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Synchronous with massive shifts in reproductive hormones, the uterus and its lining the endometrium expand to accommodate a growing fetus during pregnancy. In the absence of an embryo the endometrium, composed of epithelium and stroma, undergoes numerous hormonally regulated cycles of breakdown and regeneration. The hormonally mediated regenerative capacity of the endometrium suggests that signals that govern the growth of endometrial progenitors must be regulated by estrogen and progesterone. Here we report an antigenic profile for isolation of mouse endometrial epithelial progenitors. These cells are EpCAM+CD44+ITGA6hiThy1−PECAM1−PTPRC−Ter119−, comprise a minor subpopulation of total endometrial epithelia and possess a gene expression profile that is unique and different from other cells of the endometrium. The epithelial progenitors of the endometrium could regenerate in vivo, undergo multi-lineage differentiation and proliferate. We show that the number of endometrial epithelial progenitors is regulated by reproductive hormones. Co-administration of estrogen and progesterone dramatically expanded the endometrial epithelial progenitor cell pool. This effect was not observed when estrogen or progesterone was administered alone. Despite the remarkable sensitivity to hormonal signals, endometrial epithelial progenitors do not express estrogen or progesterone receptors. Therefore their hormonal regulation must be mediated through paracrine signals resulting from binding of steroid hormones to the progenitor cell niche. Discovery of signaling defects in endometrial epithelial progenitors or their niche can lead to development of better therapies in diseases of the endometrium.

Epithelial-specific activation of the PI3-kinase pathway is the most common genetic alteration in type I endometrial cancer. In the majority of these tumors, PTEN expression is lost in the epithelium but maintained in tumor stroma. Currently reported PTEN knockout mouse models initiate type I endometrial cancer concomitant with loss of PTEN in both uterine epithelium and stroma. Consequently, the biologic outcome of selectively activating the PI3-kinase pathway in the endometrial epithelium remains unknown. To address this question, we established a malleable in vivo endometrial regeneration system from dissociated murine uterine epithelium and stroma. Regenerated endometrial glands responded to pharmacologic variations in hormonal milieu similar to the native endometrium. Cellautonomous activation of the PI3-kinase pathway via biallelic loss of PTEN or activation of AKT in adult uterine epithelia in this model was sufficient to initiate endometrial carcinoma. AKT-initiated tumors were serially transplantable, demonstrating permanent genetic changes in uterine epithelia. Immunohistochemistry confirmed loss of PTEN or activation of AKT in regenerated hyperplastic glands that were surrounded by wild-type stroma. We demonstrate that cell-autonomous activation of the PI3-kinase pathway is sufficient for the initiation of endometrial carcinoma in naive adult uterine epithelia. This in vivo model provides an ideal platform for testing the response of endometrial carcinoma to targeted therapy against this common genetic alteration.tissue regeneration model | progesterone receptor | uterine cancer E ndometrial cancer, the most common gynecologic cancer in the United States (1), is a hormonally regulated tumor arising from epithelial cells lining the uterine cavity. Effective targeted therapy is unavailable, partly because of lack of knowledge regarding basic biologic pathways and cellular compartments that can initiate this malignancy. Women diagnosed with endometrial cancer are treated in a similar manner irrespective of the heterogeneity of this disease, with surgery or combinations of radiation and chemotherapy. Although endometrial cancer can be cured in early stages, side effects associated with the current therapy can have lifelong debilitating effects on some patients. The majority of women diagnosed with late-stage or metastatic disease die, despite undergoing radical treatments.Endometrial cancer can be divided into two distinct subtypes (2). Type I tumors occur in younger patients exposed to high levels of estrogen unopposed by progesterone. They are typically localized with better response to hormonal therapy. Type II tumors occur in older patients independent of hormonal status. These tumors are more invasive, have a greater propensity for metastatic spread, and are refractory to hormonal treatment. Activation of distinct biologic pathways has been reported in type I vs. type II cancers. Type I tumors are associated with activation of the PI3-kinase pathway, activating mutations of KRAS, mutant β-catenin, an...

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Background Central line-associated bloodstream infection (CLABSI) and catheter-associated urinary tract infection (CAUTI) continue to be the focus of external reporting of healthcare associated infections based on CDC-NHSN criteria. As facilities decrease CLABSI and CAUTI, we sought to understand our non-central line bloodstream infections (NCLABSI) and non-catheter urinary tract infections (NCAUTI). Methods We retrospectively reviewed total healthcare associated bloodstream infections (HABSI) (NCLABSI + CLABSI) and healthcare associated urinary tract infections (HAUTI) (NCAUTI + CAUTI) from July 1, 2016 to June 30, 2021 at our 334-bed quaternary care Children’s Hospital. CLABSI and CAUTI were both defined using CDC-NHSN criteria. Epidemiologic and microbiologic data, total antibiotic days related to infection, and mortality were analyzed for each subgroup. Results In a 5-year period, 255 patients were identified with HABSI and HAUTI; 164 were HABSI (26% NCLABSI, 74% CLABSI) and 91 were HAUTI (79% NCAUTI, 21% CAUTI). While our NCLABSI, CLABSI, and CAUTI infections per fiscal year (FY) have remained relatively stable, our NCAUTIs have increased since FY17 (Figure 1). Total antibiotic days for NCLABSI versus CLABSI and for NCAUTI versus CAUTI were similar (Figure 2). Staphylococcus aureus was the predominant pathogen in all HABSIs (16% CLABSI, 31% NCLABSI). Pseudomonas aeruginosa was seen in 15% of CLABSIs but in no NCLABSIs. P. aeruginosa was seen in both CAUTI (32%) and NCAUTI (11%). Escherichia coli was the predominant pathogen in NCAUTI (39%) (Figure 3). There were 2 NCLABSI (5%), 16 CLABSI (13%), 2 NCAUTI (3%) and 2 CAUTI (11%) patient deaths during hospitalization. Conclusion Our data shows that non-device related healthcare associated infections are a significant proportion of our total healthcare associated infections, comprising one quarter of HABSIs and three quarters of HAUTIs. In addition, P. aeruginosa, typically an important pathogen in device-associated infections, also contributes to non-device associated infections. We feel that total HABSI and HAUTI may provide more objective measures to report. Infection prevention measures to decrease NCLABSI and NCAUTI also need attention. Disclosures All Authors: No reported disclosures.

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Until now a lot of understanding and research of cancer biology can make it possible to develop many anticancer drugs which can inhibit the specific pathways required for growth, proliferation, and survival of cancer cells. The current success in cancer therapy using these drugs improves the survival rate of patients but unfortunately it is not the case of all cancers and still many different kinds of cancers continue to have a poor prognosis. Furthermore the incompleteness of cancer therapies causes a variety of side effects such as secondary cancers, heart or lung damage, infertility or chronic hepatitis. Therefore a reliable tumor specific therapy is urgently needed to treat cancer patients. It is widely recognized that the recent chemotherapy could be far more effective if higher doses could be specifically delivered to the tumor and not to normal tissues. Targeted nanoparticles have shown the potential to deliver the anticancer drugs to cancer cells selectively and to overcome unexpected cytotoxicity and limited efficacy of the chemotherapy caused by the unselective delivery to the normal cells. In our study a novel nanoparticle (HPLN) was used for the treatment of childhood ALL and Ewing's sarcoma. AntiCD19 and antiCD99 antibodies were used for targeting of ALL and Ewing tumor, respectively. These tumor specific HPLNs effectively inhibit tumor growth in a murine model. Removal of targeting antibody or drug eliminates the antitumor effects, which proves this anticancer effect of HPLN is very specific to the target cancer cells and dependent upon drug. No abnormalities in liver and kidney function tests, complete blood counts or pathology of major organs are observed from tail-vein administrations. Theses targeted HPLNs showed much better cytotoxicity over a conventional untargeted PEG-liposomal Doxorubicin formulation (Doxil®). Additionally the targeted HPLN could be found in the tumor cells in a murine model. In conclusion, we have found the safe and efficient targeted HPLN delivery system of anticancer drugs to childhood ALL and Ewing's Sarcoma. Citation Format: Hyunggyoo Kang, Violette Shahbazian, Amanda Schafenacker, Jon Nagy, Timothy Triche. Development of selective therapy of childhood ALL and Ewing's sarcoma using targeted-hybrid polymerized liposomal nanoparticles (HPLN). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5424. doi:10.1158/1538-7445.AM2014-5424