MNK inhibition sensitizes KRAS-mutant colorectal cancer to mTORC1 inhibition by reducing eIF4E phosphorylation and c-MYC expression.

KRAS-mutant colorectal cancers (CRC) are resistant to therapeutics, presenting a significant problem for ~40% of cases. Rapalogs, which inhibit mTORC1 and thus protein synthesis, are significantly less potent in KRAS-mutant CRC. Using Kras-mutant mouse models and mouse- and patient-derived organoids we demonstrate that KRAS with G12D mutation fundamentally rewires translation to increase both bulk and mRNA-specific translation initiation. This occurs via the MNK/eIF4E pathway culminating in sustained expression of c-MYC. By genetic and small molecule targeting of this pathway, we acutely sensitize KRASG12D models to rapamycin via suppression of c-MYC. We show that 45% of CRCs have high signaling through mTORC1 and the MNKs, with this signature correlating with a 3.5-year shorter cancer-specific survival in a subset of patients. This work provides a c-MYC-dependent co-targeting strategy with remarkable potency in multiple Kras-mutant mouse models and metastatic human organoids and identifies a patient population who may benefit from its clinical application

Nutritional status of young children in Mumbai slums: a follow-up anthropometric study

<p>Abstract</p> <p>Background</p> <p>Chronic childhood malnutrition remains common in India. As part of an initiative to improve maternal and child health in urban slums, we collected anthropometric data from a sample of children followed up from birth. We described the proportions of underweight, stunting, and wasting in young children, and examined their relationships with age.</p> <p>Methods</p> <p>We used two linked datasets: one based on institutional birth weight records for 17 318 infants, collected prospectively, and one based on follow-up of a subsample of 1941 children under five, collected in early 2010.</p> <p>Results</p> <p>Mean birth weight was 2736 g (SD 530 g), with a low birth weight (<2500 g) proportion of 22%. 21% of infants had low weight for age standard deviation (z) scores at birth (<−2 SD). At follow-up, 35% of young children had low weight for age, 17% low weight for height, and 47% low height for age. Downward change in weight for age was greater in children who had been born with higher z scores.</p> <p>Discussion</p> <p>Our data support the idea that much of growth faltering was explained by faltering in height for age, rather than by wasting. Stunting appeared to be established early and the subsequent decline in height for age was limited. Our findings suggest a focus on a younger age-group than the children over the age of three who are prioritized by existing support systems.</p> <p>Funding</p> <p>The trial during which the birth weight data were collected was funded by the ICICI Foundation for Inclusive Growth (Centre for Child Health and Nutrition), and The Wellcome Trust (081052/Z/06/Z). Subsequent collection, analysis and development of the manuscript was funded by a Wellcome Trust Strategic Award: Population Science of Maternal and Child Survival (085417ma/Z/08/Z). D Osrin is funded by The Wellcome Trust (091561/Z/10/Z).</p

Mesozoic and Cenozoic Plate Evolution of the Caribbean Region

The reconstruction of Caribbean plate history is an uncertain task, but a task that has intrigued generations of geologists. Each worker has turned to the task of historical interpretation influenced by a particular set of experiences or a special approach, and the results have been accordingly varied. A complete history of interpretations would form the subject of a fascinating chapter in the history of geological philosophy, but such is not the purpose of this chapter. Instead, I will dwell on a set of data that call for what I believe to be a relatively conservative view of Cretaceous and Tertiary plate history. My own interpretation is based heavily on my own or my students’ field experiences in the northeastern West Indies, Guatemala, Belize, and Venezuela, as well as extensive field excursions in Hispaniola, Jamaica, the Lesser Antilles, Central America, and the Dutch Antilles. I am further heavily influenced by the results of the Deep Sea Drilling Project (DSDP), Leg 15, which produced information of fundamental interest in the Venezuelan and Colombian Basins, and by several dissertations of the Princeton University group in northern Venezuela