Fibroblast growth factor receptors in cancer: genetic alterations,diagnostics, therapeutic targets and mechanisms of resistance

Fibroblast growth factor receptors (FGFRs) are aberrantly activated through single-nucleotide variants, gene fusions and copy number amplifications in 5–10% of all human cancers, although this frequency increases to 10–30% in urothelial carcinoma and intrahepatic cholangiocarcinoma. We begin this review by highlighting the diversity of FGFR genomic alterations identified in human cancers and the current challenges associated with the development of clinical-grade molecular diagnostic tests to accurately detect these alterations in the tissue and blood of patients. The past decade has seen significant advancements in the development of FGFR-targeted therapies, which include selective, non-selective and covalent small-molecule inhibitors, as well as monoclonal antibodies against the receptors. We describe the expanding landscape of anti-FGFR therapies that are being assessed in early phase and randomised controlled clinical trials, such as erdafitinib and pemigatinib, which are approved by the Food and Drug Administration for the treatment of FGFR3-mutated urothelial carcinoma and FGFR2-fusion cholangiocarcinoma, respectively. However, despite initial sensitivity to FGFR inhibition, acquired drug resistance leading to cancer progression develops in most patients. This phenomenon underscores the need to clearly delineate tumour-intrinsic and tumour-extrinsic mechanisms of resistance to facilitate the development of second-generation FGFR inhibitors and novel treatment strategies beyond progression on targeted therapy.Subject terms: Cancer, Cancer     

Does stroke impair academic achievement in children? The role of metacognition in math and spelling outcomes following pediatric stroke

Introduction: Current research suggests that pediatric stroke is associated with a reduction in intellectual functioning. However, less is known about academic achievement and the contribution of specific executive functions to math and literacy in this population. The current study investigates behavioral ratings of executive functioning and their relationship to math and spelling performance in children with a history of unilateral arterial ischemic stroke.

Method: Thirty-two pediatric patients with stroke (M_age = 9.5 ± 2.7 years) and 32 demographically equivalent, healthy controls were tested on standardized measures of arithmetic, spelling, and intelligence. Executive functioning data were collected via standardized parent questionnaire.

Results: Relative to controls, stroke participants demonstrated significantly poorer functioning in math, spelling, metacognition, and behavioral-regulation. Pencil and paper arithmetic was particularly challenging for the stroke group, with 40% of patients reaching levels of clinical impairment. Hierarchical regression in stroke participants further revealed that metacognition was a robust predictor of academic deficits. Stroke occurring in later childhood and affecting cortical and subcortical brain regions also presented as potential clinical risk factors.

Conclusions: Children with stroke were especially vulnerable to math achievement deficits. Metacognition made a substantial contribution to academic achievement abilities among stroke patients, and results underscore the importance of early metacognitive skills in the completion of schoolwork. Results also emphasize that pediatric stroke patients are a heterogeneous group with regard to functioning and that there is value in examining standard score distributions of clinical participant samples.     

Consumption of Dry Beans, Peas, and Lentils Could Improve Diet Quality in the US Population

The US Department of Agriculture's MyPyramid guidelines introduced a near doubling of the dietary recommendations for vegetables. These recommendations target specific subgroups of vegetables, including dry beans and peas. Dry beans and peas provide an array of nutrients and phytochemicals that have been shown to have beneficial health effects, yet consumption levels in the United States are quite low. Few studies have examined the influence of legume consumption on nutrient intakes. Therefore, the purpose of this study was to assess nutrient and food group intakes of dry bean and pea consumers compared to nonconsumers. Dietary intake data from the 1999-2002 National Health and Nutrition Examination Survey for adults aged ≥19 years was used. Results show that on any given day only 7.9% of adults are consuming dry beans and peas; Mexican Americans or other Hispanics are more likely to be consumers than nonconsumers. Consuming approximately ½ c dry beans or peas resulted in higher intakes of fiber, protein, folate, zinc, iron, and magnesium with lower intakes of saturated fat and total fat. These data support the specific recommendation for dry beans and peas as part of the overall vegetable recommendation. Increased consumption of dry beans and peas—economical and nutrient-rich foods—could improve the diet quality of Americans.     

Americans' Awareness, Knowledge, and Behaviors Regarding Fats: 2006-2007

In recent years, epidemiologic and clinical studies, public and regulatory policy activity, and media coverage have focused on issues related to trans fats. To help increase awareness and understanding of trans fats and other fats, the American Heart Association (AHA) launched the “Face the Fats” national consumer education campaign in April 2007. The AHA commissioned a quantitative tracking survey between 2006 and 2007 to measure changes in consumer awareness, knowledge, and behaviors related fats and oils and their perceived impact on heart disease. The survey was conducted by Cogent Research. Data were collected during March 2006 and May 2007. At both time points, the survey included a representative sample of the American population age 18 to 65 years (n=1,000). The sampling plan for the survey was designed based on the 2000 and 2003 US Census. The margin of error was ±3.10 percentage points. Awareness of trans fats increased during the 1-year study period. In 2007, 92% of respondents were aware of trans fats, an increase from 84% in 2006 (P<0.05). The 2007 level was similar to the awareness of saturated fats (93%). Perceptions that certain fats and oils heighten the risk of heart disease increased for trans fats (73% in 2007 vs 63% in 2006; P<0.05), saturated fats (77% in 2007 vs 73% in 2006; P<0.05), and partially hydrogenated oils (56% in 2007 vs 49% in 2006; P<0.05). Knowledge about food sources of different fats remained low. On an unaided basis, 21% could name three food sources of trans fats in 2007, up from 17% in 2006 (P<0.05). Knowledge of food sources of saturated fat remained unchanged at 30% in 2007. Significantly more respondents in 2007 reported behavioral changes related to trans fat information, such as buying food products because they show “zero trans fat” on labels or packages (37% in 2007 vs. 32% in 2006; P<0.05). Between 2006 and 2007, consumer awareness about trans fats increased and attained awareness levels similar to saturated fats. The increased awareness is associated with improved self-reported behaviors in grocery shopping. Nonetheless, overall knowledge, especially regarding food sources of saturated and trans fats, remains relatively low, underscoring the need for heightened consumer education activities. The positive change in consumer awareness about trans fats is likely attributable to the wide range of messages available to them, including the AHA “Face the Fats” national consumer education campaign.     

Publishing Nutrition Research: A Review of Epidemiologic Methods

The use of epidemiologic research designs and analytical methods is common in dietetics research. Food and nutrition professionals who seek to perform evidence-based practice or participate in research design, analysis, and communication need skills in the essentials of epidemiology. This is one of a series of monographs on research methodology that addresses these needs and supports the goals of the Board of Editors of the Journal of the American Dietetic Association to further enhance competency and skills. This monograph focuses on statistical approaches for univariate analyses used with the primary observational study designs associated with epidemiology. Tables illustrating the presentation and interpretation of these results are included.     

Grandmothers, Fathers, and Depressive Symptoms Are Associated with Food Insecurity among Low-Income First-Time African-American Mothers in North Carolina

African Americans experience household food insecurity, ie, the limited availability of nutritionally adequate and safe food, or ability to acquire acceptable foods in socially acceptable ways, at three times the rate of non-Hispanic whites. Thirty percent of all African-American children live in food-insecure households. The purpose of this study was to identify characteristics associated with household food insecurity among a high-risk postpartum population. Two-hundred six low-income, African-American mother−infant dyads were recruited through the Special Supplemental Nutrition Program for Women, Infants, and Children clinics. The six-item US Department of Agriculture food security scale was used to classify households as food secure, marginally food secure, or food insecure. Multinomial logistic regression was used to estimate the association between selected maternal/household characteristics and household food-security status. Fifty-three percent of households were food secure, 34% were marginally food secure, and 13% were food insecure. Maternal education less than college (relative risk ratio [RRR]=0.46; 95% confidence interval [CI]: 0.22 to 0.98) was inversely associated with marginal food security. Depressive symptoms (RRR=1.09; 95% CI: 1.02 to 1.16) and having the baby's father in the household (RRR=3.46; 95% CI: 1.22 to 9.82) were associated with household food insecurity, while having a grandmother in the household (RRR=0.15; 95% CI: 0.03 to 0.80) was inversely associated with experiencing household food insecurity. Findings from this study suggest that young, low-income, African-American families with only one child are particularly susceptible to experiencing household food insecurity. Intergenerational support and transfer of knowledge can be a key protective attribute among low-income African-American households.     

Unrealistic Weight-Loss Goals among Obese Patients Are Associated with Age and Causal Attributions

Unrealistic weight-loss goals may impede the success of weight-loss attempts. The aim of this study was to examine the frequency of unrealistic goals and their association with other patient characteristics at the start of a weight-loss program. For patients with a body mass index (calculated as kg/m²) of 30 to 35, 35 to 40, or 40 to 50, medically advised weight-loss goals were set at 10%, 15%, and 20% of current weight, respectively. Personal weight-loss goals exceeding the medically advised goal by >50% were considered unrealistic. Obesity-related beliefs were measured by the “Obesity Cognition Questionnaire” and the eating-behavior self-efficacy scale of the “Obesity Psychosocial State Questionnaire.” From September 2003 until March 2006, 90 patients were enrolled in the study, 26 men and 64 women, with a mean age of 43 years (range=18 to 68 years) and body mass indexes ranging from 30 to 50. Unrealistic goals were observed in 49% of the patients and were more frequent in younger patients (P=0.03), in patients attributing their obesity to physical causes (r=0.35, P=0.001), and in patients not attributing their obesity to behavioral causes (r=−0.28, P=0.008). This study confirms that discrepancies in weight-loss goals between obese patients and professionals occur frequently. Because unrealistic goals can hamper long-term outcomes of weight-loss programs, better outcomes could possibly be achieved by addressing unrealistic weight-loss goals before treatment.