Yield and Risk Factors for Advanced Colorectal Neoplasia and Long-term Outcomes in Veterans With 3 or More Nonadvanced Adenomas.

BACKGROUND AND AIMS: Until recently, guidelines recommended a 3-year surveillance colonoscopy for persons with 3 to 10 nonadvanced adenomas (NAA). In this study, we quantify yield for metachronous advanced neoplasia (AN); attempt to identify risk factors for AN; and measure colorectal cancer (CRC) incidence and mortality. METHODS: We used natural language processing to screen an existing data set for Veterans with 3 to 10 NAA. We manually reviewed colonoscopy and pathology reports to verify baseline findings and determine results of subsequent colonoscopy (sCY). Baseline features were extracted from the electronic medical record (EMR) and a national data set, CRC incidence was obtained from the Veterans Affairs cancer registry, and CRC mortality from the National Death Index through September 30, 2017. CRC incidence and mortality were compared between Veterans who did versus did not have sCY. RESULTS: Natural language processing identified 3673 Veterans who potentially had 3 to 10 NAA, of which 1672 were excluded after EMR review. In the analytical cohort of 2001 subjects, 1178 (59%) had sCY at a mean (SD) follow-up of 4.3 (2.2) years. The sCY group was younger (mean age: 61 vs. 67 y; P<0.01) and were less likely to have diabetes (27% vs. 31%; P=0.02) and congestive heart failure (4% vs. 9%; P<0.01). sCY showed AN in 182 subjects (15.5%). Baseline features were no different between those with versus without metachronous AN. Subjects with sCY had a greater CRC incidence (n=7 vs. n=0; P=0.046), but there was no difference in CRC mortality (0 for both subgroups). CONCLUSIONS: Among patients with 3 to 10 NAA on index colonoscopy who underwent sCY, AN was present in 15.5% at mean follow-up of 4.3 years. No risk factors for AN were identified. CRC incidence, but not CRC mortality, was higher among those with sCY.

A PEPTIDE UNCOUPLING CRMP-2 FROM THE PRESYNAPTIC Ca(2+) CHANNEL COMPLEX DEMONSTRATES EFFICACY IN ANIMAL MODELS OF MIGRAINE AND AIDS THERAPY-INDUCED NEUROPATHY.

Biological, genetic, and clinical data provide compelling proof for N-type voltage-gated calcium channels (CaV2.2) as therapeutic targets for chronic pain. While decreasing channel function is ultimately anti-nociceptive, directly targeting the channel can lead to multiple adverse effects. Targeting regulators of channel activity may facilitate improved analgesic properties associated with channel block and afford a broader therapeutic window. Towards this end, we recently identified a short peptide, designated CBD3, derived from collapsin response mediator protein 2 (CRMP-2) that suppressed inflammatory and neuropathic hypersensitivity by inhibiting CRMP-2 binding to CaV2.2 [Brittain et al., Nature Medicine 17:822-829 (2011)]. Rodents administered CBD3 intraperitoneally, fused to the HIV TAT protein cell penetrating domain, exhibited antinociception lasting ~4 hours highlighting potential instability, limited oral bioavailability, and/or rapid elimination of peptide. This report focuses on improving upon the parental CBD3 peptide. Using SPOTScan analysis of synthetic versions of the parental CBD3 peptide, we identified peptides harboring single amino acid mutations that bound with greater affinity to CaV2.2. One such peptide, harboring a phenylalanine instead of glycine (G14F), was tested in rodent models of migraine and neuropathic pain. In vivo laser Doppler blood flowmetry measure of capsaicin-induced meningeal vascular responses related to headache pain was almost completely suppressed by dural application of the G14F peptide. The G14F mutant peptide, administered intraperitoneally, also exhibited greater antinociception in Stavudine (2'-3'-didehydro-2'-3'-dideoxythymidine (d4T)/Zerit®) model of AIDS therapy-induced peripheral neuropathy compared to the parent CBD3 peptide. These results demonstrate the patent translational value of small biologic drugs targeting CaV2.2 for management of clinical pain.

Further insights into the antinociceptive potential of a peptide disrupting the N-type calcium channel-CRMP-2 signaling complex.

The N-type voltage-gated calcium channel (Cav 2.2) has gained immense prominence in the treatment of chronic pain. While decreased channel function is ultimately anti-nociceptive, directly targeting the channel can lead to multiple adverse side effects. Targeting modulators of channel activity may facilitate improved analgesic properties associated with channel block and a broader therapeutic window. A novel interaction between Cav 2.2 and collapsin response mediator protein 2 (CRMP-2) positively regulates channel function by increasing surface trafficking. We recently identified a CRMP-2 peptide (TAT-CBD3), which effectively blocks this interaction, reduces or completely reverses pain behavior in a number of inflammatory and neuropathic models. Importantly, TAT-CBD3 did not produce many of the typical side effects often observed with Cav 2.2 inhibitors. Notably chronic pain mechanisms offer unique challenges as they often encompass a mix of both neuropathic and inflammatory elements, whereby inflammation likely causes damage to the neuron leading to neuropathic pain, and neuronal injury may produce inflammatory reactions. To this end, we sought to further disseminate the ability of TAT-CBD3 to alter behavioral outcomes in two additional rodent pain models. While we observed that TAT-CBD3 reversed mechanical hypersensitivity associated with a model of chronic inflammatory pain due to lysophosphotidylcholine-induced sciatic nerve focal demyelination (LPC), injury to the tibial nerve (TNI) failed to respond to drug treatment. Moreover, a single amino acid mutation within the CBD3 sequence demonstrated amplified Cav 2.2 binding and dramatically increased efficacy in an animal model of migraine. Taken together, TAT-CBD3 potentially represents a novel class of therapeutics targeting channel regulation as opposed to the channel itself.

Altering the relative abundance of GABA A receptor subunits changes GABA- and ethanol-responses in Xenopus oocytes.

BACKGROUND: Variations in GABRA2 and GABRG3, genes encoding the alpha2 and gamma3 subunits of the pentameric GABA(A) receptor, are associated with the risk of developing alcoholism in adults, conduct disorder at younger ages, and with differences in electroencephalographic power in the beta frequency range. The SNPs associated with alcoholism did not alter the coding of these genes, and extensive DNA sequencing of GABRA2 did not find coding changes in the high-risk haplotypes. Therefore, we hypothesize that the associations arise from differences in gene expression. METHODS: Here we report studies in Xenopus oocytes to examine the functional effects of altering the relative abundance of these 2 receptor subunits on GABA current and response to ethanol, as a model of potential effects of regulatory differences. RESULTS: When human alpha2beta2gamma3 subunits are co-expressed, increasing the amount of the alpha2 subunit mRNA increased GABA current; in contrast, increasing the amount of the gamma3 subunit decreased GABA currents. Acute ethanol treatment of oocytes injected with a 1:1:1 or 2:2:1 ratio of alpha2:beta2:gamma3 subunit mRNAs resulted in significant potentiation of GABA currents, whereas ethanol inhibited GABA currents in cells injected with a 6:2:1 ratio. Overnight treatment with ethanol significantly reduced GABA currents in a manner dependent on the ratio of subunits. CONCLUSIONS: These studies demonstrate that changes in relative expression of GABA(A) receptor subunits alter the response of the resulting channels to GABA and to ethanol.