CI 1.85-4.86) among those aged 61-70 years, and 1.46 (95% CI 1.10-1.94) among those aged >70 years (Pheterogeneity = 3×10-5). These factors together were related to 65.6%, 49.7%, and 17.2% of incident pancreatic cancers in these age groups, respectively. In the GWAS and the SEER Program, the associations with the polygenic risk score, male sex, and black race were all stronger among younger individuals (Pheterogeneity ≤0.01). CONCLUSIONS: Established risk factors are more strongly associated with earlier-onset pancreatic cancer, emphasizing the importance of age at initiation for cancer prevention and control programs targeting this highly lethal malignancy.

Dissecting the self-assembly kinetics of multimeric pore-forming toxins.

Pore-forming toxins are ubiquitous cytotoxins that are exploited by both bacteria and the immune response of eukaryotes. These toxins kill cells by assembling large multimeric pores on the cell membrane. However, a quantitative understanding of the mechanism and kinetics of this self-assembly process is lacking. We propose an analytically solvable kinetic model for stepwise, reversible oligomerization. In biologically relevant limits, we obtain simple algebraic expressions for the rate of pore formation, as well as for the concentration of pores as a function of time. Quantitative agreement is obtained between our model and time-resolved kinetic experiments of Bacillus thuringiensis Cry1Ac (tetrameric pore), aerolysin, Staphylococcus aureus α-haemolysin (heptameric pores) and Escherichia coli cytolysin A (dodecameric pore). Furthermore, our model explains how rapid self-assembly can take place with low concentrations of oligomeric intermediates, as observed in recent single-molecule fluorescence experiments of α-haemolysin self-assembly. We propose that suppressing the concentration of oligomeric intermediates may be the key to reliable, error-free, self-assembly of pores.

The effect of brimonidine tartrate on retinal blood flow in patients with ocular hypertension.

PURPOSE: To study the effects of topical brimonidine tartrate 0.2%, an alpha(2)-agonist ocular hypotensive drug, on retinal capillary blood flow in patients with ocular hypertension. METHODS: The study was a double-masked, randomized, placebo-controlled trial set in a tertiary eye center. Ocular hypertensive patients with repeatable intraocular pressures greater than 21 mm Hg and normal visual fields and optic disks were consecutively recruited. After an eye examination, baseline retinal blood flow measurements were made with confocal scanning laser Doppler flowmetry in one study eye. Patients were then randomly assigned to receive either brimonidine or placebo (saline) twice daily for 8 weeks. Blood flow and intraocular pressure measurements were then repeated after 4 and 8 weeks. RESULTS: Seventeen patients were randomly assigned to receive brimonidine, and 14 received placebo. One patient in each group failed to complete the study. The mean group differences in baseline age and intraocular pressure were not statistically significant (59. 23 [+/-10.24] and 52.23 [+/-16.46] years, respectively, and 24.84 [+/-2.08] and 24.56 [+/-2.85] mm Hg, respectively). Brimonidine reduced intraocular pressure by 17.90% and 16.17% at 4 and 8 weeks, respectively, with a significant difference in treatment effect compared with the placebo group (P <.007). The group difference in treatment effect in any of the three hemodynamic parameters velocity, volume, and flow was within 8% and not significantly different at 4 or 8 weeks (P.360). Based on a type I error of 0.05, our study had a power greater than or equal to 75% to detect group differences in treatment effect of greater than or equal to 15% to 20%. CONCLUSIONS: Brimonidine reduces intraocular pressure without altering retinal capillary blood flow in patients with ocular hypertension.

The effect of brimonidine tartrate on retinal blood flow in patients with ocular hypertension [corrected].

PURPOSE: To study the effects of topical brimonidine tartrate 0.2%, an alpha2-agonist ocular hypotensive drug, on retinal capillary blood flow in patients with ocular hypertension. METHODS: The study was a double-masked, randomized, placebo-controlled trial set in a tertiary eye center. Ocular hypertensive patients with repeatable intraocular pressures greater than 21 mm Hg and normal visual fields and optic disks were consecutively recruited. After an eye examination, baseline retinal blood flow measurements were made with confocal scanning laser Doppler flowmetry in one study eye. Patients were then randomly assigned to receive either brimonidine or placebo (saline) twice daily for 8 weeks. Blood flow and intraocular pressure measurements were then repeated after 4 and 8 weeks. RESULTS: Seventeen patients were randomly assigned to receive brimonidine, and 14 received placebo. One patient in each group failed to complete the study. The mean group differences in baseline age and intraocular pressure were not statistically significant (59.23 [+/-10.24] and 52.23 [+/-16.46] years, respectively, and 24.84 [+/-2.08] and 24.56 [+/-2.85] mm Hg, respectively). Brimonidine reduced intraocular pressure by 17.90% and 16.17% at 4 and 8 weeks, respectively, with a significant difference in treatment effect compared with the placebo group (P < .007). The group difference in treatment effect in any of the three hemodynamic parameters velocity, volume, and flow was within 8% and not significantly different at 4 or 8 weeks (P > .360). Based on a type I error of 0.05, our study had a power greater than or equal to 75% to detect group differences in treatment effect of greater than or equal to 15% to 20%. CONCLUSIONS: Brimonidine reduces intraocular pressure without altering retinal capillary blood flow in patients with ocular hypertension.

Supratentorial ependymomas. Neuroimaging and clinicopathological correlation.

In 10 patients with supratentorial ependymomas, the tumors exhibited hyperdensity on computerized tomography (CT) scanning prior to contrast infusion and, with one exception, all tumors were mixed lesions with the low densities suggesting cystic or necrotic portions. Eighty percent of the tumors contained small calcifications. Characteristically, the tumors were well demarcated and demonstrated moderate to marked enhancement after the intravenous administration of contrast material. Angiograms obtained in some patients showed mild hypervascular tumor staining and absence of large feeding arteries. The degree of contrast enhancement, angiographic vascularity, and tumor stain was compared to the pathological anaplasia of the tumors. No correlation was observed. Of four patients who were still alive during a follow-up period of 4 years or longer, three had recurrences with inoperable tumors; the remaining patient is without recurrence after craniospinal radiation. This same patient belonged to a group of five patients with a diagnosis of high-grade ependymoma, four of whom had recurrence. Follow-up CT accurately recorded the clinical course of each patient. Annual routine follow-up examinations are proposed for patients with low-grade ependymomas, and for those with high-grade ependymomas follow-up CT should be performed every 6 months. The characteristic appearance and behavior of these tumors include several distinctive features on angiographic and CT images.

Parents' accuracy in estimating child weight status.

Mothers of 107 preschool children estimated their child's weight status, and the accuracy of these estimates was examined. The majority of mothers (72%) were accurate. Of those who were inaccurate, 83% had underestimated the child's weight status, whereas only 17% had overestimated. Mothers of heavier children were more likely to underestimate their child's weight status.

Multiaxial myocardial mechanics and extracellular matrix remodeling: mechanochemical regulation of cardiac fibroblast function.

Substantial evidence suggests that not only does the structure of the cardiac extracellular matrix affect the mechanical properties of myocardium, but that mechanical loading affects the synthesis of the extracellular matrix. However, loading conditions in vivo are nonhomogeneous and multiaxial. An experimental approach that combines mechanics and cell biology is used to examine the mechanisms of extracellular matrix remodeling in the heart. The results indicate that differential biological responses in adult cardiac fibroblasts can be correlated with specific physical signals, such as the magnitude and two dimensional (2D) pattern of strain. Some effects of flow-function relations are discussed.

Rac1 is required for Prkar1a-mediated Nf2 suppression in Schwann cell tumors.

Schwannomas are peripheral nerve sheath tumors that often occur in the setting of an inherited tumor predisposition syndrome, including neurofibromatosis types 1 (NF1) and 2 (NF2), familial schwannomatosis and Carney complex. Loss of the NF2 tumor suppressor (encoding NF2, or Merlin) is associated with upregulation of the Rac1 small GTPase, which is thought to have a key role in mediating tumor formation. In prior studies, we generated a mouse model of schwannomas by performing tissue-specific knockout (KO) of the Carney complex gene Prkar1a, which encodes the type 1A regulatory subunit of protein kinase A. These tumors exhibited down-regulation of Nf2 protein and an increase in activated Rac1. To assess the requirement for Rac1 in schwannoma formation, we generated a double KO (DKO) of Prkar1a and Rac1 in Schwann cells and monitored tumor formation. Loss of Rac1 reduced tumor formation by reducing proliferation and enhancing apoptosis. Surprisingly, the reduction of tumor formation was accompanied by re-expression of the Nf2 protein. Furthermore, activated Rac1 was able to downregulate Nf2 in vitro in a Pak-dependent manner. These in vivo data indicate that activation of Rac1 is responsible for suppression of Nf2 protein production; deficiency of Nf2 in Schwann cells leads to loss of cellular growth control and tumor formation. Further, PKA activation through mutation in Prkar1a is sufficient to initiate Rac1 signaling, with subsequent reduction of Nf2 and schwannomagenesis. Although in vitro evidence has shown that loss of Nf2 activates Rac1, our data indicate that signaling between Nf2 and Rac1 occurs in a bidirectional fashion, and these interactions are modulated by PKA.