Seroprevalence of Trypanosoma cruzi Among Eleven Potential Reservoir Species from Six States Across the Southern United States

Trypanosoma cruzi, the causative agent of Chagas' disease, is a substantial public health concern in Latin America. Although rare in humans and domestic animals in the United States, T. cruzi is commonly detected in some wildlife species, most commonly raccoons (Procyon lotor) and Virginia opossums (Didelphis virginiana). To increase our understanding of the reservoir host species range and geographic distribution, 11 species of mammals from six states spanning the known range of T. cruzi (Arizona, California, Florida, Georgia, Missouri, and Virginia) were tested for antibodies to T. cruzi using indirect immunofluorescent antibody testing. In addition, culture isolation attempts were conducted on a limited number of animals from Georgia and Florida. Evidence of T. cruzi was found in every state except California; however, low numbers of known reservoirs were tested in California. In general, the highest seroprevalence rates were found in raccoons (0–68%) and opossums (17–52%), but antibodies to T. cruzi were also detected in small numbers of striped skunks (Mephitis mephitis) from Arizona and Georgia, bobcats (Lynx rufus) from Georgia, two coyotes (Canis latrans) from Georgia and Virginia, and a ringtail (Bassariscus astutus) from Arizona. Culture-based prevalence rates for raccoons were significantly greater than those for opossums; however, seroprevalences of raccoons and opossums from several geographic locations in Georgia and Florida were not different, indicating that exposure rates of these two species are similar within these areas. For both raccoons and opossums, seroprevalence was significantly higher in females than in males. No difference was detected in seroprevalence between adults and juveniles and between animals caught in urban and rural locations. Our results indicate that T. cruzi prevalence varies by host species, host characteristics, and geographic region and provides data to guide future studies on the natural history of T. cruzi in the United States

Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer

A main limitation of therapies that selectively target kinase signaling pathways is the emergence of secondary drug resistance. Cetuximab, a monoclonal antibody that binds the extracellular domain of EGFR, is effective in a subset of KRAS wild type metastatic colorectal cancers(1). After an initial response, secondary resistance invariably ensues, thereby limiting the clinical benefit of this drug(2). The molecular bases of secondary resistance to cetuximab in colorectal cancer are poorly understood(3-8). Here, we show for the first time that molecular alterations (in most instances point mutations) of KRAS are causally associated with the onset of acquired resistance to anti-EGFR treatment in colorectal cancers. Expression of mutant KRAS under the control of its endogenous gene promoter was sufficient to confer cetuximab resistance but resistant cells remained sensitive to combinatorial inhibition of EGFR and MEK. Analysis of metastases from patients who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 60% (6/10) of the cases. KRAS mutant alleles were detectable in the blood of cetuximab treated patients as early as 10 months prior to radiographic documentation of disease progression. In summary, the results identify KRAS mutations as frequent drivers of acquired resistance to cetuximab in colorectal cancers, indicate that the emergence of KRAS mutant clones can be detected non-invasively months prior to radiographic progression and suggest early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance