Distinct TP53 Mutation Subtypes Differentially Influence Cellular Iron Metabolism.

The most commonly mutated gene in all human cancers is the tumor suppressor gene TP53; however, in addition to the loss of tumor suppressor functions, mutations in TP53 can also promote cancer progression by altering cellular iron acquisition and metabolism. The primary objective of this work was to determine how TP53 mutation status influences the molecular control of iron homeostasis. The effect of TP53 mutation type on cellular iron homeostasis was examined using cell lines with inducible versions of either wild-type TP53 or a representative mutated TP53 gene from exemplary "hotspot" mutations in the DNA binding domain (R248, R273, and R175) as well as H193Y. The introduction of distinct TP53 mutation types alone was sufficient to disrupt cellular iron metabolism. These effects were mediated, at least in part, due to differences in the responsiveness of iron regulatory proteins (IRPs) to cellular iron availability. IRPs are considered the master regulators of intracellular iron homeostasis because they coordinate the expression of iron storage (ferritin) and iron uptake (transferrin receptor) genes. In response to changes in iron availability, cells harboring either a wild-type TP53 or R273H TP53 mutation displayed canonical IRP-mediated responses, but neither IRP1 RNA binding activity nor IRP2 protein levels were affected by changes in iron status in cells harboring the R175H mutation type. However, all mutation types exhibited robust changes in ferritin and transferrin receptor protein expression in response to iron loading and iron chelation, respectively. These findings suggest a novel, IRP-independent mode of iron regulation in cells expressing distinct TP53 mutations. As TP53 is mutated in nearly half of all human cancers, and iron is necessary for cancer cell growth and proliferation, the studies have implications for a wide range of clinically important cancers.

Effects of Game Pitch Count and Body Mass Index on Pitching Biomechanics in 9- to 10-Year-Old Baseball Athletes.

BACKGROUND: Pitching while fatigued and body composition may increase the injury risk in youth and adult pitchers. However, the relationships between game pitch count, biomechanics, and body composition have not been reported for a study group restricted to 9- to 10-year-old athletes. HYPOTHESIS: During a simulated game with 9- to 10-year-old athletes, (1) participants will experience biomechanical signs of fatigue, and (2) shoulder and elbow kinetics will correlate with body mass index (BMI). STUDY DESIGN: Descriptive laboratory study. METHODS: Thirteen 9- to 10-year-old youth baseball players pitched a simulated game (75 pitches). Range of motion and muscular output tests were conducted before and after the simulated game to quantify fatigue. Kinematic parameters at foot contact, maximum external rotation, and maximum internal rotation velocity (MIRV), as well as maximum shoulder and elbow kinetics between foot contact and MIRV were compared at pitches 1-5, 34-38, and 71-75. Multivariate analyses of variance were used to test the first hypothesis, and linear regressions were used to test the second hypothesis. RESULTS: MIRV increased from pitches 1-5 to 71-75 (P = .007), and head flexion at MIRV decreased from pitches 1-5 to 34-38 (P = .022). Maximum shoulder horizontal adduction, external rotation, and internal rotation torques increased from pitches 34-38 to 71-75 (P = .031, .023, and .021, respectively). Shoulder compression force increased from pitches 1-5 to 71-75 (P = .011). Correlations of joint torque/force with BMI were found at every pitch period: for example, shoulder internal rotation (R2 = 0.93, P < .001) and elbow varus (R2 = 0.57, P = .003) torques at pitches 1-5. CONCLUSION: Several results differed from those of previous studies with adult pitchers: (1) pitch speed remained steady, (2) shoulder MIRV increased, and (3) shoulder kinetics increased during a simulated game. The strong correlations between joint kinetics and BMI reinforce previous findings that select body composition measures may be correlated with pitching arm joint kinetics for youth baseball pitchers. CLINICAL RELEVANCE: The results improve our understanding of pitching biomechanics for 9- to 10-year-old baseball pitchers and may be used in future studies to improve evidence-based injury prevention guidelines.

Cardiorespiratory Fitness and Reclassification of Risk for Incidence of Heart Failure: The Veterans Exercise Testing Study.

BACKGROUND: It is well established that cardiorespiratory fitness (CRF) is inversely associated with cardiovascular and all-cause mortality. However, little is known regarding the association between CRF and incidence of heart failure (HF). METHODS AND RESULTS: Between 1987 and 2014, we assessed CRF in 21 080 HF-free subjects (58.3±11 years) at the Veterans Affairs Medical Centers in Washington, DC, and Palo Alto, CA. Subjects were classified by age-specific quintiles of CRF. Multivariable Cox models were used to determine the association between HF incidence and clinical and exercise test variables. Reclassification characteristics of fitness relative to standard clinical risk factors were determined using the category-free net reclassification improvement and integrated discrimination improvement indices. During the follow-up (mean 12.3±7.4 years), 1902 subjects developed HF (9.0%; average annual incidence rate, 7.4 events per 1000 person-years). When CRF was considered as a binary variable (unfit/fit), low fitness was the strongest predictor of risk for HF among clinical and exercise test variables (hazard ratio, 1.91; 95% confidence interval, 1.74-2.09; P<0.001). In a fully adjusted model with the least-fit group as the reference, there was a graded and progressive reduction in risk for HF as fitness level was higher. Risks for developing HF were 36%, 41%, 67%, and 76% lower among increasing quintiles of fitness compared with the least-fit subjects (P<0.001). Adding CRF to standard risk factors resulted in a net reclassification improvement of 0.37 (P<0.001). CONCLUSIONS: CRF is strongly, inversely, and independently associated with the incidence of HF in veterans referred for exercise testing.