Targeting the mevalonate pathway inhibits the function of the epidermal growth factor receptor.

PURPOSE: The epidermal growth factor receptor (EGFR) is a key regulator of growth, differentiation, and survival of epithelial cancers. In a small subset of tumors, the presence of activating mutations within the ATP binding site confers increased susceptibility to gefitinib, a potent tyrosine kinase inhibitor of EGFR. Agents that can inhibit EGFR function through different mechanisms may enhance gefitinib activity in patients lacking these mutations. Mevalonate metabolites play significant roles in the function of the EGFR; therefore, mevalonate pathway inhibitors may potentiate EGFR-targeted therapies. EXPERIMENTAL DESIGN: In this study, we evaluated the effect of lovastatin on EGFR function and on gefitinib activity. Effects on EGFR function were analyzed by Western blot analysis using phosphospecific antibodies to EGFR, AKT, and extracellular signal-regulated kinase. Cytotoxic effects of lovastatin and/or gefitinib were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and flow cytometry. RESULTS: Lovastatin treatment inhibited EGF-induced EGFR autophosphorylation by 24 hours that was reversed by the coadministration of mevalonate. Combining lovastatin and gefitinib treatments showed enhanced inhibition of AKT activation by EGF in SCC9 cells. The combination of 10 mumol/L lovastatin and 10 mumol/L gefitinib treatments showed cooperative cytotoxicity in all 8 squamous cell carcinomas, 4 of 4 non-small cell lung carcinoma and 4 of 4 colon carcinoma cell lines tested. Isobologram and flow cytometric analyses of three representative cell lines with wild-type EGFR ATP binding sites confirmed that this combination was synergistic inducing a potent apoptotic response. CONCLUSIONS: Taken together, these results show that targeting the mevalonate pathway can inhibit EGFR function. They also suggest the potential utility of combining these clinically relevant therapeutic approaches.     

A phase I and pharmacologic trial of two schedules of the proteasome inhibitor, PS-341 (bortezomib, velcade), in patients with advanced cancer.

PURPOSE: To define the toxicities, pharmacodynamics, and clinical activity of the proteasome inhibitor, PS-341 (bortezomib), in patients with advanced malignancies. PATIENTS AND METHODS: Twenty-eight patients (14 male and 14 female) received PS-341 twice weekly for 4 of 6 weeks (schedule I). Because toxicity necessitated dose omissions on this schedule, 16 additional patients (12 male and 4 female) received PS-341 twice weekly for 2 of every 3 weeks (schedule II). A total of 73 courses of treatment was given (median, 2; range, 1-4). Inhibition of 20S proteasome activity in peripheral blood mononuclear cells (PBMC) and accumulation of proteasome-targeted polypeptides in tumor tissue were evaluated as pharmacodynamic markers of PS-341 activity. RESULTS: The most common toxicity was thrombocytopenia, which was dose limiting at 1.7 mg/m2 (schedule I) and 1.6 mg/m2 (schedule II), respectively. Sensory neuropathy was dose-limiting in a patient in schedule I. Grade > or =3 toxicities for schedule I were constipation, fatigue, myalgia, and sensory neuropathy. Grade > or =3 toxicities for schedule II were dehydration resulting from diarrhea, nausea and vomiting, fatigue, hypoglycemia, and hypotension. The maximum tolerated dose was 1.5 mg/m2 for both schedules. Reversible dose-dependent decreases in 20S proteasome activity in PBMCs were observed, with 36% inhibition at 0.5 mg/m2, 52% at 0.9 mg/m2, and 75% at 1.25 mg/m2. Accumulation of proteasome-targeted polypeptides was detected in tumor samples after treatment with PS-341. A patient with multiple myeloma had a partial response. CONCLUSION: PS-341 given 1.5 mg/m2 twice weekly for 2 of every 3 weeks is well tolerated and should be further studied.     

Mailable TLD system for photon and electron therapy beams

The mailable TLD system developed by the Radiological Physics Center for monitoring calibration of photon beam energies from cobalt 60 to 25 MV and electron beam energies from 6 to 20 MeV has been in use since 1977 for photons and since 1982 for electron beams. Design considerations, proper use of the system and calibration techniques are detailed. The accuracy of the system is comparable to that of ion chamber measurements made in a water phantom, although it shows less precision.     

Perceived job insecurity and risk of suicide and suicide attempts: a study of men and women in the Swedish working population

ObjectiveWhether perceived job insecurity increases the risk of suicidal behaviors is unclear. Improved understanding in this area could inform efforts to reduce suicide risk among those experiencing elevated job insecurity during the COVID-19 pandemic as well as post-pandemic. We aimed to investigate if perceived job insecurity predicted increased risk of suicide mortality and suicide attempts.MethodEmployees (N=65 571), representative of the Swedish working population who participated in the Swedish Work Environment Survey in 1991–2003, were followed up through 2016 in the National Inpatient and Death Registers. Suicide deaths and suicide attempts were defined according to International Classification of Diseases (ICD) 10 and ICD-8/9 codes of underlying cause of death and in-/outpatient care. Job insecurity and subsequent risk of suicide and suicide attempt were investigated with marginal structural Cox regression analyses and inverse probability of treatment weighting to control for confounding.ResultsPerceived job insecurity was associated with an elevated risk of suicide [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.03–2.20], but not with incident suicide attempts (HR 1.03, CI 0.86–1.24). Estimates remained similar after considering prevalent/previous poor mental health, other work factors, and when restricting the follow up time to ten years.ConclusionThe study suggests that job insecurity is associated with an increased risk of suicide mortality. Concerns about elevated job insecurity and suicide levels in the wake of the current pandemic could thus be considered in strategies to reduce the population health impact job insecurity both during and following the COVID-19 pandemic.     

The Nutritional Adequacy and Diet Quality of Vegetarian Menu Substitutions in Urban Kansas Childcare Centers

While plant-based eating has become increasingly popular, little is known of how this trend has impacted childcare center meals. The purpose of this study was to measure the nutrient content and diet quality of vegetarian alternative lunches and compare these measures to those of standard childcare lunches and nutrient benchmarks representing one-third of the Dietary Reference Intake for 3-year-olds and 4–5-year-olds. Menu data were obtained from seven urban Kansas childcare centers participating in the Child and Adult Care Food Program and regularly providing a vegetarian alternative lunch. The centers provided detailed menu information for 27 days’ worth of meals. The most common vegetarian substitution was cheese, which was used to fulfill all or part of the meat/meat alternative requirement in over three-quarters of the vegetarian alternative meals (n = 22). Compared to the standard meals, the vegetarian alternative meals were higher in calories, fat, saturated fat, calcium, and sodium and lower in protein, choline, and diet quality (p = 0.05). Both lunch options met the benchmarks for vitamin A, vitamin D, vitamin B12, calcium, and protein. Iron content for both (95% CI: standard 1.61–2.17 mg; vegetarian 1.37–2.7 mg) was below the benchmark. Although additional research is needed to better understand how vegetarianism has impacted childcare meals in the U.S., important differences in the nutrient contents were observed between the standard and vegetarian alternative meals. In addition, the results suggest vegetarian alternative meals that rely heavily on cheese may be of lower diet quality.     

Obesity,Pregnancy and the Social Contract with Today’s Adolescents

Adolescent health and well-being are of great concern worldwide, and adolescents encounter particular challenges, vulnerabilities and constraints. The dual challenges of adolescent parenthood and obesity are of public health relevance because of the life-altering health and socioeconomic effects on both the parents and the offspring. Prevention and treatment strategies at the individual and population levels have not been successful in the long term, suggesting that adolescent pregnancy and obesity cannot be managed by more of the same. Here, we view adolescent obese pregnancy through the lens of the social contract with youth. The disruption of this contract is faced by today’s adolescents, with work, social and economic dilemmas which perpetuate socioeconomic and health inequities across generations. The lack of employment, education and social opportunities, together with obesogenic settings, increase vulnerability and exposure to lifelong health risks, affecting their offspring’s life chances too. To break such vicious circles of disadvantage and achieve sustainable solutions in real-world settings, strong efforts on the part of policymakers, healthcare providers and the community must be oriented towards guaranteeing equity and healthy nutrition and environments for today’s adolescents. The involvement of adolescents themselves in developing such programs is paramount, not only so that they feel a sense of agency but also to better meet their real life needs.     

Benoxaprofen photosensitization of phospholipase activation in mammalian cells in culture

Benoxaprofen (BPF) induces a clinical photosensitivity which resembles idiopathic solar urticaria. This response is mediated by degranulation of mast cells. Since mast-cell degranulation is known to be modulated by phospholipid alteration, we examined the effect of BPF and ultraviolet radiation (UV) on phospholipid metabolism of C3H 10 T1/2 cells in culture. BPF + UVB (280-320 nm) induced release of [3H]arachidonic acid (AA) but did not alter the release of [3H]choline from prelabelled cells. This suggests that BPF photosensitizes phospholipase A2 activation. Such activation probably represents an integral step in the mechanism of BPF photosensitization of mast-cell degranulation.     

Interventricular septal thickness in fetuses of diabetic mothers.

Sixty-four diabetic women had their fetuses studied by M-mode echocardiogram between 20-41 weeks of gestation. The mean septal size during both diastole and systole increased in a linear fashion with advancing gestational age in both the normal and diabetic groups. Ventricular septal hypertrophy (ie, more than 2 standard deviations above the normal mean) was present in 48 of 64 (75%) of the fetuses of diabetic women. The ratio of septal size to the anteroposterior cardiac dimension was significantly greater in the diabetic than in the normal group (12 versus 8%; P less than .05). The anteroposterior cardiac dimension indexed to the estimated fetal weight was also greater in the diabetic group. Because both septum and cardiac dimension are larger with maternal diabetes, there may be a specific diabetic cardiomyopathy that originates in utero.     

Laryngeal configuration associated with glottography

This report describes a method for testing and confirming the relationship of glottography to the vibratory movements of the vocal folds. According to this method, vocal fold movement is monitored by photoglottography (PGG) and electroglottography (EGG) as photographs are taken using a 80-microsecond flash provided by a laryngostroboscope. The flash is recorded as an impulse on the PGG waveform, indicating the location on the glottographic signals of the corresponding single frame photograph. We then present a test case, in which various vocal fold configurations are documented, demonstrating that the timing of glottal events can be correlated to glottographic signals by this method.     

Further delineation of Weaver syndrome

Seven new cases of Weaver syndrome are described, including the first reported case in an adult. Overgrowth is usually but not always present. The combination of characteristic facies and developmental delay, with the peculiar radiographic findings of accelerated dysharmonic osseous maturation and splaying of the distal long bones, is diagnostic of Weaver syndrome.