School Closures During COVID-19: Opportunities for Innovation in Meal Service.

In 2019, the National School Lunch Program and School Breakfast Program served approximately 15 million breakfasts and 30 million lunches daily at low or no cost to students.Access to these meals has been disrupted as a result of long-term school closures related to the COVID-19 pandemic, potentially decreasing both student nutrient intake and household food security. By the week of March 23, 2020, all states had mandated statewide school closures as a result of the pandemic, and the number of weekly missed breakfasts and lunches served at school reached a peak of approximately 169.6 million; this weekly estimate remained steady through the final week of April.We highlight strategies that states and school districts are using to replace these missed meals, including a case study from Maryland and the US Department of Agriculture waivers that, in many cases, have introduced flexibility to allow for innovation. Also, we explore lessons learned from the pandemic with the goal of informing and strengthening future school nutrition policies for out-of-school time, such as over the summer.

Wellness School Assessment Tool Version 3.0: An Updated Quantitative Measure of Written School Wellness Policies.

Schools play an important role in promoting student wellness. As directed by the Healthy Hunger-Free Kids Act, the US Department of Agriculture updated the requirements for written school wellness policies in 2016. The WellSAT (Wellness School Assessment Tool) is an online tool that provides a quantitative score for wellness policy comprehensiveness and strength. The WellSAT has been updated 3 times over the past decade to remain current with federal law and best practices. In this article, we describe the process of updating to WellSAT 3.0. The steps included: reviewing the language of each item linked to a federal provision; adding and deleting items based on frequencies from the National Wellness Policy Study and the empirical support for specific policies; gathering feedback from a survey of experts (N = 77) about best practices and measure usability; and establishing intercoder reliability in a national sample (N = 50) of policies. We conclude with recommendations and guidance for the use of WellSAT 3.0.

Estimates of the Nutritional Impact of Non-Participation in the National School Lunch Program during COVID-19 School Closures.

The COVID-19 pandemic resulted in widespread school closures, reducing access to school meals for millions of students previously participating in the US Department of Agriculture (USDA) National School Lunch Program (NSLP). School-prepared meals are, on average, more nutritious than home-prepared meals. In the absence of recent data measuring changes in children's diets during the pandemic, this article aims to provide conservative, back-of-the-envelope estimates of the nutritional impacts of the pandemic for school-aged children in the United States. We used administrative data from the USDA on the number of NSLP lunches served in 2019 and 2020 and nationally representative data from the USDA School Nutrition and Meal Cost Study on the quality of school-prepared and home-prepared lunches. We estimate changes in lunchtime calories and nutrients consumed by NSLP participants from March to November 2020, compared to the same months in 2019. We estimate that an NSLP participant receiving no school meals would increase their caloric consumption by 640 calories per week and reduce their consumption of nutrients such as calcium and vitamin D. Because 27 to 78 million fewer lunches were served per week in March-November 2020 compared to the previous year, nationally, students may have consumed 3 to 10 billion additional calories per week. As students return to school, it is vital to increase school meal participation and update nutrition policies to address potentially widening nutrition disparities.

Implementing School-Based Policies to Prevent Obesity: Cluster Randomized Trial.

INTRODUCTION: Healthier school environments can benefit students, and school wellness policies may result in meaningful enhancements. Schools participating in federal child nutrition programs must implement wellness policies as mandated by law. The primary study objective is to assess effectiveness of implementing school-based nutrition and physical activity policies on student BMI trajectories. STUDY DESIGN: Cluster randomized trial using 2 × 2 factorial design. SETTING/PARTICIPANTS: Twelve randomly selected schools in an urban district. Students were followed for 3 years through middle school, fifth to eighth grades (2011-2015, n=595 students, 92.3% participation, 85.2% retention). INTERVENTION: Specific to randomized condition, support was provided for implementation of nutrition policies (e.g., alternatives to food-based rewards/celebrations) and physical activity policies (e.g., opportunities for physical activity during/after school). MAIN OUTCOME MEASURES: Sex-/age-adjusted BMI percentile and BMI z-score; behavioral indicators. Data collected via standardized protocols. RESULTS: Analyses followed intention-to-treat principles, with planned secondary analyses (conducted 2016-2018). Students at schools randomized to receive support for nutrition policy implementation had healthier BMI trajectories over time (F=3.20, p=0.02), with a greater magnitude over time and cumulatively significant effects 3 years post-intervention (ß=-2.40, p=0.04). Overall, students at schools randomized to receive the nutrition intervention had an increase in BMI percentile of <1%, compared with students in other conditions, whereas BMI percentile increased 3%-4%. There was no difference in student BMI between those in schools with and without physical activity policy implementation. Examining behavioral correlates in eighth grade, students at schools randomized to the nutrition condition consumed fewer unhealthy foods and sugar-sweetened beverages, and ate less frequently at fast-food restaurants (all p<0.03). CONCLUSIONS: This cluster randomized trial demonstrated effectiveness of providing support for implementation of school-based nutrition policies, but not physical activity policies, to limit BMI increases among middle school students. Results can guide future school interventions. TRIAL REGISTRATION: This study is registered at www.clinicaltrials.gov NCT02043626.

Impact of the Smoothened inhibitor, IPI-926, on smoothened ciliary localization and Hedgehog pathway activity.

A requisite step for canonical Hedgehog (Hh) pathway activation by Sonic Hedgehog (Shh) ligand is accumulation of Smoothened (Smo) to the primary cilium (PC). Activation of the Hh pathway has been implicated in a broad range of cancers, and several Smo antagonists are being assessed clinically, one of which is approved for the treatment of advanced basal cell carcinoma. Recent reports demonstrate that various Smo antagonists differentially impact Smo localization to the PC while still exerting inhibitory activity. In contrast to other synthetic small molecule Smo antagonists, the natural product cyclopamine binds to and promotes ciliary accumulation of Smo and "primes" cells for Hh pathway hyper-responsiveness after compound withdrawal. We compared the properties of IPI-926, a semi-synthetic cyclopamine analog, to cyclopamine with regard to potency, ciliary Smo accumulation, and Hh pathway activity after compound withdrawal. Like cyclopamine, IPI-926 promoted accumulation of Smo to the PC. However, in contrast to cyclopamine, IPI-926 treatment did not prime cells for hyper-responsiveness to Shh stimulation after compound withdrawal, but instead demonstrated continuous inhibition of signaling. By comparing the levels of drug-induced ciliary Smo accumulation with the degree of Hh pathway activity after compound withdrawal, we propose that a critical threshold of ciliary Smo is necessary for "priming" activity to occur. This "priming" appears achievable with cyclopamine, but not IPI-926, and is cell-line dependent. Additionally, IPI-926 activity was evaluated in a murine tumor xenograft model and a pharmacokinetic/pharmacodynamic relationship was examined to assess for in vivo evidence of Hh pathway hyper-responsiveness. Plasma concentrations of IPI-926 correlated with the degree and duration of Hh pathway suppression, and pathway activity did not exceed baseline levels out to 96 hours post dose. The overall findings suggest that IPI-926 possesses unique biophysical and pharmacological properties that result in Hh pathway inhibition in a manner that differentiates it from cyclopamine.

New developments in the discovery of small molecule Hedgehog pathway antagonists.

The Hedgehog (Hh) signaling pathway is crucial for normal embryonic development. Aberrant Hh signaling is implicated in numerous pathologic conditions including proliferative diseases such as cancer. During the past decade, academic and industrial research efforts have resulted in the discovery of a variety of Hh pathway antagonists. This review focuses on the most recent advances in this field with particular emphasis on the medicinal chemistry approaches used to discover these Hh antagonists. While most of the small molecule modulators of the Hh pathway were discovered through screening and subsequent medicinal chemistry, a number of them originated from rational design or natural products.

Discovery of a potent and orally active hedgehog pathway antagonist (IPI-926).

Recent evidence suggests that blocking aberrant hedgehog pathway signaling may be a promising therapeutic strategy for the treatment of several types of cancer. Cyclopamine, a plant Veratrum alkaloid, is a natural product antagonist of the hedgehog pathway. In a previous report, a seven-membered D-ring semisynthetic analogue of cyclopamine, IPI-269609 (2), was shown to have greater acid stability and better aqueous solubility compared to cyclopamine. Further modifications of the A-ring system generated three series of analogues with improved potency and/or solubility. Lead compounds from each series were characterized in vitro and evaluated in vivo for biological activity and pharmacokinetic properties. These studies led to the discovery of IPI-926 (compound 28), a novel semisynthetic cyclopamine analogue with substantially improved pharmaceutical properties and potency and a favorable pharmacokinetic profile relative to cyclopamine and compound 2. As a result, complete tumor regression was observed in a Hh-dependent medulloblastoma allograft model after daily oral administration of 40 mg/kg of compound 28.

Semisynthetic cyclopamine analogues as potent and orally bioavailable hedgehog pathway antagonists.

Herein is reported the synthesis of a novel class of hedgehog antagonists derived from cyclopamine. The acid sensitive D-ring of cyclopamine was homologated utilizing a sequence of chemoselective cyclopropanation and stereoselective acid-catalyzed rearrangement. Further modification of the A/B-ring homoallylic alcohol to the conjugated ketone led to the discovery of new cyclopamine analogues with improved pharmaceutical properties and in vitro potency (EC 50) ranging from 10 to 1000 nM.

Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90.

Heat shock protein 90 (Hsp90) is an emerging therapeutic target of interest for the treatment of cancer. Its role in protein homeostasis and the selective chaperoning of key signaling proteins in cancer survival and proliferation pathways has made it an attractive target of small molecule therapeutic intervention. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), the most studied agent directed against Hsp90, suffers from poor physical-chemical properties that limit its clinical potential. Therefore, there exists a need for novel, patient-friendly Hsp90-directed agents for clinical investigation. IPI-504, the highly soluble hydroquinone hydrochloride derivative of 17-AAG, was synthesized as an Hsp90 inhibitor with favorable pharmaceutical properties. Its biochemical and biological activity was profiled in an Hsp90-binding assay, as well as in cancer-cell assays. Furthermore, the metabolic profile of IPI-504 was compared with that of 17-AAG, a geldanamycin analog currently in clinical trials. The anti-tumor activity of IPI-504 was tested as both a single agent as well as in combination with bortezomib in myeloma cell lines and in vivo xenograft models, and the retention of IPI-504 in tumor tissue was determined. In conclusion, IPI-504, a potent inhibitor of Hsp90, is efficacious in cellular and animal models of myeloma. It is synergistically efficacious with the proteasome inhibitor bortezomib and is preferentially retained in tumor tissues relative to plasma. Importantly, it was observed that IPI-504 interconverts with the known agent 17-AAG in vitro and in vivo via an oxidation-reduction equilibrium, and we demonstrate that IPI-504 is the slightly more potent inhibitor of Hsp90.

An intact NEDD8 pathway is required for Cullin-dependent ubiquitylation in mammalian cells.

Skp1-Cdc53/Cul1-F-box (SCF) complexes constitute a class of E3 ubiquitin ligases. Recently, a multiprotein complex containing pVHL, elongin C and Cul2 (VEC) was shown to structurally and functionally resemble SCF complexes. Cdc53 and the Cullins can become covalently linked to the ubiquitin-like molecule Rub1/NEDD8. Inhibition of neddylation inhibits SCF function in vitro and in yeast and plants. Here we show that ongoing neddylation is likewise required for VEC function in vitro and for the degradation of SCF and VEC targets in mammalian cells. Thus, neddylation regulates the activity of two specific subclasses of mammalian ubiquitin ligases.