Major clinical issues in bladder cancer include the identification of prediction markers and novel therapeutic targets for invasive bladder cancer. In the current study, we describe the isolation and characterization of a tumor-initiating cell (T-IC) subpopulation in primary human bladder cancer, based on the expression of markers similar to that of normal bladder basal cells (Lineage-CD44 ؉ CK5 ؉ CK20 ؊ ). The bladder T-IC subpopulation was defined functionally by its enriched ability to induce xenograft tumors in vivo that recapitulated the heterogeneity of the original tumor. Further, molecular analysis of more than 300 bladder cancer specimens revealed heterogeneity among activated oncogenic pathways in T-IC (e.g., 80% Gli1, 45% Stat3, 10% Bmi-1, and 5% -catenin). Despite this molecular heterogeneity, we identified a unique bladder T-IC gene signature by gene chip analysis. This T-IC gene signature, which effectively distinguishes muscle-invasive bladder cancer with worse clinical prognosis from non-muscle-invasive (superficial) cancer, has significant clinical value. It also can predict the progression of a subset of recurring non-muscleinvasive cancers. Finally, we found that CD47, a protein that provides an inhibitory signal for macrophage phagocytosis, is highly expressed in bladder T-ICs compared with the rest of the tumor. Blockade of CD47 by a mAb resulted in macrophage engulfment of bladder cancer cells in vitro. In summary, we have identified a T-IC subpopulation with potential prognostic and therapeutic value for invasive bladder cancer.antibody therapy ͉ bladder cancer ͉ cancer stem cell ͉ CD44 ͉ CD47
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.
Although blood–brain barrier (BBB) compromise is central to the etiology of diverse central nervous system (CNS) disorders, endothelial receptor proteins that control BBB function are poorly defined. The endothelial G-protein-coupled receptor (GPCR) Gpr124 has been reported to be required for normal forebrain angiogenesis and BBB function in mouse embryos, but the role of this receptor in adult animals is unknown. Here Gpr124 conditional knockout (CKO) in the endothelia of adult mice did not affect homeostatic BBB integrity, but resulted in BBB disruption and microvascular hemorrhage in mouse models of both ischemic stroke and glioblastoma, accompanied by reduced cerebrovascular canonical Wnt–β-catenin signaling. Constitutive activation of Wnt–β-catenin signaling fully corrected the BBB disruption and hemorrhage defects of Gpr124-CKO mice, with rescue of the endothelial gene tight junction, pericyte coverage and extracellular-matrix deficits. We thus identify Gpr124 as an endothelial GPCR specifically required for endothelial Wnt signaling and BBB integrity under pathological conditions in adult mice. This finding implicates Gpr124 as a potential therapeutic target for human CNS disorders characterized by BBB disruption.
ABSTRACT. Objective. Voiding cystourethrography (VCUG) is a commonly performed radiologic procedure in children that can be both painful and frightening. Given the distress that some children experience during the VCUG and the need for children to be alert and cooperative during the procedure, finding a psychological intervention that helps children to manage anxiety, distress, and pain is clearly desirable. This study was designed to examine whether relaxation and analgesia facilitated with hypnosis could reduce distress and procedure time for children who undergo this procedure.Methods. Forty-four children who were scheduled for an upcoming VCUG were randomized to receive hypnosis (n ؍ 21) or routine care (n ؍ 23) while undergoing the procedure. The sample consisted of 29 (66%) girls and 15 (34%) boys with a mean age of 7.6 years (SD: 2.5; range: 4 -15 years). Ethnic/racial backgrounds were 72.7% white, 18.2% Asian, 4.5% Latino, 2.3% black, and 2.3% Filipino. The mean number of previous VCUGs was 2.95 (SD: 2.51; mode: 2; range: 1-15). Potential participants were identified through computerized hospital records of upcoming VCUGs. Parents were contacted by telephone and invited to participate if their child was eligible. To be eligible for the study, the child must have undergone at least 1 previous VCUG, been at least 4 years of age at that time, and experienced distress during that procedure, and both the child and the participating parent had to be English speaking. Each eligible child and parent met with the research assistant (RA) before the day of the scheduled procedure for an initial assessment. Children were queried regarding the degree of crying, fear, and pain that they had experienced during their most recent VCUG. Parents completed a series of parallel questions. Immediately after this assessment, those who were randomized to the hypnosis condition were given a 1-hour training session in self-hypnotic visual imagery by a trained therapist. Parents and children were instructed to practice using the imaginative self-hypnosis procedure several times a day in preparation for the upcoming procedure. The therapist was also present during the procedure to conduct similar exercises with the child. The majority (83%) of those who were randomized to the routine care control group chose to participate in a hospital-provided recreation therapy program (offered as part of routine care). The program includes demonstration of the procedure with dolls, relaxation and breath work training, and assistance during the procedure. On the day of the VCUG, the RA met the family at the clinic before the procedure, and both the child and the parent rated the child's present level of fearfulness. During the procedure, the RA recorded observational ratings of the child's emotional tone and behavior and timed the overall procedure and its phases. Immediately after the VCUG, the child was asked how much crying, fear, and pain he or she had experienced during the procedure; the parent rated the child's experience on the same ...
Fifty-eight patients with metastatic transitional cell carcinoma of the urinary tract received cisplatin, methotrexate, and vinblastine (CMV) combination chemotherapy. Complete responses (CRs) were noted in 14 of the 50 (28%) evaluable patients and partial responses (PRs) in 14 patients for an overall response rate of 56% (95% confidence limits of 42% to 70%). The median duration of the 14 CRs was 9 months. Six of the 14 CRs (43%) remain in unmaintained remission from 6 + to 35 + months from onset of treatment. The median survival of evaluable patients receiving CMV was 8 months. Median survival for CRs was 11 months v 7 months for PRs (P less than .05) and 6 months for nonresponders. Renal and hematologic toxicities with this regimen were moderate. CMV is an effective regimen for patients with metastatic transitional cell carcinoma of the bladder. Prolonged disease-free survival may result from a CR to this regimen.
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