Preclinical characterization of the efficacy and safety of biologic N-001 as a novel pain analgesic for post-operative acute pain treatment.

Inhibition of actin remodeling in nerves modulates action potential propagation and therefore could be used to treat acute pain. N-001 is a novel protein analgesic engineered from several C. Botulinum toxins. N-001 targets sensory neurons through ganglioside GT1b binding and ADP-ribosylates G-actin reducing actin remodeling. The activity and efficacy of N-001 was evaluated previously in vitro and in a mouse inflammatory pain model. To assess the relevance of N-001 for treatment of acute post-surgical pain, the current study evaluated the efficacy of N-001 in a mouse hind-paw incision model by peri-incisional and popliteal nerve block administration combined with mechanical testing. N-001 provided relief of pain-like behavior over 3 days and 2 days longer than the conventional long-acting anesthetic bupivacaine. Preclinical safety studies of N-001 indicated the drug produced no toxic or adverse immunological reactions over multiple doses in mice. These results combined with past targeting results encourage further investigation of N-001 as an analgesic for post-operative pain management with the potential to function as a differential nociceptor-specific nerve block.

Intracellular G-actin targeting of peripheral sensory neurons by the multifunctional engineered protein C2C confers relief from inflammatory pain.

The engineered multifunctional protein C2C was tested for control of sensory neuron activity by targeted G-actin modification. C2C consists of the heptameric oligomer, C2II-CI, and the monomeric ribosylase, C2I. C2C treatment of sensory neurons and SH-SY5Y cells in vitro remodeled actin and reduced calcium influx in a reversible manner. C2C prepared using fluorescently labeled C2I showed selective in vitro C2I delivery to primary sensory neurons but not motor neurons. Delivery was dependent on presence of both C2C subunits and blocked by receptor competition. Immunohistochemistry of mice treated subcutaneously with C2C showed colocalization of subunit C2I with CGRP-positive sensory neurons and fibers but not with ChAT-positive motor neurons and fibers. The significance of sensory neuron targeting was pursued subsequently by testing C2C activity in the formalin inflammatory mouse pain model. Subcutaneous C2C administration reduced pain-like behaviors by 90% relative to untreated controls 6 h post treatment and similarly to the opioid buprenorphene. C2C effects were dose dependent, equally potent in female and male animals and did not change gross motor function. One dose was effective in 2 h and lasted 1 week. Administration of C2I without C2II-CI did not reduce pain-like behavior indicating its intracellular delivery was required for behavioral effect.

Familial urothelial cell carcinoma of the bladder with autosomal dominant inheritance and late onset phenotype.

OBJECTIVE: Familial Urothelial cell bladder cancer is rare. We report two families with urothelial cell carcinoma (UCC) of bladder with family history in other relatives, displaying probable autosomal dominant inheritance and a late onset pure UCC phenotype, and document the phenotype in each family. METHODS: Descriptive familial study on two pedigrees over three generations. RESULTS: Two families with UCC bladder were identified, and the phenotype documented, each family having three cases of late onset UCC. CONCLUSION: Some cases of UCC are hereditary and may display autosomal dominant inheritance with late onset of the cancer. Clinicians should be aware of the existence of a familial late onset UCC phenotype when managing cases of UCC.

Retrospective analysis of resected primary colorectal cancer revealed no correlation between node harvest and node involvement.

OBJECTIVE: To analyze the correlation between lymph nodes harvest (LNH) and lymph nodes involvement (LNI). METHODS: A retrospective analysis was done from January 2002 - August 2008 (6.5 years). The data was obtained from medical records, pathology and radiology. The patients with primary colorectal carcinoma (CRC) including synchronous or metachronous cancer, were included. These patients were treated with curative or palliative intent. Exclusion criteria was recurrent colorectal cancer, cancer not operated, cancer not resected (stoma-only, open-close) and endomucosal resection. LNH and LNI were obtained. The data was analyzed and also compared with the literature and the national audit. RESULTS: There were 177 resections (mean=28 +/- 3 per annum). Male to female ratio was 0.9:1 and median age was 71 years. There were 112 (63.3%) colonic and 65 (36.7%) rectal cancers. There were 14 Anterio-posterior resections (APRs) (21.5% of all rectal resections). Eighty four percent of resections were elective (OR=2.2 p=0.003 compared to the national audit). Metastasis was found in 14.6% at presentation. Adenocarcinoma (not otherwise specified) NOS constituted 94% of all histology results. Median lymph node harvest was 12 (mean=13.4 p=0.08). There was no significant LNH-LNI correlation (r=0.17 p=0.02). Survival figures for stages I-III CRC revealed 3-year disease-free survival of 82% (all-stage=69%). CONCLUSION: LNI as a function of tumour and host behaviour is of prognostic significance whereas LNH may be a quality assurance (QA) tool.

Copper-catalyzed synthesis of unsymmetrical triarylphosphines.

Various triarylphosphines have been prepared by coupling diphenylphosphine with aryl iodides with catalytic amounts of CuI in the presence of either K(2)CO(3) or Cs(2)CO(3), in good yields. This method can tolerate a variety of functional groups and does not require the use of expensive additives, or harsh reaction conditions, and is palladium free.