Citations

Abstract Protein kinase C (PKC) isozymes have long been implicated in carcinogenesis. However, little is known about the functional significance of these enzymes in human cancer. We recently showed that the atypical PKC (aPKC) isozyme PKCι is overexpressed in human non–small cell lung cancer (NSCLC) cells and that PKCι plays a critical role in the transformed growth of the human lung adenocarcinoma A549 cell line in vitro and tumorigenicity in vivo. Here we provide compelling evidence that PKCι is an oncogene in NSCLC based on the following criteria: (a) aPKCι is overexpressed in the vast majority of primary NSCLC tumors; (b) tumor PKCι expression levels predict poor survival in patients with NSCLC; (c) the PKCι gene is frequently amplified in established NSCLC cell lines and primary NSCLC tumors; (d) gene amplification drives PKCι expression in NSCLC cell lines and primary NSCLC tumors; and (e) disruption of PKCι signaling with a dominant negative PKCι allele blocks the transformed growth of human NSCLC cells harboring PKCι gene amplification. Taken together, our data provide conclusive evidence that PKCι is required for the transformed growth of NSCLC cells and that the PKCι gene is a target for tumor-specific genetic alteration by amplification. Interestingly, PKCι expression predicts poor survival in NSCLC patients independent of tumor stage. Therefore, PKCι expression profiling may be useful in identifying early-stage NSCLC patients at elevated risk of relapse. Our functional data indicate that PKCι is an attractive target for development of novel, mechanism-based therapeutics to treat NSCLC.

Background— The goal of this study was to determine whether the expression of vascular endothelial growth factor (VEGF) is critical for coronary collateral growth. Previous studies have provided an association between coronary collateral growth and VEGF, but none have allowed determination of a causal role. Methods and Results— We measured coronary collateral growth in rats subjected to repetitive episodes of myocardial ischemia (RI; one 40-second occlusion every 20 minutes for 2 hours 40 minutes, followed by 5 hours 20 minutes of rest, with this 8-hour cycle repeated 3 times per day for 10 days). Collateral growth was measured from blood flow (radioactive microspheres), visualization of arterial-arterial anastomoses (x-ray micro-CT), and maintenance of function during complete coronary occlusion in 3 groups of animals: sham (received instrumentation but no RI), experimental (subjected to RI), and anti–vascular endothelial growth factor (RI+anti-VEGF 0.6 mg/100 g per day) to block the endogenous actions of VEGF. In the 3 groups, native collateral flow (measurement for RI or sham protocol) averaged 0.2 to 0.3 mL · min −1 · g −1 of tissue. In the sham group, collateral flow did not increase during the protocol. Collateral flow in the control RI group increased by ≈6-fold to 1.63 mL · min −1 · g −1 tissue, but in the anti-VEGF group, collateral flow did not increase after the RI protocol (0.22 mL · min −1 · g −1 ). In acute experiments, collateral flow was unchanged during vasodilation with dipyridamole, indicating the increases in collateral flow are due to collateral growth and not vasodilation. X-ray micro-CT analysis revealed a 3-fold increase (versus sham group) in the number of arterial-arterial anastomoses per heart after RI, which was prevented by treatment with anti-VEGF. The growth of the collateral circulation was functional in the RI group because complete coronary occlusion did not induce any untoward effects on hemodynamics or arrhythmias. In the sham or anti-VEGF groups, coronary occlusion at the end of the protocol induced many arrhythmias and deterioration of function. Conclusions— From these results, we conclude that the expression of VEGF is critical to the growth of coronary collaterals.

Background— Increases in vascular (Ea), ventricular systolic (Ees), and ventricular diastolic (Ed) elastance (stiffness) may contribute to the pathogenesis of heart failure (HF) with preserved ejection fraction (HFnlEF). The prevalence of HFnlEF increases strikingly with age, particularly in women. We hypothesized that ventricular-vascular stiffening may occur with age and be more pronounced in women in the general community. Methods and Results— In a cross-sectional sample of Olmsted County, Minn, residents ≥45 years old (n=2042), clinical data, Doppler echocardiography, and blood pressure (BP) measurements were obtained. Ea was calculated from stroke volume and systolic BP and indexed to body size (EaI). Ees was calculated by a modified single-beat method using systolic and diastolic BP, stroke volume, ejection fraction, timing intervals, and an estimated normalized ventricular elastance at arterial end diastole. Operant Ed was calculated from Doppler indices reflective of atrial pressures and the diastolic filling volume. EaI, Ees, and Ed all increased with age in men and in women ( P <0.0001 for all). Ees increased more steeply with age in women ( P =0.002). Adjusted for age, EaI, Ees, and Ed were higher in women than in men ( P <0.0001 for all). Findings were similar in those without known or suspected cardiovascular disease (n=623). Conclusions— In the community, advancing age and female gender are associated with increases in vascular and ventricular systolic and diastolic stiffness even in the absence of cardiovascular disease. We speculate that this combined ventricular-vascular stiffening may contribute to the increased prevalence of HFnlEF in elderly persons and particularly in elderly women.

Policy has not adequately addressed the unique circumstances of pediatric subspecialties, many of which are facing workforce shortages. Pediatric subspecialties, which we define to include all medical and surgical subspecialties, are discrete disciplines that differ significantly from each other and from adult medicine subspecialties. Concerns about a current shortage of pediatric subspecialists overall are driven by indicators ranging from recruitment difficulties to long wait times for appointments. The future supply of pediatric subspecialists and patient access to pediatric subspecialty care will be affected by a number of key factors or forces for change. We discuss 5 of these factors: changing physician and patient demographics; debt load and lifestyle considerations; competition among providers of subspecialty care; equitable reimbursement for subspecialty services; and policy to regulate physician supply. We also identify issues and strategies that medical and specialty societies, pediatric subspecialists, researchers, child advocates, policy makers, and others should consider in the development of subspecialty-specific workforce-policy agendas.

The present series of experiments was undertaken in an effort to delineate those aspects of ultrasonic irradiation that might be destructive to malignant tumors of bone. The experiments were performed on rabbits having Vx-2 carcinoma implanted within the tibias. In preliminary, experiments, it was shown that the destructive effect of ultrasound on normal bone and on the circulation through normal bone was probably primarily due to heat. In the current series of experiments, it was shown that the heating of the bone was critically dependent on the exact location of the focus of the ultrasonic transducer within the rabbit leg. Our experiments suggested that (1) exposure of Vx-2 carcinoma to a temperature of 50°C for at least 10 min is sufficient to destroy the transmissible characteristics of this tumor, (2) exposure of Vx-2 carcinoma to ultrasonic fields with intense cavitation (applied in the absence of heat) has an effect that is far less than that of heating to 50°C for 10 min, and (3) controlled ultrasonic heating can increase the temperature of a bone to levels sufficient to destroy tumor growth within the bone.

Direct measurements were made of the displacement of the guinea-pig eardrum when acted upon by acoustic pressures (200–6000 cps). The mechanical nonlinearities of the ear were studied by introducing a static pressure (0 to ±3000 dyn/cm2) in the middle-ear cavity. Below 1000 cps, the ratio of the tympanum displacement to the sound pressure was frequency-independent, with a value of about 4×10−7 cm3/dyn. Above 1000 cps, this ratio exhibited a series of maxima and minima. A static-pressure difference across the tympanum changed the frequency at which the maximum occurred and generally decreased the displacement/pressure ratio. It was concluded (1) for low frequencies, the lumped-parameter description of the ear as a cavity was valid; (2) the tympanum acts as a flexible, conical plate under slight tension; (3) the measurements were best explained in terms of two nonlinearities: hysteresis and a nonlinearity of the elastic properties of the ear.

Many therapeutic procedures have been introduced into the art and science of medical practice empirically by a method of trial and error. Such a method has marked limitations and may produce unfavorable consequences. The facilities available in experimental medicine permit a thorough and extensive investigation of biological effects of many therapeutic agents or procedures before any clinical application is made. Optimal doses of the therapeutic agent can be approximated and a comparative study of various technics designed for clinical application can be made. Unfortunately ultrasound was used clinically by certain enthusiastic therapeutists before a thorough study of its biologic effects was completed. These therapeutists regarded the major biologic effect of ultrasonic energy to be mechanical. They were aware of a heating effect, but considered that it played a minor role. Experimental measurements have shown clearly that the major effect of ultrasound on living tissues is thermal when an intensity suitable for therapy is employed. The heating of bone by ultrasound is spectacular. No other heating agent used in therapy can raise the temperature of bone to such high levels so quickly. The application of ultrasound for diagnostic purposes and also for instrumentation will be described.

Experimental investigations indicate that ultrasound may prove useful for therapy, for diagnosis, and for biologic measurement. Ultrasound, although it may be dangerous in unskilled hands, is an excellent agent for the structural heating of living tissues. The term “structural heating” is used to denote heating at abrupt interfaces.The living organism presents numerous abrupt interfaces. Ultrasound promises to become a reliable diagnostic tool. Either the transmitted or the reflected ultrasonic energy can be used in this application. Tumors, gallstones, kidney stones, stones in the salivary glands, foreign bodies, and abnormal collections of fluid have been located accurately. Preliminary observations on the use of ultrasound for certain biologic measurements are encouraging. Instrumentation for biologic measurement includes ultrasonic flowmeters, devices for measuring thickness of some tissue structures, and equipment for measuring the viscosity of blood.

Experiments have been carried out to investigate ultrasound as a possible therapeutic agent. These show that selective heating occurs in nerves and bones treated in situ. Effects of direct heat on nerves are strikingly similar to the effects of ultrasound. Blocking of nerves by sound or heat with present techniques seems impractical because the margin of safety is too narrow.