Long term latency of highly mutated cells in normal mouse skin is reversed by exposure to tumor promoters and chronic tissue damage.

Historical studies performed nearly a century ago using mouse skin models identified two key steps in cancer evolution: initiation, a likely mutational event, and promotion, driven by inflammation and cell proliferation. Initiation was proposed to be permanent, with promotion as the critical rate-limiting step for cancer development. Here, we carried out whole genome sequencing to demonstrate that initiated cells with thousands of mutagen-induced mutations can persist for long periods and are not removed by cell competition or by immune intervention, thus mimicking the persistence of cells with cancer driver mutations in normal human tissues.

Stem-cell states converge in multistage cutaneous squamous cell carcinoma development.

Stem cells play a critical role in cancer development by contributing to cell heterogeneity, lineage plasticity, and drug resistance. We created gene expression networks from hundreds of mouse tissue samples (both normal and tumor) and integrated these with lineage tracing and single-cell RNA-seq, to identify convergence of cell states in premalignant tumor cells expressing markers of lineage plasticity and drug resistance. Two of these cell states representing multilineage plasticity or proliferation were inversely correlated, suggesting a mutually exclusive relationship.

Targeting KRAS4A splicing through the RBM39/DCAF15 pathway inhibits cancer stem cells.

The commonly mutated human KRAS oncogene encodes two distinct KRAS4A and KRAS4B proteins generated by differential splicing. We demonstrate here that coordinated regulation of both isoforms through control of splicing is essential for development of Kras mutant tumors. The minor KRAS4A isoform is enriched in cancer stem-like cells, where it responds to hypoxia, while the major KRAS4B is induced by ER stress.

Efficacy and patient satisfaction after NovaSure and Minerva endometrial ablation for treating abnormal uterine bleeding: a retrospective comparative study.

Objective: Compare amenorrhea rate, menstrual symptoms, patient satisfaction, and adverse events in women who underwent endometrial ablation with the NovaSure versus the Minerva radiofrequency ablation systems.

Methods: We surveyed 189 premenopausal women (mean 40.8±6.

K-Ras Promotes Tumorigenicity through Suppression of Non-canonical Wnt Signaling.

K-Ras and H-Ras share identical effectors and have similar properties; however, the high degree of tumor-type specificity associated with K-Ras and H-Ras mutations suggests that they have unique roles in oncogenesis. Here, we report that oncogenic K-Ras, but not H-Ras, suppresses non-canonical Wnt/Ca(2+) signaling, an effect that contributes strongly to its tumorigenic properties. K-Ras does this by binding to calmodulin and so reducing CaMKii activity and expression of Fzd8.

The mutational landscapes of genetic and chemical models of Kras-driven lung cancer.

Next-generation sequencing of human tumours has refined our understanding of the mutational processes operative in cancer initiation and progression, yet major questions remain regarding the factors that induce driver mutations and the processes that shape mutation selection during tumorigenesis. Here we performed whole-exome sequencing on adenomas from three mouse models of non-small-cell lung cancer, which were induced either by exposure to carcinogens (methyl-nitrosourea (MNU) and urethane) or by genetic activation of Kras (Kras(LA2)). Although the MNU-induced tumours carried exactly the same initiating mutation in Kras as seen in the Kras(LA2) model (G12D), MNU tumours had an average of 192 non-synonymous, somatic single-nucleotide variants, compared with only six in tumours from the Kras(LA2) model.

Identification of Hipk2 as an essential regulator of white fat development.

Homeodomain-interacting protein kinase 2 (Hipk2) has previously been implicated in the control of several transcription factors involved in embryonic development, apoptosis, cell proliferation, and tumor development, but very little is understood about the exact mechanisms through which Hipk2 influences these processes. Analysis of gene expression in normal tissues from genetically heterogeneous mouse or human populations can reveal network motifs associated with the structural or functional components of the tissue, and may predict roles for genes of unknown function. Here we have applied this network strategy to uncover a role for the Hipk2 gene in the transcriptional system controlling adipogenesis.

Pten regulates Aurora-A and cooperates with Fbxw7 in modulating radiation-induced tumor development.

The Aurora-A kinase gene is frequently amplified and/or overexpressed in a variety of human cancers, leading to major efforts to develop therapeutic agents targeting this pathway. Here, we show that Aurora-A is targeted for ubiquitination and subsequent degradation by the F-box protein FBXW7 in a process that is regulated by GSK3β. Using a series of truncated Aurora-A proteins and site-directed mutagenesis, we identified distinct FBXW7 and GSK3β-binding sites in Aurora-A.

Allele-specific deletions in mouse tumors identify Fbxw7 as germline modifier of tumor susceptibility.

Genome-wide association studies (GWAS) have been successful in finding associations between specific genetic variants and cancer susceptibility in human populations. These studies have identified a range of highly statistically significant associations between single nucleotide polymorphisms (SNPs) and susceptibility to development of a range of human tumors. However, the effect of each SNP in isolation is very small, and all of the SNPs combined only account for a relatively minor proportion of the total genetic risk (5-10%).

Hipk2 cooperates with p53 to suppress γ-ray radiation-induced mouse thymic lymphoma.

A genome-wide screen for genetic alterations in radiation-induced thymic lymphomas generated from p53+/- and p53-/- mice showed frequent loss of heterozygosity (LOH) on chromosome 6. Fine mapping of these LOH regions revealed three non-overlapping regions, one of which was refined to a 0.2 Mb interval that contained only the gene encoding homeobox-interacting protein kinase 2 (Hipk2).

Deletion of the PER3 gene on chromosome 1p36 in recurrent ER-positive breast cancer.

Purpose: To investigate the role of the PER3 circadian rhythm gene, located within the commonly deleted region of chromosome 1p36, in human breast cancer development.

Patients And Methods: The frequency of genetic alterations at 1p36 and PER3 gene copy number status were analyzed in 180 lymph node-negative breast cancers from patients who had received treatment with chemotherapy and/or tamoxifen. The expression levels of PER3 were also analyzed using published microarray profiles from > 400 breast cancer samples.

FBXW7 targets mTOR for degradation and cooperates with PTEN in tumor suppression.

The enzyme mTOR (mammalian target of rapamycin) is a major target for therapeutic intervention to treat many human diseases, including cancer, but very little is known about the processes that control levels of mTOR protein. Here, we show that mTOR is targeted for ubiquitination and consequent degradation by binding to the tumor suppressor protein FBXW7. Human breast cancer cell lines and primary tumors showed a reciprocal relation between loss of FBXW7 and deletion or mutation of PTEN (phosphatase and tensin homolog), which also activates mTOR.

Atm heterozygosity does not increase tumor susceptibility to ionizing radiation alone or in a p53 heterozygous background.

Ataxia-Telangiectasia (A-T) is an autosomal recessive human disease characterized by genetic instability, radiosensitivity, immunodeficiency and cancer predisposition, because of mutation in both alleles of the ATM (ataxia-telangiectasia mutated) gene. The role of Atm heterozygosity in cancer susceptibility is controversial, in both human and mouse. Earlier studies identified deletions near the Atm gene on mouse chromosome 9 in radiation-induced lymphomas from p53 heterozygous mice.

Genomic instability in radiation-induced mouse lymphoma from p53 heterozygous mice.

Although radiation can directly induce DNA damage and is a known human and animal carcinogen, the number of genetic changes in radiation-induced tumors, and the pathways responsible for generating them, are unknown. We have used high-density BAC arrays covering >95% of the mouse genome for analysis of genomic patterns of aberrations in spontaneous and radiation-induced mouse lymphomas. The majority of radiation-induced tumors exhibit one of three 'signatures' based on gene copy number changes.

p63 and p73 do not contribute to p53-mediated lymphoma suppressor activity in vivo.

p53 is one of the most important tumor suppressor genes in human cancer, but the roles of its homologues p63 and p73 in tumor suppression, alone or in collaboration with p53, remains controversial. Both p63 and p73 can be deregulated after DNA damage, and induce cell cycle arrest and apoptosis, but mice carrying inactive alleles of these genes do not develop spontaneous tumors. Since heterozygous loss of p53 confers strong sensitization to radiation-induced lymphoma development, we investigated the possibility that radiation exposure may reveal previously undetected tumor suppressor properties in p63 or p73, alone or in combination with p53.

Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene.

The FBXW7/hCDC4 gene encodes a ubiquitin ligase implicated in the control of chromosome stability. Here we identify the mouse Fbxw7 gene as a p53-dependent tumour suppressor gene by using a mammalian genetic screen for p53-dependent genes involved in tumorigenesis. Radiation-induced lymphomas from p53+/- mice, but not those from p53-/- mice, show frequent loss of heterozygosity and a 10% mutation rate of the Fbxw7 gene.

Abdominal pregnancy on the bladder wall following embryo transfer with cryopreserved-thawed embryos: a case report.

Objective: To describe the occurrence and management of an abdominal pregnancy of the bladder after ET with cryopreserved-thawed embryos.

Design: Case report.

Setting: Infertility program in a tertiary care hospital.

Imaging, dosimetry, and radioimmunotherapy with iodine 131-labeled anti-CD37 antibody in B-cell lymphoma.

Purpose: This study was undertaken to evaluate the tumor targeting, toxicity, and therapeutic potential of the anti-B-cell-reactive monoclonal antibody MB-1 (anti-CD37) labeled with iodine 131 given in a nonmarrow ablative dose range in B-cell lymphoma patients who relapsed after chemotherapy.

Patients And Methods: Twelve patients with MB-1-reactive tumors were infused first with 40 mg of trace-labeled (3 to 7 mCi) MB-1. Ten patients who had no serious toxicity postinfusion and who had successful tumor imaging on serial gamma scans then received at least one 40-mg radioimmunotherapy (RIT) dose (25 to 161 mCi).