Clinical evaluation of ZD6474, an orally active inhibitor of VEGF and EGF receptor signaling, in patients with solid, malignant tumors.

BACKGROUND: ZD6474 selectively inhibits the tyrosine kinase activity of vascular endothelial growth factor receptor and epidermal growth factor receptor. The safety, tolerability and pharmacokinetics of ZD6474 were assessed in a phase I dose-escalation study of patients with advanced solid tumors. PATIENTS AND METHODS: Adult patients with tumors refractory to standard treatments received once-daily oral ZD6474 (50-600 mg) in 28-day cycles, until disease progression or unacceptable toxicity was observed. RESULTS: Seventy-seven patients were treated at doses of 50 mg (n=9), 100 mg (n=19), 200 mg (n=8), 300 mg (n=25), 500 mg (n=8), and 600 mg (n=8). Adverse events were generally mild, and the most common dose-limiting toxicities (DLT) were diarrhea (n=4), hypertension (n=4), and rash (n=3). The incidence of most adverse events appeared to be dose-dependant. In the 500 mg/day cohort, 3/8 patients experienced DLT and this dose was therefore considered to exceed the maximum tolerated dose. Pharmacokinetic analysis confirmed that ZD6474 was suitable for once-daily oral dosing. CONCLUSIONS: Once-daily oral dosing of ZD6474 at 300 mg/day is generally well tolerated in patients with advanced solid tumors, and this dose is being investigated in phase II trials.     

Timely follow‐up of positive cancer screening results: A systematic review and recommendations from the PROSPR Consortium

Timely follow‐up for positive cancer screening results remains suboptimal, and the evidence base to inform decisions on optimizing the timeliness of diagnostic testing is unclear. This systematic review evaluated published studies regarding time to follow‐up after a positive screening for breast, cervical, colorectal, and lung cancers. The quality of available evidence was very low or low across cancers, with potential attenuated or reversed associations from confounding by indication in most studies. Overall, evidence suggested that the risk for poorer cancer outcomes rises with longer wait times that vary within and across cancer types, which supports performing diagnostic testing as soon as feasible after the positive result, but evidence for specific time targets is limited. Within these limitations, we provide our opinion on cancer‐specific recommendations for times to follow‐up and how existing guidelines relate to the current evidence. Thresholds set should consider patient worry, potential for loss to follow‐up with prolonged wait times, and available resources. Research is needed to better guide the timeliness of diagnostic follow‐up, including considerations for patient preferences and existing barriers, while addressing methodological weaknesses. Research is also needed to identify effective interventions for reducing wait times for diagnostic testing, particularly in underserved or low‐resource settings. CA Cancer J Clin 2018;68:199–216 . © 2018 American Cancer Society .     

Reduced H+ channel activity disrupts pH homeostasis and calcification in coccolithophores at low ocean pH

Coccolithophores are major producers of ocean biogenic calcite, but this process is predicted to be negatively affected by future ocean acidification scenarios. Since coccolithophores calcify intracellularly, the mechanisms through which changes in seawater carbonate chemistry affect calcification remain unclear. Here we show that voltage-gated H⁺ channels in the plasma membrane of Coccolithus braarudii serve to regulate pH and maintain calcification under normal conditions but have greatly reduced activity in cells acclimated to low pH. This disrupts intracellular pH homeostasis and impairs the ability of C. braarudii to remove H⁺ generated by the calcification process, leading to specific coccolith malformations. These coccolith malformations can be reproduced by pharmacological inhibition of H⁺ channels. Heavily calcified coccolithophore species such as C. braarudii, which make the major contribution to carbonate export to the deep ocean, have a large intracellular H⁺ load and are likely to be most vulnerable to future decreases in ocean pH.

Anthropogenic CO₂ emissions and the subsequent dissolution of CO₂ in seawater have resulted in substantial changes in ocean carbonate chemistry (1). The resultant decrease in seawater pH, termed ocean acidification, is predicted to be particularly detrimental for calcifying organisms (2). Mean global surface ocean pH is currently around 8.2 but is predicted to fall as low as 7.7 by 2100 (3) and is likely to continue to fall further in the following centuries. Present-day marine organisms can experience significant fluctuations in seawater pH, particularly in coastal and upwelling regions (4, 5). Ocean acidification is therefore predicted to have an important influence not only on mean surface ocean pH but also on the extremes of pH experienced by marine organisms (6, 7).Coccolithophores (Haptophyta) are a group of globally distributed unicellular phytoplankton that are characterized by their covering of intricately formed calcite scales (coccoliths). Coccolithophores account for a significant proportion of ocean productivity and are the main producers of biogenic calcite, making major contributions to global biogeochemical cycles, including the long-term export of both inorganic and organic carbon from the ocean photic zone to deep waters (8, 9). Unlike the vast majority of calcifying organisms, coccolithophore calcification occurs in an intracellular compartment, the Golgi-derived coccolith vesicle (CV), effectively isolating the calcification process from direct changes in seawater carbonate chemistry. Nevertheless, extensive laboratory observations indicate that ocean acidification may negatively impact coccolithophore calcification, albeit with significant variability of responses between species and strains (10–14). The negative impact on calcification rates occurs at calcite saturation states (Ω_calcite) >1, indicating that it results primarily from impaired cellular production rather than dissolution (10, 15). However, prediction of how natural coccolithophore populations may respond to future changes in ocean pH are hampered by lack of mechanistic understanding of pH impacts at the cellular level (10).As calcification occurs intracellularly using external HCO₃⁻ as the primary dissolved inorganic carbon (DIC) source (16–18), coccolith formation is not directly dependent on external CO₃²⁻ concentrations. However, the uptake of HCO₃⁻ as a substrate for calcification results in the equimolar production of CaCO₃ and H⁺ in the CV (18). In order to maintain saturation conditions for calcite formation, H⁺ produced by the calcification process must be rapidly removed from the CV, placing extraordinary demands for cellular pH regulation to prevent cellular acidosis (18).Lower calcification rates under ocean acidification conditions appear to be primarily due to decreased pH rather than other aspects of carbonate chemistry (10, 19, 20). Coccolithophores exhibit highly unusual membrane physiology, including the presence of voltage-gated H⁺ channels in the plasma membrane (21) and a high sensitivity of cytosolic pH (pH_cyt) to changes in external pH (pH_o) (21, 22). Voltage-gated H⁺ channels are associated with rapid H⁺ efflux in a number of specialized animal cell types (23) and contribute to effective pH regulation in coccolithophores (21). As H⁺ channel function is dependent on the electrochemical gradient of H⁺ across the plasma membrane, this mechanism could be impaired under lower seawater pH. However, it remains unknown whether H⁺ channels play a direct role in removal of calcification-derived H⁺ or contribute to the sensitivity of coccolithophores to ocean acidification.Coccolithophores exhibit significant diversity in their extent of calcification (SI Appendix, Fig. S1). The ratio of particulate inorganic carbon to particulate organic carbon (PIC/POC) of a coccolithophore culture is a measure of the relative rates of inorganic carbon fixation by calcification and organic carbon fixation by photosynthesis, respectively, and is commonly used as a simple metric to define the degree of calcification. The abundant bloom-forming species Emiliania huxleyi is moderately calcified (PIC/POC of around 1) and has been the focus of the vast majority of the studies into the effects of environmental change in coccolithophores (13). Coastal species belonging to the Pleurochrysidaceae and Hymenomonadaceae are lightly calcified, commonly exhibiting a PIC/POC of less than 0.5 (24–27). Species such as Coccolithus braarudii, Calcidiscus leptoporus, and Helicosphaera carteri exhibit much higher PIC/POC ratios and contribute the majority of carbonate export to the deep ocean in many areas (28–30). The physiological response of heavily calcified coccolithophores to ocean acidification is therefore of considerable biogeochemical significance. Growth and calcification rates in C. leptoporus and C. braarudii are sensitive to pH values predicted to prevail on a future decadal timescale (10, 15, 31, 32). However, a mechanistic understanding of the different sensitivity of coccolithophore species to changing ocean carbonate chemistry is lacking.The net H⁺ load in a cell is determined by the combination of metabolic processes that consume or produce H⁺. H⁺ fluxes in coccolithophores will be primarily determined by the balance of H⁺ consumed by photosynthesis and H⁺ generated by calcification, with uptake of different carbon sources a particularly important consideration (Fig. 1A). CO₂ uptake for photosynthesis results in no net production or consumption of H⁺, whereas uptake of HCO₃⁻ requires the equimolar consumption of H⁺ in order to generate CO₂. Growth at elevated CO₂ causes a switch from HCO₃⁻ uptake to predominately CO₂ uptake in E. huxleyi (33, 34). The associated net decrease in H⁺ consumption will therefore increase the H⁺ load in coccolithophores grown at elevated CO₂, which may exacerbate the potential for cytosolic acidosis caused by lower seawater pH.Open in a separate windowFig. 1.Physiology and H⁺ fluxes of C. braarudii cells grown at different seawater pH. (A) Schematic indicating H⁺ fluxes associated with photosynthesis and calcification in a coccolithophore cell. While many metabolic processes may contribute to the cellular H⁺ budget, these two processes are likely to be the major contributors. In a cell taking up HCO₃⁻, the overall H⁺ budget is determined by the relative rates of H⁺ consumed during photosynthesis and H⁺ generated during calcification. In a cell taking up CO₂, the H⁺ budget is determined primarily by calcification, as 2 H⁺ are produced for each molecule of CaCO₃ produced and H⁺ are no longer consumed during photosynthesis. In both scenarios, excess H⁺ may be removed from the cell by H⁺ transporters in the plasma membrane, such as voltage-gated H⁺ channels (H_v). Coccolithophores take up both HCO₃⁻ and CO₂ across the plasma membrane, with increasing proportions of DIC taken up as CO₂ as seawater CO₂ increases (34). (B) Growth rate of C. braarudii cells acclimated to different seawater pH. n = 3 replicates per treatment; line represents polynomial fit to mean. (C) Cellular production of POC through photosynthesis and PIC through calcification. The optima for both processes are close to the control conditions (pH 8.15). (D) As a consequence of the unequal changes in cellular POC and PIC production across the applied pH values, cellular PIC/POC ratios are minimal at pH 7.55 (∼1.0) and maximal at pH 8.45 (∼1.8). (E) Calculated net H⁺ budgets under the different pH regimes, based on rates of photosynthesis and calcification shown in C (see Materials and Methods). The concentration of CO₂ in seawater is also shown (dashed line). Estimates are shown for cells using taking up only HCO₃⁻ or only CO₂. As C. braarudii cells will likely take up a mixture of both DIC species, with a shift toward greater CO₂ usage at elevated CO₂, the shaded area represents the potential range of H⁺ production. Regardless of DIC species used C. braarudii produces excess H⁺ at all applied pH values, but H⁺ production is much lower at pH 7.55 due to the decrease in calcification.In this study we set out to better understand the cellular mechanisms underlying the sensitivity of coccolithophore calcification to lower pH. We subjected the heavily calcified species C. braarudii, which is commonly found in temperate upwelling regions (35, 36), to conditions that reflect the range of pH values it may experience in current and future oceans. We show that acclimation to low pH leads to loss of H⁺ channel function and disruption of cellular pH regulation in C. braarudii. These effects are coincident with very specific defects in coccolith morphology that can be reproduced by direct inhibition of H⁺ channels. We conclude that H⁺ efflux through H⁺ channels is essential for maintaining both calcification rate and coccolith morphology. By providing a mechanistic insight into pH regulation during the calcification process, our results indicate that disruption of coccolithophore calcification in a future acidified ocean is likely to be most severe in heavily calcified species.     

Effects of Ambient Coarse,Fine, and Ultrafine Particles and Their Biological Constituents on Systemic Biomarkers: A Controlled Human Exposure Study

Background

Ambient coarse, fine, and ultrafine particles have been associated with mortality and morbidity. Few studies have compared how various particle size fractions affect systemic biomarkers.

Objectives

We examined changes of blood and urinary biomarkers following exposures to three particle sizes.

Methods

Fifty healthy nonsmoking volunteers, mean age of 28 years, were exposed to coarse (2.5–10 μm; mean, 213 μg/m³) and fine (0.15–2.5 μm; mean, 238 μg/m³) concentrated ambient particles (CAPs), and filtered ambient and/or medical air. Twenty-five participants were exposed to ultrafine CAP (< 0.3 μm; mean, 136 μg/m³) and filtered medical air. Exposures lasted 130 min, separated by ≥ 2 weeks. Blood/urine samples were collected preexposure and 1 hr and 21 hr postexposure to determine blood interleukin-6 and C-reactive protein (inflammation), endothelin-1 and vascular endothelial growth factor (VEGF; vascular mediators), and malondialdehyde (lipid peroxidation); as well as urinary VEGF, 8-hydroxy-deoxy-guanosine (DNA oxidation), and malondialdehyde. Mixed-model regressions assessed pre- and postexposure differences.

Results

One hour postexposure, for every 100-μg/m³ increase, coarse CAP was associated with increased blood VEGF (2.41 pg/mL; 95% CI: 0.41, 4.40) in models adjusted for O_3, fine CAP with increased urinary malondialdehyde in single- (0.31 nmol/mg creatinine; 95% CI: 0.02, 0.60) and two-pollutant models, and ultrafine CAP with increased urinary 8-hydroxydeoxyguanosine in single- (0.69 ng/mg creatinine; 95% CI: 0.09, 1.29) and two-pollutant models, lasting < 21 hr. Endotoxin was significantly associated with biomarker changes similar to those found with CAPs.

Conclusions

Ambient particles with various sizes/constituents may influence systemic biomarkers differently. Endotoxin in ambient particles may contribute to vascular mediator changes and oxidative stress.

Citation

Liu L, Urch B, Poon R, Szyszkowicz M, Speck M, Gold DR, Wheeler AJ, Scott JA, Brook JR, Thorne PS, Silverman FS. 2015. Effects of ambient coarse, fine, and ultrafine particles and their biological constituents on systemic biomarkers: a controlled human exposure study. Environ Health Perspect 123:534–540; http://dx.doi.org/10.1289/ehp.1408387     

Three-generation reproduction study of rats ingesting up to 10% sorbitol in the diet--and a brief review of the toxicological status of sorbitol

Groups of 12 male and 24 female 5-wk-old Charles River CD (SD) BR rats (F0) were fed a sucrose-containing ground cereal-based diet in which 0, 2.5, 5.0 and 10.0% (w/w) sorbitol was included at the expense of sucrose. The rats were first mated after 14 wk on the diet. F1a litters were born 19 wk after the start of the study and F1b litters at wk 30. Groups of 12 male and 24 female F1b rats were first mated when 18 wk old. They gave rise to F2a litters after 3 wk and to F2b litters 10 wk later. Likewise, groups of 12 male and 24 female F2b rats were first mated when 18 wk old, producing F3a and F3b litters 3 wk and 10 wk later, respectively. F0 rats were killed 33 wk after the start of the study, F1a in wk 22, F1b in wk 68, F2a in wk 57, F2b in wk 92 and F3a in wk 96. Apart from slight reductions in food consumption in sorbitol-fed F1b males and in body-weight gain in sorbitol-fed F0, F1b and F2b rats of both sexes, treatment was associated with no clinically observed effects. There were no deaths attributable to treatment and no adverse effects on mating performance or pregnancy rates in the parent animals of any generation. Treatment was associated with no consistent adverse effect on any measure of reproductive performance or behaviour during gestation or lactation. No abnormal pups were observed in any generation. Not unexpectedly, caecal enlargement was consistently observed at necropsy of sorbitol-treated rats of all generations and significant rises in serum calcium were observed in F0 males and females exposed to 10% sorbitol and in F1b males exposed to either 5 or 10% sorbitol. Differences between treated and control F3a rats in respect of T3 and TSH levels were probably spurious as they followed no consistent pattern. Similarly, between-group variations in gonadal weight were considered to have no toxicological significance because they lacked consistency and were not accompanied by any histologically-evident changes. Microscopic examination of lesions from F1a and F2a animals, of gonads from F1b and F2b and of selected tissues from the F3a generation revealed no changes of toxicological significance.(ABSTRACT TRUNCATED AT 400 WORDS)     

The value of the Ghanaian traditional diet in relation to the energy needs of young children

The energy intakes at individual meals, and the energy densities of traditional foods, consumed by Ghanaian children of 1–3 years, have been studied at two locations—a village and an orphanage.

In both locations, a wide range of food intakes and food energy densities was found, and there were children who consumed more than an estimated energy requirement (based on FAO recommendations) of 120 KJ(28 kCals)/kg at single meals. The maximum weight of food consumed at the meal was around 70 g/kg.

It is concluded that the Ghanaian traditional diet can adequately satisfy a healthy child's energy needs without the addition of milk and other Western foods.     

Household Pesticide Usage in the United States

A total of 10,000 U.S. households in 25 standard metropolitan statistical areas and 25 counties were included in a study to determine the household use of pesticides in the United States. More than 8,200 households granted an interview. Nine of every ten households in the United States used some type of pesticide in their house, garden, or yard. Households in the southeastern United States used the most pesticides. Although more than 500 different pesticide formulations were used by the sampled households, 15 pesticides accounted for 65.5% of all pesticides reported in this study. Thirteen of these 15 pesticides were insecticides, one was a herbicide, and one was a rodentickle.