Site-specific inductive and inhibitory activities of MMP-2 and MMP-3 orchestrate mammary gland branching morphogenesis

During puberty, mouse mammary epithelial ducts invade the stromal mammary fat pad in a wave of branching morphogenesis to form a complex ductal tree. Using pharmacologic and genetic approaches, we find that mammary gland branching morphogenesis requires transient matrix metalloproteinase (MMP) activity for invasion and branch point selection. MMP-2, but not MMP-9, facilitates terminal end bud invasion by inhibiting epithelial cell apoptosis at the start of puberty. Unexpectedly, MMP-2 also represses precocious lateral branching during mid-puberty. In contrast, MMP-3 induces secondary and tertiary lateral branching of ducts during mid-puberty and early pregnancy. Nevertheless, the mammary gland is able to develop lactational competence in MMP mutant mice. Thus, specific MMPs refine the mammary branching pattern by distinct mechanisms during mammary gland branching morphogenesis

Orthotopic Ileal Neobladder Reconstruction for Bladder Cancer: Is Adjuvant Chemotherapy Safe?

ABSTRACT Objective: We examined our database of patients undergoing radical cystectomy (RC) with orthotopic neobladder (NB) to determine whether adjuvant chemotherapy in this group is safe. Materials and Methods: We performed a retrospective analysis of patients who underwent radical cystectomy and urinary diversion between 1992 and 2004. Relevant clinical and therapeutic data were entered into a database. High-risk bladder cancer patients who underwent NB were identified. They were stratified into 2 groups, those who received adjuvant chemotherapy and those who did not. The incidence of complications between the 2 groups was analyzed and compared. Results: Over the 12-year period, 136 patients underwent RC and NB construction for bladder cancer. Of these, 83 patients were at high risk for recurrence. Nineteen patients received adjuvant chemotherapy and 64 did not. The complication rate in the adjuvant chemotherapy group was 53% and it was 23% in those who did not receive chemotherapy. There were no perioperative or treatment related death. There were 2 patients with grade 4 toxicity in the adjuvant chemotherapy group. There was a statistical difference between these two groups with regard to the incidence of complications. However, none of these complications was life-threatening, required only conservative treatment and caused no long-term disability. Conclusions: Adjuvant chemotherapy is a safe treatment for patients undergoing RC and NB substitution. Hence, the option of orthotopic NB should not be denied in selected bladder cancer patients with high risk for recurrent disease

Regioselective routes to orthogonally-substituted aromatic MIDA boronates

A series of tetrasubstituted aromatics has been synthesized, many of which are based on elaborated N-methyliminodiacetic acid (MIDA)-boronates. A sequence employing nitration, bromination, stepwise Suzuki-Miyaura (SM) coupling with a boronic acid, then base-mediated unmasking of the boronic acid from the MIDA-boronate and a second SM-coupling has led to our desired, mainly 1,2,4,5-substituted tetrasubstituted aromatic targets

The quality of surgical pathology care for men undergoing radical prostatectomy in the U.S.

BACKGROUND. The authors assessed adherence with the College of American Pathologists (CAP) radical prostatectomy (RP) practice protocol in a national sample of men who underwent RP for early-stage prostate cancer. METHODS. Using the National Cancer Data Base, the authors identified a nationally representative sample of 1240 men (unweighted) who underwent RP. For each patient, local cancer registrars performed an explicit medical record review to assess patient-level compliance with surgical pathology report documentation of 7 morphologic criteria (ie, quality indicators). Applying the CAP prognostic factor classification framework, composite measures and all-or-none measures of quality indicator compliance were calculated for the following analytic categories: 1) a strict subset of CAP category I prognostic factors (3 indicators), 2) a broad subset of CAP category I factors (6 indicators), and 3) the full set of 7 indicators. RESULTS. Among a weighted sample of 24,420 patients who underwent RP, compliance with documentation of the CAP category I factors varied from 54% (95% confidence interval [95% CI], 50–58%) for pathologic tumor, lymph node, metastases classification (according to the American Joint Committee on Cancer staging system) to 97% (95% CI, 96–99%) for Gleason score. In composite, RP pathology reports contained 83% (95% CI, 81–84%), 85% (95% CI, 84–87%), and 79% (95% CI, 78–80%) of the recommended data elements measured by the strict CAP category I subset, the broad CAP category I subset, and the full set of 7 indicators, respectively. In contrast to the generally higher composite scores, only 52% (95% CI, 48–56%) and 41% (95% CI, 37–45%) of men who underwent RP had complete documentation in their pathology reports for the strict and broad CAP category I subsets, respectively. CONCLUSIONS. RP surgical pathology reports contained most of the recommended data elements; however, the frequent absence of pathologic stage provides an opportunity for quality improvement. Cancer 2007. © 2007 American Cancer Society.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/56046/1/22698_ftp.pd

Oncological and functional outcomes following open radical prostatectomy: how patients may achieve the "trifecta"?

PURPOSE: The desirable outcomes after open radical prostatectomy (RP) for localized prostate cancer (PC) are to: a) achieve disease recurrence free, b) urinary continence (UC), and c) maintain sexual potency (SP). These 3 combined desirable outcomes we called it the "Trifecta". Our aim is to assess the likelihood of achieving the Trifecta, and to analyze the influencing the Trifecta . MATERIALS AND METHODS: A total of 1738 men with localized PC underwent RP from 1992-2007 by a single surgeon. The exclusion criteria for this analysis were: preoperative hormonal or radiation therapy, preoperative urinary incontinence or erectile dysfunction, follow-up less than 24 months or insufficient data. Post-operative Trifecta factors were analyzed, including biochemical recurrence (BR).. We defined: BR as PSA > 0.2 ng/mL, urinary continence as wearing no pads, and sexual potency as having erections sufficient for intercourse with or without a phosphodiesterase-5 inhibitor. RESULTS: A total of 831 patients met the inclusion criteria. The mean age of the entire cohort was 59 years old. The median follow-up was 52 months (mean 60, range 24-202). The BR, UC and SP rates were 18.7%, 94.5%, and 71% respectively. Trifecta was achieved in 64% at 2 year follow-up, and 61% at 5 year follow-up. Multivariate analysis revealed age at time of surgery, pathologic Gleason score (PGS), pathologic stage, specimen weight, and nerve sparing (NS) were independent factors. CONCLUSIONS: Age at time of surgery, pathologic GS, pathologic stage, specimen weight and NS were independent predictors to achieve the Trifecta following radical prostatectomy. This information may help patients counseling undergoing radical prostatectomy for localized prostate cancer

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN