A Model for Investigating Developmental Eye Repair in Xenopus Laevis

Vertebrate eye development is complex and requires early interactions between neuroectoderm and surface ectoderm during embryogenesis. In the African clawed frog, Xenopus laevis, individual eye tissues such as the retina and lens can undergo regeneration. However, it has been reported that removal of either the specified eye field at the neurula stage or the eye during tadpole stage does not induce replacement. Here we describe a model for investigating Xenopus developmental eye repair. We found that tailbud embryos can readily regrow eyes after surgical removal of over 83% of the specified eye and lens tissues. The regrown eye reached a comparable size to the contralateral control by 5 days and overall animal development was normal. It contained the expected complement of eye cell types (including the pigmented epithelium, retina and lens), and is connected to the brain. Our data also demonstrate that apoptosis, an early mechanism that regulates appendage regeneration, is also required for eye regrowth. Treatment with apoptosis inhibitors (M50054 or NS3694) blocked eye regrowth by inhibiting caspase activation. Together, our findings indicate that frog embryos can undergo successful eye repair after considerable tissue loss and reveals a required role for apoptosis in this process. Furthermore, this Xenopus model allows for rapid comparisons of productive eye repair and developmental pathways. It can also facilitate the molecular dissection of signaling mechanisms necessary for initiating repair

Spectrum and risk of neoplasia in Werner syndrome

Background: Werner syndrome (WS) is an autosomal recessive genetic instability and progeroid syndrome that is associated with an elevated risk of cancer. Methods: We used case reports of neoplasms in WS patients identified in previous case series or newly identified through searches of PubMed, Google Scholar and J-EAST (a database of articles from Japan) to define the spectrum (types and sites) of neoplasia in WS. Neoplasm type-specific risk was calculated by determining standardized incidence and proportionate incidence ratios (SIR and SPIR, respectively) of neoplasms in Japan-resident WS patients versus population control data from the Osaka prefecture and Osaka Cancer Registry. Results: Our study population consisted of 188 WS patients with 246 neoplasms. The most frequent neoplasms in WS patients, representing 2/3 of all reports, were thyroid neoplasms, malignant melanoma, meningioma, soft tissue sarcomas, leukemia and pre-leukemic conditions of the bone marrow, and primary bone neoplasms. SIRs were significantly elevated in Japanese WS patients for the five most frequent cancer types and meningiomas, from 83.2-fold for melanomas of the skin (95% CI: 45.5, 139.6) to 3.6-fold for leukemias (95% CI: 1.7, 6.9), and for all five cancer types except leukemias by SPIR analysis. Conclusions: WS confers a strong predisposition to several specific types of neoplasia, and this spectrum differs between WS patients residing in, as opposed to outside, Japan. These results provide a guide for WS clinical care and cancer screening, and for analyses to define the mechanistic basis for cancer in WS and in the general population

Spectrum and risk of neoplasia in Werner syndrome: a systematic review.

Werner syndrome (WS) is an autosomal recessive genetic instability and progeroid ('premature aging') syndrome which is associated with an elevated risk of cancer.Our study objectives were to characterize the spectrum of neoplasia in WS using a well-documented study population, and to estimate the type-specific risk of neoplasia in WS relative to the general population.We obtained case reports of neoplasms in WS patients through examining previous case series and reviews of WS, as well as through database searching in PubMed, Google Scholar, and J-EAST, a search engine for articles from Japan. We defined the spectrum (types and sites) of neoplasia in WS using all case reports, and were able to determine neoplasm type-specific risk in Japan WS patients by calculating standardized incidence and proportionate incidence ratios (SIR and SPIR, respectively) relative to Osaka Japan prefecture incidence rates.We used a newly assembled study population of 189 WS patients with 248 neoplasms to define the spectrum of neoplasia in WS. The most frequent neoplasms in WS patients, representing 2/3 of all reports, were thyroid neoplasms, malignant melanoma, meningioma, soft tissue sarcomas, leukemia and pre-leukemic conditions of the bone marrow, and primary bone neoplasms. Cancer risk defined by SIRs was significantly elevated in Japan-resident WS patients for the six most frequent neoplasms except leukemia, ranging from 53.5-fold for melanoma of the skin (95% CI: 24.5, 101.6) to 8.9 (95% CI: 4.9, 15.0) for thyroid neoplasms. Cancer risk as defined by SPIR was also significantly elevated for the most common malignancies except leukemia.WS confers a strong predisposition to several specific types of neoplasia. These results serve as a guide for WS clinical care, and for additional analyses to define the mechanistic basis for cancer in WS and the general population

Standardized proportionate incidence ratios (SPIRs) for malignancies in Japan-resident Werner syndrome patients.

*<p>statistically significant result (p<0.05).</p>**<p>includes WS patients with high WS diagnostic confidence (1965–2009, ages 10–69). Includes benign meningiomas diagnosed prior to 1988, but excludes non-melanoma skin neoplasms.</p>***<p>obtained using Osaka, Japan <i>CI5</i> volume case data (i.e., representative sample from 1970–2002).</p

Cumulative percentage of malignancies (%) by age at diagnosis in Japan-resident WS cases (1965–2009) versus Osaka population (1998–2002).

<p>*Osaka prefecture neoplasm-specific population incidence data were categorized by gender and aggregated into 5-year age groups. Hence we were able to calculate only a median age range from Osaka population data, in contrast to the exact median age we were able to calculate for our WS patient cohort.</p

Werner syndrome study population.

*<p>ns = not specified or reported.</p>**<p>among patients whose age at diagnosis is specified.</p>***<p>number of patients by WS diagnostic confidence: definite (n = 50), probable (n = 35), possible (n = 22), and unknown (n = 32).</p>****<p>number of patients by WS diagnostic confidence: definite (n = 22), probable (n = 13), possible (n = 10), and unknown (n = 5).</p

Spectrum of neoplasia in Werner syndrome patients.

<p>Distribution of neoplasms by histopathologic type and frequency among study population subjects included in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0059709#pone.0059709.s003" target="_blank">Table S1</a>.</p

Werner syndrome diagnostic criteria.

*<p>WS signs and symptoms are from the diagnostic criteria established by the International Registry of Werner Syndrome: <a href="http://www.wernersyndrome.org/registry/diagnostic.html" target="_blank">www.wernersyndrome.org/registry/diagnostic.html</a>.</p>**<p>Reported cataracts were assumed bilateral if not explicitly stated, and characteristic dermatological pathology was considered to be present if any one of the six skin pathologies was reported, again as defined by the Werner Syndrome Registry diagnostic signs and symptoms list. Where height was not designated as ‘short stature’, we classified males with heights <164 cm and females with heights <154 cm as of short stature. Diabetes mellitus was considered present if a diagnosis of diabetes and/or evidence of abnormal glucose homeostasis was provided.</p