The FABP12/PPARγ pathway promotes metastatic transformation by inducing epithelial‐to‐mesenchymal transition and lipid‐derived energy production in prostate cancer cells

Early stage localized prostate cancer (PCa) has an excellent prognosis; however, patient survival drops dramatically when PCa metastasizes. The molecular mechanisms underlying PCa metastasis are complex and remain unclear. Here, we examine the role of a new member of the fatty acid‐binding protein (FABP) family, FABP12, in PCa progression. FABP12 is preferentially amplified and/or overexpressed in metastatic compared to primary tumors from both PCa patients and xenograft animal models. We show that FABP12 concurrently triggers metastatic phenotypes (induced epithelial‐to‐mesenchymal transition (EMT) leading to increased cell motility and invasion) and lipid bioenergetics (increased fatty acid uptake and accumulation, increased ATP production from fatty acid β‐oxidation) in PCa cells, supporting increased reliance on fatty acids for energy production. Mechanistically, we show that FABP12 is a driver of PPARγ activation which, in turn, regulates FABP12''s role in lipid metabolism and PCa progression. Our results point to a novel role for a FABP‐PPAR pathway in promoting PCa metastasis through induction of EMT and lipid bioenergetics.

Abbreviations

AR

androgen receptor

ATP

adenosine triphosphate

CN

copy number

CPT1

carnitine palmitoyltransferase I

CS

citrate synthase

EMT

epithelial–mesenchymal transition

ET

electron transfer‐state

FABP

fatty acid‐binding protein

LD

lipid droplet

OA

oleic acid

PCa

prostate cancer

PPAR

peroxisome proliferator‐activated receptor

PPRE

peroxisome proliferator‐activated receptor response element

TZD

thiazolidinediones

     

Quantified simulation of canine retraction: evaluation of frictional resistance

The purpose of this study was to evaluate the frictional resistance of various bracket/archwire combinations. The friction testing apparatus allowed dynamic and progressive bracket tipping and uprighting concurrent with linear bracket traction which experimentally approximated canine retraction with sliding mechanics. Multiple ANOVA using general linear models procedure demonstrated significant effects (P < 0.05) for bracket type, archwire type, archwire size, and archwire shape, as well as pair-wise interactions for bracket type/archwire type, bracket type/archwire size, bracket type/archwire shape, archwire type/archwire size, archwire type/archwire shape, and archwire size/archwire shape. Duncan’s multiple range test (P < 0.05) revealed the general trends regarding frictional performance of brackets and archwires tested, while Least squares means table (P < 0.05) illustrated significant interactions of pair-wise factors that differed from the general trends. It was concluded that: (1) Ceramic brackets with and without metal slots had the greatest friction followed by metal brackets, active self-ligating brackets, variable self-ligating brackets, and passive self-ligating brackets. (2) Stainless steel and braided stainless archwires measured greater friction than nickel-titanium. (3) Smaller dimension wires had less friction than larger wires, and round wires had less friction than rectangular wires. In addition, consideration of specific bracket-archwire coupling appear to reduce the frictional resistance with sliding.     

Nucleus of the solitary tract in the C57BL/6J mouse: Subnuclear parcellation,chorda tympani nerve projections,and brainstem connections

The nucleus of the solitary tract (NST) processes gustatory and related somatosensory information rostrally and general viscerosensory information caudally. To compare its connections with those of other rodents, this study in the C57BL/6J mouse provides a subnuclear cytoarchitectonic parcellation (Nissl stain) of the NST into rostral, intermediate, and caudal divisions. Subnuclei are further characterized by NADPH staining and P2X₂ immunoreactivity (IR). Cholera toxin subunit B (CTb) labeling revealed those NST subnuclei receiving chorda tympani nerve (CT) afferents, those connecting with the parabrachial nucleus (PBN) and reticular formation (RF), and those interconnecting NST subnuclei. CT terminals are densest in the rostral central (RC) and medial (M) subnuclei; less dense in the rostral lateral (RL) subnucleus; and sparse in the ventral (V), ventral lateral (VL), and central lateral (CL) subnuclei. CTb injection into the PBN retrogradely labels cells in the aforementioned subnuclei; RC and M providing the largest source of PBN projection neurons. Pontine efferent axons terminate mainly in V and rostral medial (RM) subnuclei. CTb injection into the medullary RF labels cells and axonal endings predominantly in V at rostral and intermediate NST levels. Small CTb injections within the NST label extensive projections from the rostral division to caudal subnuclei. Projections from the caudal division primarily interconnect subnuclei confined to the caudal division of the NST; they also connect with the area postrema. P2X₂‐IR identifies probable vagal nerve terminals in the central (Ce) subnucleus in the intermediate/caudal NST. Ce also shows intense NADPH staining and does not project to the PBN. J. Comp. Neurol. 522:1565–1596, 2014. © 2013 Wiley Periodicals, Inc.     

The Effect of Medial Release of the Distal Patellar Tendon Insertion on Lateral Patella Translation and Residual Insertion Strength: A Cadaveric Study

Patellar tendon avulsion is a risk with difficult exposure in a stiff knee, patella baja or previous tibial osteotomy. We sought to define a safe amount of release of the patellar tendon insertion for such cases. Eleven pairs of fresh frozen cadaveric lower limb specimens were acquired and randomized to either intact or partial release of the distal tibial insertion. Partial release of the tibial insertion of the tendon increased lateral exposure a mean 29% ± 15% (P = 0.002) while reducing ultimate strength to a mean of 80% that of the intact contralateral tendon. Measured patella release increased lateral patella translation and can be performed without risk of catastrophic rupture with basic activities of daily living following TKA.     

Point-of-care testing for coagulation studies in a stroke protocol: a time-saving innovation

Study Objectives

Time counts in thrombolytic therapy for stroke. An international normalized ratio (INR) greater than 1.7 may preclude its use. We studied whether the use of point-of-care testing (POCT) for INR in the emergency department (ED) may substitute for the same test done in the central hospital laboratory, thereby reducing time to treatment.

Methods

We performed a prospective observational study comparing a POCT analysis of INR (i-STAT-1; Abbott Inc, Abbott Park, Ill) with a simultaneously drawn sample sent to the central laboratory. We tested a convenience sample of adult patients taking warfarin who presented to the ED of a tertiary teaching hospital.

Results

Thirty-two patients were enrolled. A receiver operator curve analysis was performed. Sensitivity and specificity were calculated for laboratory INR cutoff of 1.7. The area under the curve was 0.979 (95% confidence interval [CI], 0.843-0.991). When POCT INR was 2.1, the sensitivity for laboratory INR being higher than 1.7 was 100% (CI, 62.9%-100.0%), and the specificity was 90.5 (CI, 69.6-98.5). When POCT INR was 1.8, the specificity for laboratory INR being lower than 1.7 was 100% (CI, 83.7%-100%), and the sensitivity was 62.5% (CI, 24.7%-91.0%). The regression coefficient (r) value was 0.9648.

Conclusion

Correlation of POCT INR with that of the central laboratory and receiver operator curve characteristics are excellent. In general, POCT INR is about 0.3 higher than the laboratory INR. This is not generally of clinical importance, but when using cutoff of 1.7 (central laboratory), it may be. We describe a 3-tiered system for use of POCT INR in determining use of tissue-type plasminogen activator.     

Warfarin response and vitamin K epoxide reductase complex 1 in African Americans and Caucasians

The objective of this study was to determine whether two vitamin K epoxide reductase complex 1 (VKORC1) polymorphisms contribute to the variability in warfarin response, particularly in African Americans. The effect of the VKORC1 1173C/T and -1639G/A polymorphisms was examined in a prospective cohort study of 338 warfarin users. Subjects carrying an 1173T allele had a lower warfarin maintenance dose compared with subjects with the CC genotype in African Americans (-12.10 mg/week+/-4.93; P=0.02) and Caucasians (-14.41 mg/week+/-3.28; P<0.001). Before reaching maintenance dose, only Caucasians with the T allele had significantly increased risk of international normalized ratio >3 (odds ratio=3.10; 95% confidence interval: 1.73-5.55) compared with Caucasians with the CC genotype. Polymorphisms in the VKORC1 gene are associated with warfarin maintenance dose requirements among both African Americans and Caucasians. However, these polymorphisms may not be as useful in predicting over-anticoagulation among African Americans.