Publications

The use of the fecal occult blood test (FOBT) for colorectal cancer (CRC) screening is supported by randomized trials demonstrating effectiveness in cancer prevention and widely recommended by guidelines for this purpose. The fecal immunochemical test (FIT), as a direct measure of human hemoglobin in stool has a number of advantages relative to conventional FOBT and is increasingly used relative to that test. This review summarizes current evidence for FIT in colorectal neoplasia detection and the comparative effectiveness of FIT relative to other commonly used CRC screening modalities. Based on evidence, guidance statements on FIT application were developed and quality metrics for program implementation proposed.

The use of the fecal occult blood test (FOBT) for colorectal cancer (CRC) screening is supported by randomized trials demonstrating effectiveness in cancer prevention and widely recommended by guidelines for this purpose. The fecal immunochemical test (FIT), as a direct measure of human hemoglobin in stool has a number of advantages relative to conventional FOBT and is increasingly used relative to that test. This review summarizes current evidence for FIT in colorectal neoplasia detection and the comparative effectiveness of FIT relative to other commonly used CRC screening modalities. Based on evidence, guidance statements on FIT application were developed and quality metrics for program implementation proposed.

Elevated basal serum tryptase levels are present in 4-6% of the general population, but the cause and relevance of such increases are unknown. Previously, we described subjects with dominantly inherited elevated basal serum tryptase levels associated with multisystem complaints including cutaneous flushing and pruritus, dysautonomia, functional gastrointestinal symptoms, chronic pain, and connective tissue abnormalities, including joint hypermobility. Here we report the identification of germline duplications and triplications in the TPSAB1 gene encoding α-tryptase that segregate with inherited increases in basal serum tryptase levels in 35 families presenting with associated multisystem complaints. Individuals harboring alleles encoding three copies of α-tryptase had higher basal serum levels of tryptase and were more symptomatic than those with alleles encoding two copies, suggesting a gene-dose effect. Further, we found in two additional cohorts (172 individuals) that elevated basal serum tryptase levels were exclusively associated with duplication of α-tryptase-encoding sequence in TPSAB1, and affected individuals reported symptom complexes seen in our initial familial cohort. Thus, our findings link duplications in TPSAB1 with irritable bowel syndrome, cutaneous complaints, connective tissue abnormalities, and dysautonomia.

Streptococcus sanguinis is a leading cause of bacterial infective endocarditis, a life-threatening infection of heart valves. S. sanguinis binds to human platelets with high avidity, and this adherence is likely to enhance virulence. Previous studies suggest that a serine-rich repeat adhesin termed SrpA mediates the binding of S. sanguinis to human platelets via its interaction with sialoglycans on the receptor GPIbα. However, in vitro binding assays with SrpA and defined sialoglycans failed to identify specific high-affinity ligands. To improve our understanding of the interaction between SrpA and human platelets, we determined cocrystal structures of the SrpA sialoglycan binding region (SrpA) with five low-affinity ligands: three sialylated trisaccharides (sialyl-T antigen, 3'-sialyllactose, and 3'-sialyl-N-acetyllactosamine), a sialylated tetrasaccharide (sialyl-Lewis), and a sialyl galactose disaccharide component common to these sialoglyans. We then combined structural analysis with mutagenesis to further determine whether our observed interactions between SrpA and glycans are important for binding to platelets and to better map the binding site for the physiological receptor. We found that the sialoglycan binding site of SrpA is significantly larger than the sialoglycans cocrystallized in this study, which suggests that binding of SrpA to platelets either is multivalent or occurs via a larger, disialylated glycan.