P23H-hRho-GFP mice provide a valuable tool for evaluating the efficacy of potential therapies for ADRP that influence the levels or localization of P23H-rhodopsin.

Purpose There is increasing interest in non-operative management (NOM) for rectal cancer with complete clinical (cCR) response after neoadjuvant chemoradiation (nCRT). The aim of this review is to summarize the available data on NOM, with the intention of formulating standardised protocols on which to base future investigation. Methods Systematic review following PRISMA guidelines was conducted. A highly sensitive literature search identified all relevant studies published between Jan 2004 and Dec 2016. Data extraction and quality assessment was performed independently by two authors, and resolved by consensus with a third. Results In total, 15 studies met inclusion criteria including 920 patients, 575 (62.5%) who underwent NOM after cCR, and the rest forming a surgical control group. The weighted mean followup was 39.4 (12.7) months in the NOM group and 39.8 (5.1) months in the surgery group. The pooled re-growth rate in the NOM group was 21.3% at a mean of 15.6 (7.0) months. Surgical salvage was possible and undertaken in 93.2% of these patients. Overall survival in the NOM group was 91.7%, and disease free survival was 82.7%. For the comparison proctectomy group, pooled rates of local recurrence, overall survival and disease free survival were 8.4%, 92.4%, and 87.5%, respectively. Conclusion NOM may be a feasible option for surgically eligible rectal cancer patients with cCR after nCRT. Before such a strategy can be widely implemented, further prospective data is required with standardised definitions, diagnostic criteria, and management protocols, with an emphasis on shared patient-provider decision making and patient centered outcomes.

Two outstanding unknowns in the biology of photoreceptors are the molecular determinants of cell size, which is remarkably uniform among mammalian species, and the mechanisms of rod cell death associated with inherited neurodegenerative blinding diseases such as retinitis pigmentosa. We have addressed both questions by performing an in vivo titration with rhodopsin gene copies in genetically engineered mice that express only normal rhodopsin or an autosomal dominant allele, encoding rhodopsin with a disease-causing P23H substitution. The results reveal that the volume of the rod outer segment is proportional to rhodopsin gene expression; that P23H-rhodopsin, the most common rhodopsin gene disease allele, causes cell death via a dominant-negative mechanism; and that long term survival of rod cells carrying P23H-rhodopsin can be achieved by increasing the levels of wild type rhodopsin. These results point to promising directions in gene therapy for autosomal dominant neurodegenerative diseases caused by dominant-negative mutations.

BACKGROUND: Genomic profiling of colorectal cancer aims to identify actionable somatic mutations, but can also discover incidental germline findings. OBJECTIVE: To report the detection of pathogenic germline variants that confer heritable cancer predisposition.

For sensitive detection of rare gene repair events in terminally differentiated photoreceptors, we generated a knockin mouse model by replacing one mouse rhodopsin allele with a form of the human rhodopsin gene that causes a severe, early-onset form of retinitis pigmentosa. The human gene contains a premature stop codon at position 344 (Q344X), cDNA encoding the enhanced green fluorescent protein (EGFP) at its 3′ end, and a modified 5′ untranslated region to reduce translation rate so that the mutant protein does not induce retinal degeneration. Mutations that eliminate the stop codon express a human rhodopsin-EGFP fusion protein (hRho-GFP), which can be readily detected by fluorescence microscopy. Spontaneous mutations were observed at a frequency of about one per retina; in every case, they gave rise to single fluorescent rod cells, indicating that each mutation occurred during or after the last mitotic division. Additionally, the number of fluorescent rods did not increase with age, suggesting that the rhodopsin gene in mature rod cells is less sensitive to mutation than it is in developing rods. Thus, there is a brief developmental window, coinciding with the transcriptional activation of the rhodopsin locus, in which somatic mutations of the rhodopsin gene abruptly begin to appear.