Genemo (United States)

We thank Drs. Hartl and Gao for pointing out the difference in read lengths between the cancer and normal samples (1). Indeed, Illumina discontinued their 50-base pair (bp) sequencing kits after we finished sequencing the cancer samples, forcing us to switch to 75-bp sequencing kits on the normal samples. The different sequencing kits did incur small changes of sequence alignment metrics. While acknowledging the possibility that this may bias the assessment of cancer vs. normal discrimination performance of our method, we believe such a possibility is substantially ameliorated by the following considerations. First, a recent study reported that “with the exception of 25 bp reads, there is little difference for the detection of … [↵][1]1To whom correspondence may be addressed. Email: shuchien{at}ucsd.edu, hisu{at}ucsd.edu, or szhong{at}ucsd.edu. [1]: #xref-corresp-1-1

The effect of spinal adenosine receptor ligation on peripheral leukocyte accumulation was studied in two rat models of inflammation. Neutrophil infiltration into dermal inflammatory sites was signficantly reduced by adenosine A1 receptor agonists injected through intrathecal catheters. These effects were reversed by N-methyl-D-aspartate (NMDA), and were mimicked by (+/-)-2-amino-5-phosphonopentanoic acid (AP-5), a glutamate NMDA receptor antagonist. Peripheral adenosine levels, as measured in air pouch exudates, decreased markedly in inflamed pouches but remained near normal after intrathecal treatment with AP-5. Moreover, the antiinflammatory effects of intrathecal A1 receptor agonists and AP-5 were reversed by an adenosine A2 receptor antagonist administered intraperitoneally. Hence, central NMDA receptor activity can regulate neutrophil accumulation in peripheral inflammatory sites by reducing local levels of adenosine, an antiinflammatory autacoid which inhibits neutrophil function through A2 receptor activation. This represents a previously unknown pathway by which the central nervous system influences inflammatory responses.