Three differentiation states risk-stratify bladder cancer into distinct subtypes

Current clinical judgment in bladder cancer (BC) relies primarily on pathological stage and grade. We investigated whether a molecular classification of tumor cell differentiation, based on a developmental biology approach, can provide additional prognostic information. Exploiting large preexisting gene-expression databases, we developed a biologically supervised computational model to predict markers that correspond with BC differentiation. To provide mechanistic insight, we assessed relative tumorigenicity and differentiation potential via xenotransplantation. We then correlated the prognostic utility of the identified markers to outcomes within gene expression and formalin-fixed paraffin-embedded (FFPE) tissue datasets. Our data indicate that BC can be subclassified into three subtypes, on the basis of their differentiation states: basal, intermediate, and differentiated, where only the most primitive tumor cell subpopulation within each subtype is capable of generating xenograft tumors and recapitulating downstream populations. We found that keratin 14 (KRT14) marks the most primitive differentiation state that precedes KRT5 and KRT20 expression. Furthermore, KRT14 expression is consistently associated with worse prognosis in both univariate and multivariate analyses. We identify here three distinct BC subtypes on the basis of their differentiation states, each harboring a unique tumor-initiating population.     

The influence of glucocorticoid receptor single nucleotide polymorphisms on outcome after haematopoietic stem cell transplantation

Haematopoietic stem cell transplantation (HSCT) remains the only cure for most haematological malignancies, however, the mortality rate remains high. Complications after HSCT include relapse, graft versus host disease (GvHD), graft rejection and infection. Over the last few years several groups, have demonstrated that non‐HLA gene polymorphisms can be predictive of outcome after HSCT. Since the glucocorticoid cortisol is pivotal in the regulation of the immune system, we decided to examine single nucleotide polymorphisms (SNPs; rs6198, rs33388 and rs33389) within the glucocorticoid receptor (GR) and correlate with HSCT outcome. The training set consisted of patients (n = 458) who underwent HSCT for acute leukaemia between 1983 and 2005. In the recipients, the absence of the ACT haplotype and absence of the T allele of rs33388 were associated with decreased OS and the absence of the ACT haplotype, the absence of the T allele of rs33388 and the presence of the ATA haplotype were associated with increased risk of relapse. In addition, the presence of the ACT haplotype in the recipient showed a trend to be associated with increased risk of chronic graft versus host disease (cGvHD). The patients in this cohort received mainly myeloablative conditioning (n = 327). The SNPs in the glucocorticoid receptor were then investigated in a validation set (n = 251) of HSCT patients transplanted for acute leukaemia from 2006. This cohort contained significantly more patients that had received reduced intensity conditioning (RIC). Some of the results could be validated in these patients. However, contrary to the training set, the absence of the haplotype ACT in the donor in this cohort was associated with increased risk of cGvHD. Differences in the conditioning were shown to influence the results. These results are the first to associate GR SNPs with HSCT outcome and demonstrate the inherent problems of replicating SNP association studies in HSCT, due to different pre‐transplant regimens.     

Asymptomatic Anomalous Origin of the Left Coronary Artery from the Pulmonary Artery

Anomalous origin of the left coronary artery from the pulmonary artery is a rare congenital anomaly of the coronary arteries which usually presents with heart failure in early infancy. We describe the unusual occurrence of this in an older child with no signs of cardiac ischemia. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Prognostic significance of recurrent grade 1B rejection in the first year after pediatric cardiac transplantation: a case for reinstatement of the 1B rejection grade

Feingold B, Irving C, Tatum GH, Webber SA. Prognostic significance of recurrent grade 1B rejection in the first year after pediatric cardiac transplantation: A case for reinstatement of the 1B rejection grade.
Pediatr Transplantation 2011: 15: 589–593. © 2011 John Wiley & Sons A/S. Abstract: The 2005 ISHLT rejection grading system merged grades 1A, 1B, and 2 into a single grade (1R) assuming equivalent prognostic significance. We hypothesized that recurrent 1B ACR is associated with adverse outcomes. Data on all heart transplant recipients at our center from 1990 to 2007 were reviewed. Patients were excluded if they had more than one grade ≥3A/2R biopsy in the first six wk or any grade ≥3A/2R biopsies during the first year thereafter. Patients with ≥2 grade 1B biopsies from six wk to one yr were classified as “recurrent 1B.” Outcomes were freedom from late (greater than one yr) ACR (grade ≥3A/2R), CAD, retransplantation/death, and a composite end‐point. Sixty‐two patients (53 non‐recurrent 1B, nine recurrent 1B) met inclusion criteria. In univariate analyses, recurrent 1B status was associated with decreased freedom from late ACR (p < 0.001), CAD (p = 0.004), and the composite outcome (p < 0.001). There was no difference in freedom from retransplantation/death (p = 0.48). After controlling for demographic differences between the groups, recurrent 1B status was independently associated with late ACR (HR 5.90; p = 0.002) and the composite outcome (HR 4.52; p = 0.002). These data suggest that further study of the impact of removal of the 1B classification from the ISHLT grading scheme is warranted.     

Serum anti-Mullerian hormone levels during controlled ovarian hyperstimulation in women with polycystic ovaries with and without hyperandrogenism

BACKGROUND: Anti-Mullerian hormone (AMH) is expressed in pre- and small-antral follicles. High serum levels are found in women with polycystic ovaries (PCO), accordant with their increased content of small follicles. To evaluate the relationship between AMH, folliculogenesis and hyperandrogenism, we compared serum AMH levels between women with PCO with and without hyperandrogenism and normal controls during controlled ovarian hyperstimulation (COH). METHODS: Nineteen women with PCO and hyperandrogenism (group A), 10 women with PCO but no hyperandrogenism (group B) and 23 ovulatory women with normal ovarian morphology (group C, controls) underwent COH with the long protocol. Serum levels of AMH, estradiol, androstenedione and follicular tracking were determined before gonadotropins treatment (day 0) and every 2-4 days up to the day of HCG administration. RESULTS: AMH levels declined gradually throughout COH in the three groups, but remained higher in groups A and B compared with the controls. Significantly higher levels were found in group A compared with group B, despite comparable numbers of small follicles. Multiple regression analysis revealed that both the number of small follicles and serum androgens were correlated to AMH. CONCLUSIONS: Women with PCO have higher serum AMH levels during COH than controls. Hyperandrogenism is associated with an additional increase in AMH. It is conceivable that hyperandrogenism may reflect more severe disruption of folliculogenesis in women with PCO or may affect AMH secretion.     

A Nice development: The first joint meeting of the British and French Societies for Developmental Biology, 13-16th September, 2003, Nice, France.

Held this autumn on the beautiful Cote d'Azur, the first joint meeting of the BSDB and SFBD provided delegates with the perfect informal setting for discussion spanning a broad cross-section of Developmental Biology. Participants' interests were diverse, ranging from the implementation of genome-wide approaches aimed at identifying all the molecular components of cell proliferation, signalling, patterning, and morphogenesis, to those engaged in capturing mesmerising glimpses of the minute and intricate workings of the cell. The meeting considered a wide spectrum of model organisms, including the simple plant Arabidopsis, the invertebrates Dictyostelium, Caenorhabditis elegans, and Drosophila melanogaster, the ascidian Ciona intestinalis, and the vertebrates Xenopus, zebrafish, chick, and mouse. Such a diverse approach served to highlight both similarities and differences in the molecular mechanisms that govern embryonic development among different species. Here, we highlight a few aspects of the meeting that illustrate this point.