Sunlight is a carcinogen to which everyone is exposed. Its UV component is the major epidemiologic risk factor for squamous cell carcinoma of the skin. Of the multiple steps in tumor progression, those that are sunlight-related would be revealed if they contained mutations specific to UV. In a series of New England and Swedish patients, we find that 14/24 (58%) of invasive squamous cell carcinomas of the skin contain mutations in the p53 tumor suppressor gene, each altering the amino acid sequence. Involvement of UV light in these p53 mutations is indicated by the presence in three of the tumors of a CC --TT double-base change, which is only known to be induced by UV. UV is also implicated by a UV-like occurrence of mutations exclusively at dipyrimidine sites, including a high frequency of C --T substitutions. p53 mutations in internal malignancies do not show these UVspecific mutations. The dipyrimidine specificity also implicates dipyrimidine photoproducts containing cytosine as oncogenic photoproducts. We believe these results identify a carcinogenrelated step in a gene involved in the subsequent human cancer.The frequency of skin cancers induced by sunlight in the United States approaches that of all other cancers combined and is doubling each decade (1-3). Ninety-five percent of these are non-melanoma skin cancers, resulting in one-third as many deaths as melanoma (4).Epidemiology has identified causal agents for many human cancers, including skin cancer (5), and reagents such as retroviruses have revealed genes that become oncogenic when mutated (6). Yet, the events between a human carcinogen and the human tumor mutations are unknown. Several questions central to oncology converge on these missing events. In the case of squamous cell carcinoma of the skin, they include the wavelength oflight, the gene that absorbs the photon, the DNA photoproduct, the contribution of mutagenesis versus systemic effects of sunlight such as immunosuppression, the type of mutation, possible hotspot sequences, and confidence that the genetic alterations observed in a tumor participated in tumor formation.Squamous cell carcinoma of the skin is an ideal cancer for determining which of the multiple steps in tumorigenesis are carcinogen-related for the following reasons.(i) The carcinogen is known; in lightly pigmented individuals of all races, the majority of skin cancers are due to sunlight. Of these, squamous cell carcinoma is more sunlightdependent than basal cell carcinoma or melanoma (1, 7). This carcinogen is physically well-defined, whereas agents such as tobacco smoke are complex mixtures.(ii) UV light produces distinctive mutations, leaving a "signature" in the DNA. Mutations due to direct absorption of UV light by DNA are predominantly C --T transitions at dipyrimidine sites, including CC --TT double-base mutations, in organisms from viral to human (refs. 8-12 and references therein). Because CC -* TT base changes are only known to be caused by UV, their presence identifies UV as the mutagen. The appearance of C...

Objective To characterize the natural history of intestinal failure (IF) among 14 pediatric centers during the intestinal transplantation (ITx) era. Study design The Pediatric Intestinal Failure Consortium performed a retrospective analysis of clinical and outcome data for a multi-center cohort of infants with IF. Entry criteria included infants <12 mo receiving parenteral nutrition (PN) for >60 continuous days. Enteral autonomy was defined as discontinuation of PN for >3 consecutive months. Values are presented as median (25th, 75th percentiles) or as (n, %). Results 272 infants with a gestational age of 34 wks (30, 36) and birth weight of 2.1 kg (1.2, 2.7) were followed for 25.7 mo (11.2, 40.9). Residual small bowel length in 144 patients was 41 cm (25.0, 65.5). Diagnoses were necrotizing enterocolitis (71, 26%), gastroschisis (44, 16%), atresia (27, 10%), volvulus (24, 9%), combinations of these diagnoses (46, 17%), aganglionosis (11, 4%), and other single or multiple diagnoses (48, 18%). Prescribed medications included oral antibiotics (207, 76%), H2 blockers (187, 69%), and PPIs (156, 57%). Enteral feeding approaches varied among centers; 19% of the cohort received human milk. The cohort experienced 8.9 new catheter-related blood stream infections per 1,000 catheter days. The cumulative incidences for enteral autonomy, death, and ITx were 47%, 27%, and 26%, respectively. Enteral autonomy continued into the 5th year after study entry. Conclusions Children with IF endure significant mortality and morbidity. Enteral autonomy may require years to achieve. Improved medical, nutritional, and surgical management may reduce time on PN, mortality and need for transplantation.

Objectives In a large cohort of children with intestinal failure (IF), we sought to determine the cumulative incidence of achieving enteral autonomy and identify patient and institutional characteristics associated with enteral autonomy. Study design A multicenter retrospective cohort analysis from the Pediatric Intestinal Failure Consortium (PIFCon) was performed. IF was defined as severe congenital or acquired gastrointestinal diseases during infancy with PN dependence >60 days. Enteral autonomy was defined as PN discontinuation >3 months. Results 272 infants were followed for a median (IQR) of 33.5(16.2, 51.5) months. Enteral autonomy was achieved in 118(43%); 36(13%) remained PN dependent and 118 (43%) patients died or underwent transplantation. Multivariable analysis identified NEC [OR 95% CI: 2.42 (1.33, 4.47)], care at an IF site without an associated intestinal transplant (ITx) program [OR 2.73 (1.56, 4.78)] and an intact ileocecal valve (ICV) [OR 2.80 (1.63, 4.83)] as independent risk factors for enteral autonomy. A second model (n=144) including only patients with intra-operatively measured residual small bowel length (RSB) found NEC [OR 3.44 (1.36, 8.71)], care at a non-ITx center [OR 6.56 (2.53, 16.98)] and RSB (cm) [OR 1.04 (1.02, 1.06)] to be independently associated with enteral autonomy. Conclusions A substantial proportion of infants with IF can achieve enteral autonomy. Underlying NEC, preserved ICV and longer bowel length are associated with achieving enteral autonomy. It is likely that variations in institutional practices and referral patterns also affect outcomes in children with IF.

Heat-stable enterotoxin (STa), elaborated by enterotoxigenic Echerichia coli, is a worldwide cause of secretory diarrhea in infants and travelers. Both STa and guanylin, a peptide structurally similar to STa, increase intracellular cGMP levels after binding to the same intestinal receptor, guanylate cyclase C (GC-C). Distinct from its role as an intestinal secretagogue, guanylin may also have a role in intestinal proliferation, as guanylin expression is lost in intestinal adenomas. To determine the function of guanylin in intestinal epithelia, guanylin null mice were generated using a Cre/loxP-based targeting vector. Guanylin null mice grew normally, were fertile and showed no signs of malabsorption. However, the levels of cGMP in colonic mucosa of guanylin null mice were significantly reduced. The colonic epithelial cell migration rate was increased and increased numbers of colonocytes expressing proliferating cell nuclear antigen (PCNA) were present in crypts of guanylin null mice as well. The apoptotic index was similar in guanylin null mice and littermate controls. We conclude from these studies that loss of guanylin results in increased proliferation of colonic epithelia. We speculate that the increase in colonocyte number is related to decreased levels of cGMP and that this increase in proliferation plays a role in susceptibility to intestinal adenoma formation and/or progression.