A 5-FU precursor designed to evade anabolic and catabolic drug pathways and activated by Pd chemistry in vitro and in vivo

We are grateful to the EPSRC (EP/N021134/1) for funding. T.L.B. thanks the CMVM of the University of Edinburgh (Principal's scholarship), and B.R.-R. thanks the EC (H2020MSCA-IF-2014-658833, ChemoBOOM) for financial support. A.U.-B. and D.J.B. thank Medical Research Scotland (PHD-1046-2016) for funding. We acknowledge support from the MRC Confidence in Concept scheme (MRC/CIC6/52) and EPSRC Impact Acceleration Account (PIII024).5-Fluorouracil (5-FU) is an antineoplastic antimetabolite that is widely administered to cancer patients by bolus injection, especially to those suffering from colorectal and pancreatic cancer. Because of its suboptimal route of administration and dose-limiting toxicities, diverse 5-FU prodrugs have been developed to confer oral bioavailability and increase the safety profile of 5-FU chemotherapy regimens. Our contribution to this goal is presented herein with the development of a novel palladium-activated prodrug designed to evade the metabolic machinery responsible for 5-FU anabolic activation and catabolic processing. The new prodrug is completely innocuous to cells and highly resistant to metabolization by primary hepatocytes and liver S9 fractions (the main metabolic route for 5-FU degradation), whereas it is rapidly converted into 5-FU in the presence of a palladium (Pd) source. In vivo pharmokinetic analysis shows the prodrug is rapidly and completely absorbed after oral administration and exhibits a longer half-life than 5-FU. In vivo efficacy studies in a xenograft colon cancer model served to prove, for the first time, that orally administered prodrugs can be locally converted to active drugs by intratumorally inserted Pd implants.UK Research & Innovation (UKRI) Engineering & Physical Sciences Research Council (EPSRC) EP/N021134/1CMVM of the University of EdinburghEuropean Commission European Commission Joint Research Centre H2020MSCA-IF-2014-658833Medical Research Scotland PHD-1046-2016UK Research & Innovation (UKRI) Medical Research Council UK (MRC) MRC/CIC6/52 UK Research & Innovation (UKRI)Engineering & Physical Sciences Research Council (EPSRC) PIII02

Influence of intense multidisciplinary follow-up and orlistat on weight reduction in a primary care setting

BACKGROUND: Obesity is the most common health problem in developed countries. Recently, several physicians' organizations have issued recommendations for treating obesity to family physicians, including instructions in nutrition, physical activity and medications. The aim of this study was to examine if effective weight-reducing treatment can be given by a family physician. It compares regular treatment with intensive treatment that include close follow-up and orlistat treatment. METHODS: The study was conducted in three primary care clinics. 225 patients were divided into three groups according to their choice. Group A received a personal diet with fortnightly meetings with the family physician and dietitian and orlistat treatment. Group B received a general diet, monthly meetings with the family physician only and orlistat treatment. Group C received a personal diet, monthly meetings with the dietitian only and no drug treatment. The primary endpoint was reduction of at least 5% of the initial weight during the study period. RESULTS: A greater percentage of patients in group A achieved their weight reduction goals than in other groups (51%, 13% and 9% in groups A, B and C, respectively, p < 0.001). There was a significant reduction in triglycerides in all groups, a significant reduction of low density lipids (LDL) in groups A and B and no significant difference in high density lipids (HDL) in any group. CONCLUSIONS: Significant weight reduction was obtained in a family physician setting. Further research is needed to evaluate if, by providing the family physician with the proper tools, similar success can be achieved in more clinics

Cortical Factor Feedback Model for Cellular Locomotion and Cytofission

Eukaryotic cells can move spontaneously without being guided by external cues. For such spontaneous movements, a variety of different modes have been observed, including the amoeboid-like locomotion with protrusion of multiple pseudopods, the keratocyte-like locomotion with a widely spread lamellipodium, cell division with two daughter cells crawling in opposite directions, and fragmentations of a cell to multiple pieces. Mutagenesis studies have revealed that cells exhibit these modes depending on which genes are deficient, suggesting that seemingly different modes are the manifestation of a common mechanism to regulate cell motion. In this paper, we propose a hypothesis that the positive feedback mechanism working through the inhomogeneous distribution of regulatory proteins underlies this variety of cell locomotion and cytofission. In this hypothesis, a set of regulatory proteins, which we call cortical factors, suppress actin polymerization. These suppressing factors are diluted at the extending front and accumulated at the retracting rear of cell, which establishes a cellular polarity and enhances the cell motility, leading to the further accumulation of cortical factors at the rear. Stochastic simulation of cell movement shows that the positive feedback mechanism of cortical factors stabilizes or destabilizes modes of movement and determines the cell migration pattern. The model predicts that the pattern is selected by changing the rate of formation of the actin-filament network or the threshold to initiate the network formation

Biomass Smoke Exposure Is Associated With Gastric Cancer and Probably Mediated Via Oxidative Stress and DNA Damage: A Case-Control Study.

PURPOSE: We investigated the association between gastric cancer and environmental and dietary exposures. In addition, we explored probable mechanistic pathways for the influence of biomass smoke on gastric carcinogenesis. PATIENTS AND METHODS: The study was conducted in Lusaka, Zambia. Questionnaires were used to collect data on risk factors, whereas enzyme-linked immunosorbent assays and high-performance liquid chromatography were used to measure biologic exposures. Study data were analyzed using contingency tables and logistic regression. RESULTS: We enrolled 72 patients with gastric adenocarcinoma and 244 controls. Gastric cancer was positively associated with rural residence (odds ratio [OR], 2.9; 95% CI, 1.5 to 5.3), poverty (OR, 4.2; 95% CI, 1.9 to 9.1), and daily consumption of processed meat (OR, 6.4; 95% CI, 1.3 to 32) and negatively associated with consumption of green vegetables (OR, 0.2; 95% CI, 0.1 to 0.5). Gastric cancer was also associated with biomass smoke exposure (OR, 3.5; 95% CI, 1.9 to 6.2; P < .0001), an association that was stronger for intestinal-type cancers (OR, 3.6; 95% CI, 1.5 to 9.1; P = .003). Exposure to biomass smoke in controls was associated with higher urinary levels of 8-isoprostane (P < .0001), 8-hydroxydeoxyguanosine (P = .029), and 1-hydroxypyrene (P = .041). Gastric cancer was not associated with biochemical measures of current exposure to aflatoxins or ochratoxins. CONCLUSION: In Zambia, exposure to biomass smoke, daily consumption of processed meat, and poverty are risk factors for gastric cancer, whereas daily consumption of green vegetables is protective against gastric cancer. Exposure to biomass smoke was associated with evidence of oxidative stress and DNA damage, suggesting mechanistic plausibility for the observed association, and the association was restricted to intestinal-type gastric cancer

Risk Factors for Periventricular-Intraventricular Hemorrhage in Premature Infants

Periventricular-intraventricular hemorrhage (PV-IVH) is a major cause of neurological disabilities in preterm newborns. This study aimed to determine the perinatal factors associated with PV-IVH. We conducted a retrospective case-control study from preterm infants born at ≤34 weeks of gestation and admitted to Neonatal Intensive Care Units of Seoul National University Children's Hospital and Seoul National University Bundang Hospital between June 2003 and December 2007. Neonates with no cranial sonographic data or infants transferred from other centers after three days of age were excluded. Of 1,044 eligible subjects, 59 infants with PV-IVH grade 2, 3, and 4 were allocated to the case group. The control group consisted of 118 infants without PV-IVH who were matched for gestational age and birth weight to each case of PV-IVH. At the multivariate logistic regression model, metabolic acidosis (odds ratio [OR]: 6.94; 95% confidence interval [CI]: 1.12-43.23) and use of inotropes (OR: 3.70; 95% CI: 1.16-11.84) were associated with an increased risk of PV-IVH. Maternal use of antenatal corticosteroids decreases the risk of PV-IVH (OR: 0.36; 95% CI: 0.14-0.92)

No effect of 24 h severe energy restriction on appetite regulation and ad libitum energy intake in overweight and obese males

Background/Objectives: Long-term success of weight loss diets might depend on how the appetite regulatory system responds to energy restriction (ER). This study determined the effect of 24 h severe ER on subjective and hormonal appetite regulation, subsequent ad libitum energy intake and metabolism. Subjects/Methods: In randomised order, eight overweight or obese males consumed a 24 h diet containing either 100% (12105 (1174 kJ; energy balance; EB) or 25% (3039 (295) kJ; ER) of estimated daily energy requirements (EER). An individualised standard breakfast containing 25% of EER (3216 (341) kJ) was consumed the following morning and resting energy expenditure, substrate utilisation and plasma concentrations of acylated ghrelin, glucagon-like peptide-1 (GLP-17–36), glucose-dependant insulinotropic peptide (GIP1–42), glucose, insulin and non-esterified fatty acid (NEFA) were determined for 4 h after breakfast. Ad libitum energy intake was assessed in the laboratory on day 2 and via food records on day 3. Subjective appetite was assessed throughout. Results: Energy intake was not different between trials for day 2 (EB: 14946 (1272) kJ; ER: 15251 (2114) kJ; P=0.623), day 3 (EB: 10580 (2457) kJ; 10812 (4357) kJ; P=0.832) or day 2 and 3 combined (P=0.693). Subjective appetite was increased during ER on day 1 (P0.381). Acylated ghrelin, GLP-17–36 and insulin were not different between trials (P>0.104). Post-breakfast area under the curve (AUC) for NEFA (P<0.05) and GIP1–42 (P<0.01) were greater during ER compared with EB. Fat oxidation was greater (P<0.01) and carbohydrate oxidation was lower (P<0.01) during ER, but energy expenditure was not different between trials (P=0.158). Conclusions: These results suggest that 24 h severe ER does not affect appetite regulation or energy intake in the subsequent 48 h. This style of dieting may be conducive to maintenance of a negative EB by limiting compensatory eating behaviour, and therefore may assist with weight loss

Obesity promotes 7,12-dimethylbenz(a)anthracene-induced mammary tumor development in female zucker rats

INTRODUCTION: High body mass index has been associated with increased risk for various cancers, including breast cancer. Here we describe studies using 7,12-dimethylbenz(a)anthracene (DMBA) to investigate the role of obesity in DMBA-induced mammary tumor susceptibility in the female Zucker rat (fa/fa), which is the most widely used rat model of genetic obesity. METHOD: Fifty-day-old female obese (n = 25) and lean (n = 28) Zucker rats were orally gavaged with 65 mg/kg DMBA. Rats were weighed and palpated twice weekly for detection of mammary tumors. Rats were killed 139 days after DMBA treatment. RESULTS: The first mammary tumor was detected in the obese group at 49 days after DMBA treatment, as compared with 86 days in the lean group (P < 0.001). The median tumor-free time was significantly lower in the obese group (P < 0.001). Using the days after DMBA treatment at which 25% of the rats had developed mammary tumors as the marker of tumor latency, the obese group had a significantly shorter latency period (66 days) than did the lean group (118 days). At the end of the study, obese rats had developed a significantly (P < 0.001) greater mammary tumor incidence (68% versus 32%) compared with the lean group. The tumor histology of the mammary tumors revealed that obesity was associated with a significant (P < 0.05) increase in the number of rats with at least one invasive ductal and lobular carcinoma compared with lean rats. CONCLUSION: Our results indicate that obesity increases the susceptibility of female Zucker rats to DMBA-induced mammary tumors, further supporting the hypothesis that obesity and some of its mediators play a significant role in carcinogenesis

Nutritional profile and obesity: results from a random‑sample population‑based study in Córdoba, Argentina

Introduction Obesity is a chronic, heterogeneous, multifactorial disease, which has sharply increased in prevalence in both developed and developing countries. This study aimed to estimate the prevalence of obesity and to identify socio-demographic risk factors associated with it, with special emphasis on diet. Methods Nutritional status, demographic characteristics, lifestyle habits, and food consumption patterns derived from a Food Frequency Questionnaire were investigated. Exhaustive exploratory analyses were performed in order to describe dietary patterns, and logistic regression models were used for odds ratio estimation. Results The study included 4328 subjects, over 18 years old and resident in Cordoba city. The prevalence of overweight and obesity was 34 and 17 %, respectively, with 60 % in men and 45 % in women of BMI ≥ 25. Obesity risk factors were high intake of sodium, refined grains, starchy vegetables, and snacks. A lower risk of overweight and obesity was associated with an adequate, moderate intake of meats, eggs, alcoholic beverages, sugar and sweets, milk, yogurt, and pulses. Conclusions A high intake of snacks, refined grains, starchy vegetables and sodium and low intake of yogurt, milk, pulses, and whole grains seem to be associated with the emergence and high prevalence of obesity in Cordoba, Argentina.publishedVersionFil: Aballay, Laura Rosana. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Escuela de Nutrición. Estadística y Bioestadística; ArgentinaFil: Aballay, Laura Rosana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ciencias de la Salud; Argentina.Fil: De la Quintana, Ana Gabriela. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Escuela de Nutrición; Argentina.Fil: Díaz, María del Pilar. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Escuela de Nutrición. Estadística y Bioestadística; Argentina.Fil: Díaz, María del Pilar. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ciencias de la Salud; Argentina.Fil: Osella, Alberto R. Hospital Saverio de Bellis. Laboratorio de Epidemiologia y Bioestadística; Italia

Receptor conversion in distant breast cancer metastases

Introduction: When breast cancer patients develop distant metastases, the choice of systemic treatment is usually based on tissue characteristics of the primary tumor as determined by immunohistochemistry (IHC) and/or molecular analysis. Several previous studies have shown that the immunophenotype of distant breast cancer metastases may be different from that of the primary tumor (receptor conversion), leading to inappropriate choice of systemic treatment. The studies published so far are however small and/or methodologically suboptimal. Therefore, definite conclusions that may change clinical practice could not yet be drawn. We therefore aimed to study receptor conversion for estrogen receptor alpha (ER alpha), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) in a large group of distant (non-bone) breast cancer metastases by re-staining all primary tumors and metastases with current optimal immunohistochemical and in situ hybridization methods on full sections. Methods: A total of 233 distant breast cancer metastases from different sites (76 skin, 63 liver, 43 lung, 44 brain and 7 gastro-intestinal) were IHC stained for ER alpha, PR and HER2, and expression was compared to that of the primary tumor. HER2 in situ hybridization (ISH) was done in cases of IHC conversion or when primary tumors or metastases showed an IHC 2+ result. Results: Using a 10% threshold, receptor conversion by IHC for ER alpha, PR occurred in 10.3%, 30.0% of patients, respectively. In 10.7% of patients, conversion from ER+ or PR+ to ER-/PR- and in 3.4% from ER-/PR- to ER+ or PR+ was found. Using a 1% threshold, ER alpha and PR conversion rates were 15.1% and 32.6%. In 12.4% of patients conversion from ER+ or PR+ to ER-/PR-, and 8.2% from ER-/PR-to ER+ or PR+ occurred. HER2 conversion occurred in 5.2%. Of the 12 cases that showed HER2 conversion by IHC, 5 showed also conversion by ISH. One further case showed conversion by ISH, but not by IHC. Conversion was mainly from positive in the primary tumor to negative in the metastases for ER alpha and PR, while HER2 conversion occurred equally both ways. PR conversion occurred significantly more often in liver, brain and gastro-intestinal metastases. Conclusions: Receptor conversion by immunohistochemistry in (non-bone) distant breast cancer metastases does occur, is relatively uncommon for ER alpha and HER2, and is more frequent for PR, especially in brain, liver and gastrointestinal metastase

Role of hydrodynamic factors in controlling the formation and location of unconformity-related uranium deposits: insights from reactive-flow modeling

The role of hydrodynamic factors in controlling the formation and location of unconformity-related uranium (URU) deposits in sedimentary basins during tectonically quiet periods is investigated. A number of reactive-flow modeling experiments at the deposit scale were carried out by assigning different dip angles and directions to a fault and various permeabilities to hydrostratigraphic units). The results show that the fault dip angle and direction, and permeability of the hydrostratigraphic units govern the convection pattern, temperature distribution, and uranium mineralization. Avertical fault results in uranium mineralization at the bottom of the fault within the basement, while a dipping fault leads to precipitation of uraninite below the unconformity either away from or along the plane of the fault, depending on the fault permeability. A more permeable fault causes uraninite precipitates along the fault plane,whereas a less permeable one gives rise to the precipitation of uraninite away from it. No economic ore mineralization can form when either very low or very high permeabilities are assigned to the sandstone or basement suggesting that these units seem to have an optimal window of permeability for the formation of uranium deposits. Physicochemical parameters also exert an additional control in both the location and grade of URU deposits. These results indicate that the difference in size and grade of different URU deposits may result from variation in fluid flow pattern and physicochemical conditions, caused by the change in structural features and hydraulic properties of the stratigraphic units involved