The recent emergence of multidrug resistance (MDR) in Acinetobacter baumannii has raised concern in health care settings worldwide. In order to understand the repertoire of resistance determinants and their organization and origins, we compared the genome sequences of three MDR and three drug-susceptible A. baumannii isolates. The entire MDR phenotype can be explained by the acquisition of discrete resistance determinants distributed throughout the genome. A comparison of closely related MDR and drug-susceptible isolates suggests that drug efflux may be a less significant contributor to resistance to certain classes of antibiotics than inactivation enzymes are. A resistance island with a variable composition of resistance determinants interspersed with transposons, integrons, and other mobile genetic elements is a significant but not universal contributor to the MDR phenotype. Four hundred seventy-five genes are shared among all six clinical isolates but absent from the related environmental species Acinetobacter baylyi ADP1. These genes are enriched for transcription factors and transporters and suggest physiological features of A. baumannii that are related to adaptation for growth in association with humans.Among gram-negative pathogens that are reported as "multidrug resistant" (MDR), Acinetobacter baumannii is rapidly becoming a focus of significant attention (1,10,35,56). A. baumannii, a pleomorphic, gram-negative coccobacillus, is currently recognized by the Infectious Diseases Society of America as one of the most important pathogens threatening our health care delivery system (48). Global surveillance programs conducted over the last decade show an unparalleled increase in resistance rates among clinical Acinetobacter isolates (26). Acinetobacter spp. are now the third leading cause of respiratory tract infections among patients in intensive care units, and A. baumannii is responsible for up to 10% of hospital-acquired infections (26). These nosocomial infections are typically found in immunocompromised patients and are associated with an increased length of stay and excess morbidity (13,25,38,47 (19,40). Molecular typing of isolates from this outbreak revealed eight major clone types, and about 60% of the isolates were related to three pan-European types (5, 52), suggesting multiple independent origins (40). Examination of specific resistance determinants in the WRAMC isolates demonstrated considerable variability in the composition of resistance genes within each clone type and similar patterns across certain divergent clone types. Thus, genetic relatedness was a poor predictor of the MDR phenotype. This led to the hypothesis that there exist multiple independent genetic mechanisms leading to MDR in A. baumannii. A large cluster of antibiotic resistance genes and mobile genetic elements is present as an 86-kb "resistance island" (RI) in the A. baumannii AYE genome (15). The RI is not present in the genomes of the drug-susceptible A. baumannii isolates ATCC 17978 (43) and SDF (51), suggesting that it i...

We used whole-exome and targeted sequencing to characterize somatic mutations in 103 colorectal cancers (CRC) from African Americans, identifying 20 new genes as significantly mutated in CRC. Resequencing 129 Caucasian derived CRCs confirmed a 15-gene set as a preferential target for mutations in African American CRCs. Two predominant genes, ephrin type A receptor 6 (EPHA6) and folliculin (FLCN), with mutations exclusive to African American CRCs, are by genetic and biological criteria highly likely African American CRC driver genes. These previously unsuspected differences in the mutational landscapes of CRCs arising among individuals of different ethnicities have potential to impact on broader disparities in cancer behaviors.

Multidrug resistance has emerged as a significant concern with infections caused by Acinetobacter baumannii. Ample evidence supports the involvement of mobile genetic elements in the transfer of antibiotic resistance genes, but the extent of variability and the rate of genetic change associated with the acquisition of antibiotic resistance have not been studied in detail. Whole-genome sequence analysis of six closely related clinical isolates of A. baumannii, including four from the same hospital, revealed extensive divergence of the resistance genotype that correlated with observed differences in antimicrobial susceptibility. Resistance genes associated with insertion sequences, plasmids, and a chromosomal resistance gene island all showed variability. The highly dynamic resistance gene repertoire suggests rapid evolution of drug resistance.

Alveolar epithelial type II (AETII) cells are important for lung epithelium maintenance and function. We demonstrate that AETII cells from mouse lungs exposed to cigarette smoke (CS) increase the levels of the mitochondria-encoded non-coding RNA, mito-RNA-805, generated by the control region of the mitochondrial genome. The protective effects of mito-ncR-805 are associated with positive regulation of mitochondrial energy metabolism, and respiration. Levels of mito-ncR-805 do not relate to steady-state transcription or replication of the mitochondrial genome. Instead, CS-exposure causes the redistribution of mito-ncR-805 from mitochondria to the nucleus, which correlated with the increased expression of nuclear-encoded genes involved in mitochondrial function. These studies reveal an unrecognized mitochondria stress associated retrograde signaling, and put forward the idea that mito-ncRNA-805 represents a subtype of small non coding RNAs that are regulated in a tissue- or cell-type specific manner to protect cells under physiological stress.

HPGD and SLCO2A1 genes encode components of the prostaglandin catabolic pathway, HPGD encoding the degradative enzyme 15-PGDH, and SLCO2A1 encoding the prostaglandin transporter PGT that brings substrate to 15-PGDH. HPGD null mice show increased PGE2, marked susceptibility to developing colon tumors, and resistance to colon tumor prevention by NSAIDs. But in humans, HPGD and SLCO2A1 mutations have only been associated with familial digital clubbing. We here characterize a family with digital clubbing and early onset colon neoplasia. Whole exome sequencing identified a heterozygous nonsense mutation (G104X) in the SLCO2A1 gene segregating in three males with digital clubbing. Two of these males further demonstrated notably early onset colon neoplasia, one with an early onset colon cancer and another with an early onset sessile serrated colon adenoma. Two females also carried the mutation, and both these women developed sessile serrated colon adenomas without any digital clubbing. Males with clubbing also showed marked elevations in the levels of urinary prostaglandin E2 metabolite, PGE-M; whereas, female mutation carriers were in the normal range. Furthermore, in the male proband urinary PGE-M remained markedly elevated during NSAID treatment with either celecoxib or sulindac. Thus, in this human kindred, a null SLCO2A1 allele mimics the phenotype of the related HPGD null mouse, with increased prostaglandin levels that cannot be normalized by NSAID therapy, plus with increased colon neoplasia. The development of early onset colon neoplasia in male and female human SLCO2A1 mutation carriers suggests that disordered prostaglandin catabolism can mediate inherited susceptibility to colon neoplasia in man.