Psychosocial outcome measures for conductive and mixed hearing loss treatment: An overview of the relevant literature.

OBJECTIVE: To identify the psychosocial assessments utilized with individuals with conductive and/or mixed hearing loss as part of a broader effort by the Auditory Rehabilitation Outcomes Network (AURONET) group to develop a core set of patient-centred outcome measures. DESIGN: A review of articles published between 2006 and 2016 was completed. Included studies had more than three adult participants, were available in English, and reported a psychosocial outcome from any treatment of mixed and/or conductive hearing loss. STUDY SAMPLE: Sixty-six articles from seven databases. RESULTS: Sixty-six articles met our inclusion/exclusion criteria. Within this set, 15 unique psychosocial or patient-reported outcome measures (PROs) were identified, with the Abbreviated Profile of Hearing Aid Benefit (APHAB) and Glasgow Benefit Inventory (GBI) being the most frequently dispensed. Five of the fifteen were only administered in one study. In-house questionnaires (IHQs) were reported in 19 articles. CONCLUSIONS: Only 66 (22%) of the 300 articles with outcomes contained a PRO. Some of the mostly frequently employed PROs (e.g., APHAB) were judged to include only social items and no psychological items. Lack of PRO standardization and the use of IHQs make psychosocial comparisons across treatments in this population difficult for patients, clinicians and stakeholders.

Hearing outcome measures for conductive and mixed hearing loss treatment in adults: a scoping review.

OBJECTIVE: Rehabilitation options for conductive and mixed hearing loss are continually expanding, but without standard outcome measures comparison between different treatments is difficult. To meaningfully inform clinicians and patients core outcome sets (COS), determined via a recognised methodology, are needed. Following our previous work that identified hearing, physical, economic and psychosocial as core areas of a future COS, the AURONET group reviewed hearing outcome measures used in existing literature and assigned them into different domains within the hearing core area. DESIGN: Scoping review. STUDY SAMPLE: Literature including hearing outcome measurements for the treatment of conductive and/or mixed hearing loss. RESULTS: The literature search identified 1434 studies, with 278 subsequently selected for inclusion. A total of 837 hearing outcome measures were reported and grouped into nine domains. The largest domain constituted pure-tone threshold measurements accounting for 65% of the total outcome measures extracted, followed by the domains of speech testing (20%) and questionnaires (9%). Studies of hearing implants more commonly included speech tests or hearing questionnaires compared with studies of middle ear surgery. CONCLUSIONS: A wide range of outcome measures are currently used, highlighting the importance of developing a COS to inform individual practice and reporting in trials/research.

Eukaryotic Translation Initiation Factor 5A (EIF5A) Regulates Pancreatic Cancer Metastasis by Modulating RhoA and Rho-associated Kinase (ROCK) Protein Expression Levels.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers with an overall survival rate of less than 5%. The poor patient outcome in PDAC is largely due to the high prevalence of systemic metastasis at the time of diagnosis and lack of effective therapeutics that target disseminated cells. The fact that the underlying mechanisms driving PDAC cell migration and dissemination are poorly understood have hindered drug development and compounded the lack of clinical success in this disease. Recent evidence indicates that mutational activation of K-Ras up-regulates eIF5A, a component of the cellular translational machinery that is critical for PDAC progression. However, the role of eIF5A in PDAC cell migration and metastasis has not been investigated. We report here that pharmacological inhibition or genetic knockdown of eIF5A reduces PDAC cell migration, invasion, and metastasis in vitro and in vivo. Proteomic profiling and bioinformatic analyses revealed that eIF5A controls an integrated network of cytoskeleton-regulatory proteins involved in cell migration. Functional interrogation of this network uncovered a critical RhoA/ROCK signaling node that operates downstream of eIF5A in invasive PDAC cells. Importantly, eIF5A mediates PDAC cell migration and invasion by modulating RhoA/ROCK protein expression levels. Together our findings implicate eIF5A as a cytoskeletal rheostat controlling RhoA/ROCK protein expression during PDAC cell migration and metastasis. Our findings also implicate the eIF5A/RhoA/ROCK module as a potential new therapeutic target to treat metastatic PDAC cells.

Improving Quality by Taking Aim at Incontinence-Associated Dermatitis in Hospitalized Adults.

A practice-improvement project was launched to implement an evidence-based intervention bundle for incontinence-associated dermatitis (IAD) and evaluate its impact on the identification, prevention, and management of IAD in hospitalized adults.

Improving Quality by Taking Aim at Incontinence-Associated Dermatitis in Hospitalized Adults.

A practice-improvement project was launched to implement an evidence-based intervention bundle for incontinence-associated dermatitis (IAD) and evaluate its impact on the identification, prevention, and management of IAD in hospitalized adults.

Advanced practice nurse psychiatric bridging intervention.

Depression is a prevalent and treatable condition; however, extensive waiting periods for treatment are associated with high failure to attend initial psychiatric evaluation (IPE) appointments. This article describes the development, implementation, and pilot evaluation of the Advanced Practice Nurse (APN) Psychiatric Bridging Intervention. The project was grounded in Peplau's theory of interpersonal relations and designed to provide supportive psychoeducational counseling and initiation of psychotropic medication for clients with depressive symptoms during the time between intake and IPE. Project development was guided by Roger's Diffusion of Innovations framework used for adopting an evidence-based innovation into an organization. A two-group design allowed comparison of preintervention clients (38 clients who received standard care) and intervention clients (19 clients who participated in the bridging intervention). The difference in IPE appointment attendance rates between the two groups approached statistical significance (p = 0.08). An unanticipated finding was that APN Psychiatric Bridging Intervention clients required only 30-minute IPE appointments compared to the typical 60-minute appointment.

Redundant and dosage sensitive requirements for Fgf3 and Fgf10 in cardiovascular development.

Heart development requires contributions from, and coordinated signaling interactions between, several cell populations, including splanchnic and pharyngeal mesoderm, postotic neural crest and the proepicardium. Here we report that Fgf3 and Fgf10, which are expressed dynamically in and near these cardiovascular progenitors, have redundant and dosage sensitive requirements in multiple aspects of early murine cardiovascular development. Embryos with Fgf3(-/+);Fgf10(-/-), Fgf3(-/-);Fgf10(-/+) and Fgf3(-/-);Fgf10(-/-) genotypes formed an allelic series of increasing severity with respect to embryonic survival, with double mutants dead by E11.5. Morphologic analysis of embryos with three mutant alleles at E11.5-E13.5 and double mutants at E9.5-E11.0 revealed multiple cardiovascular defects affecting the outflow tract, ventricular septum, atrioventricular cushions, ventricular myocardium, dorsal mesenchymal protrusion, pulmonary arteries, epicardium and fourth pharyngeal arch artery. Assessment of molecular markers in E8.0-E10.5 double mutants revealed abnormalities in each progenitor population, and suggests that Fgf3 and Fgf10 are not required for specification of cardiovascular progenitors, but rather for their normal developmental coordination. These results imply that coding or regulatory mutations in FGF3 or FGF10 could contribute to human congenital heart defects.

Parental self-efficacy and online support among parents of children diagnosed with type 1 diabetes mellitus.

Families faced with the challenges of caring for a child newly diagnosed with type 1 diabetes mellitus are often overwhelmed by the regimented demands of diabetes care management. Social support for families has been recognized as an important component to adaptation and has been deemed necessary for helping families develop healthy coping strategies. The purpose of this evidence-based practice (EBP) project was to develop a Web-based platform to enhance social support and increase self-efficacy of parents with a child with type 1 diabetes. The following clinical question guided the project: "Among parents of children diagnosed with type 1 diabetes in a small Midwestern city, what are parents' self-reported self-efficacy scores related to diabetic care management pre- and post-implementation of a Web-based social support platform?" A one-group pretest/post-test descriptive design was used, with parental self-efficacy measured pre- and post-intervention (Web-based platform access) using the Diabetes Empowerment Scale (DES) and Self-Efficacy for Diabetes Scale (SED), and parent satisfaction with the online support platform assessed through parental comments. Project outcomes corroborated the use of online social support as evidenced by improvement in parental self-efficacy scores in both the DES and SED survey measurements. A statistically significant increase (p < 0.05) was found between the pre- and post-implementation scores of the SED survey. Secondary data supported the positive relationship of social support and self-efficacy in raising a child with type 1 diabetes. This online social support platform was found to be an easily adaptable, cost-effective, and innovative means of networking and information sharing among families facing similar challenges in raising a child with type 1 diabetes.

A small molecule AMPK activator protects the heart against ischemia-reperfusion injury.

AMP-activated protein kinase (AMPK) is a stress signaling enzyme that orchestrates the regulation of energy-generating and -consuming pathways. Intrinsic AMPK activation protects the heart against ischemic injury and apoptosis, but whether pharmacologic AMPK stimulation mitigates ischemia-reperfusion damage is unknown. The aims of this study were to determine whether direct stimulation of AMPK using a small molecule activator, A-769662, attenuates myocardial ischemia-reperfusion injury and to examine its cardioprotective mechanisms. Isolated mouse hearts pre-treated with A-769662 had better recovery of left ventricular contractile function (55% vs. 29% of baseline rate-pressure product; p=0.03) and less myocardial necrosis (56% reduction in infarct size; p<0.01) during post-ischemic reperfusion compared to control hearts. Pre-treatment with A-769662 in vivo attenuated infarct size in C57Bl/6 mice undergoing left coronary artery occlusion and reperfusion compared to vehicle (36% vs. 18%, p=0.025). Mouse hearts with genetically inactivated AMPK were not protected by A-769662, indicating the specificity of this compound. Pre-treatment with A-769662 increased the phosphorylation and inactivation of eukaryotic elongation factor 2 (eEF2), preserved energy charge during ischemia, delayed the development of ischemic contracture, and reduced myocardial apoptosis and necrosis. A-769662 also augmented endothelial nitric oxide synthase (eNOS) activation during ischemia, which partially attenuated myocardial stunning, but did not prevent necrosis. AMPK is a therapeutic target that can be stimulated by a direct-acting small molecule in order to prevent injury during ischemia-reperfusion. The use of AMPK activators may represent a novel strategy to protect the heart and other solid organs against ischemia.

Whole-genome sequencing and phenotypic analysis of Bacillus subtilis mutants following evolution under conditions of relaxed selection for sporulation.

Little is known about how genetic variation at the nucleotide level contributes to competitive fitness within species. During a 6,000-generation study of Bacillus subtilis evolved under relaxed selection for sporulation, a new strain, designated WN716, emerged with significantly different colony and cell morphologies; loss of sporulation, competence, acetoin production, and motility; multiple auxotrophies; and increased competitive fitness (H. Maughan and W. L. Nicholson, Appl. Environ. Microbiol. 77:4105-4118, 2011). The genome of WN716 was analyzed by OpGen optical mapping, whole-genome 454 pyrosequencing, and the CLC Genomics Workbench. No large chromosomal rearrangements were found; however, 34 single-nucleotide polymorphisms (SNPs) and +1 frameshifts were identified in WN716 that resulted in amino acid changes in coding sequences of annotated genes, and 11 SNPs were located in intergenic regions. Several classes of genes were affected, including biosynthetic pathways, sporulation, competence, and DNA repair. In several cases, attempts were made to link observed phenotypes of WN716 with the discovered mutations, with various degrees of success. For example, a +1 frameshift was identified at codon 13 of sigW, the product of which (SigW) controls a regulon of genes involved in resistance to bacteriocins and membrane-damaging antibiotics. Consistent with this finding, WN716 exhibited sensitivity to fosfomycin and to a bacteriocin produced by B. subtilis subsp. spizizenii and exhibited downregulation of SigW-dependent genes on a transcriptional microarray, consistent with WN716 carrying a knockout of sigW. The results suggest that propagation of B. subtilis for less than 2,000 generations in a nutrient-rich environment where sporulation is suppressed led to rapid initiation of genomic erosion.

Eph-dependent tyrosine phosphorylation of ephexin1 modulates growth cone collapse.

Ephs regulate growth cone repulsion, a process controlled by the actin cytoskeleton. The guanine nucleotide exchange factor (GEF) ephexin1 interacts with EphA4 and has been suggested to mediate the effect of EphA on the activity of Rho GTPases, key regulators of the cytoskeleton and axon guidance. Using cultured ephexin1-/- mouse neurons and RNA interference in the chick, we report that ephexin1 is required for normal axon outgrowth and ephrin-dependent axon repulsion. Ephexin1 becomes tyrosine phosphorylated in response to EphA signaling in neurons, and this phosphorylation event is required for growth cone collapse. Tyrosine phosphorylation of ephexin1 enhances ephexin1's GEF activity toward RhoA while not altering its activity toward Rac1 or Cdc42, thus changing the balance of GTPase activities. These findings reveal that ephexin1 plays a role in axon guidance and is regulated by a switch mechanism that is specifically tailored to control Eph-mediated growth cone collapse.

eIF5A-PEAK1 Signaling Regulates YAP1/TAZ Protein Expression and Pancreatic Cancer Cell Growth.

In pancreatic ductal adenocarcinoma (PDAC), mutant KRAS stimulates the translation initiation factor eIF5A and upregulates the focal adhesion kinase PEAK1, which transmits integrin and growth factor signals mediated by the tumor microenvironment. Although eIF5A-PEAK1 signaling contributes to multiple aggressive cancer cell phenotypes, the downstream signaling processes that mediate these responses are uncharacterized. Through proteomics and informatic analyses of PEAK1-depleted PDAC cells, we defined protein translation, cytoskeleton organization, and cell-cycle regulatory pathways as major pathways controlled by PEAK1. Biochemical and functional studies revealed that the transcription factors YAP1 and TAZ are key targets of eIF5A-PEAK1 signaling. YAP1/TAZ coimmunoprecipitated with PEAK1. Interfering with eIF5A-PEAK1 signaling in PDAC cells inhibited YAP/TAZ protein expression, decreasing expression of stem cell-associated transcription factors (STF) including Oct4, Nanog, c-Myc, and TEAD, thereby decreasing three-dimensional (3D) tumor sphere growth. Conversely, amplified eIF5A-PEAK1 signaling increased YAP1/TAZ expression, increasing expression of STF and enhancing 3D tumor sphere growth. Informatic interrogation of mRNA sequence databases revealed upregulation of the eIF5A-PEAK1-YAP1-TEAD signaling module in PDAC patients. Taken together, our findings indicate that eIF5A-PEAK1-YAP signaling contributes to PDAC development by regulating an STF program associated with increased tumorigenicity. Cancer Res; 77(8); 1997-2007. ©2017 AACR.

Telephone Calls Make a Difference in Home Balance Training Outcomes: A Randomized Trial.

BACKGROUND AND PURPOSE: To determine the benefit of a weekly telephone contact on balance control for community-dwelling frail older adults participating in home-exercise programs. Falls in frail older adults often lead to hospitalization and sometimes death. Evidence supports the effectiveness of home exercise programs in reducing fall risk in older adults. As well, there is a high cost for the delivery of a home exercise program in a traditional manner. Poor adherence to a home exercise program can limit the expected reduction in fall risk in the older adult population. We hypothesized that a weekly telephone call would improve adherence to a home-exercise program and, therefore, improve outcomes on the Berg Balance Test. METHODS: Seventy-five community-dwelling, frail older adult participants, at risk for falling (mean age: 76 years, range: 64-88 years; 3 women), were randomized in alternating pairs to a Telephone Call or No Telephone Call group. All participants received physical therapy home-exercise programs focused on balance control and were assessed and progressed 4 times over 12 weeks. All participants used an exercise log in which they were asked to record the amount of time and the number of repetitions performed of all daily exercises. The Telephone Call group received an additional 15-minute weekly telephone call with standard questions and encouragement to discuss their program. The primary outcome measure was the Berg Balance Scale. RESULTS: A total of 11 subjects dropped out of the study with 8 from the No Telephone Call group and 3 from the Telephone Call group. For both groups, a significant effect for time was noted, demonstrating that both groups improved significantly in balance control with the home exercise intervention. For the Berg Balance Scale, an interaction occurred whereby the Telephone Call group improved significantly more in balance control than the No Telephone Call group (Telephone Call group = 6.3 points; No Telephone Call group = 3.9 points). CONCLUSIONS: A home exercise program was beneficial to improve the balance of community-dwelling frail older adults. More importantly for health policy consideration, a simple, weekly, telephone call made a significant difference in how much balance improvement was made. Telephone calls are a cost-effective way to provide effective follow-up support for older adults participating in home exercise programs.

Cochlear implants for pre-lingually profoundly deaf adults.

INTRODUCTION: Increasing numbers of pre-lingually profoundly deaf adults are seeking a cochlear implant (CI). Pre- and post-operative outcomes are presented on 20 of these patients. RESULTS: An Adult Pre-Lingually Profoundly Deaf Implant Profile (APDIP) weighted the pre-operative level of concern about potential CI benefit. Results indicated no group mean post-operative open-set improvement. However CUNY sentence testing (auditory plus lip-reading cues) revealed improved performance with a CI. Twelve out of 20 patients used their CIs for more than 10 hours per day, suggesting good usage. Moreover, hours of usage were positively associated with measured benefit on CUNY sentences in the lip-reading plus sound via CI condition. There was no apparent relationship between pre-operative level of concern and post-operative CI performance or hours of processor use. CONCLUSION: Results suggest implantation is beneficial and effective in this group.

Short-term enhancement of visual field sensitivity in glaucomatous eyes following surgical intraocular pressure reduction.

PURPOSE: To examine the hypothesis that surgical intraocular pressure (IOP) reduction leads to enhancement of visual field (VF) sensitivity in glaucomatous eyes. DESIGN: Prospective case-control study. METHODS: Patients with uncontrolled IOP requiring trabeculectomy or aqueous drainage device were enrolled. Controls consisted of medically treated glaucoma patients with stable IOP and no change in medical therapy during follow-up. Two baseline preoperative VFs and 3 follow-up VF examinations at 1, 2, and 3 months postoperatively were used for analysis. The same number of VF examinations measured within an 18-month interval was used for control eyes. VF locations with significant change were defined as exceeding 95% test-retest confidence limits based upon the mean sensitivity using the 2 baseline VF exams. The number of significantly changing locations per eye and changes in mean and pattern standard deviation (PSD) from the mean baseline fields were compared between groups using a Poisson generalized estimating equation model. RESULTS: Thirty eyes of 30 surgically treated glaucoma patients and 41 eyes of 28 stable controls were enrolled. Postoperative IOP was decreased at follow-up 3 compared with baseline (P < .001) in the surgical eyes, but was similar in control eyes (P = .92). At follow-up 3, the number of test locations improving in central (P = .014) and peripheral (P = .019) VF locations was significantly greater in the surgical eyes. The number of eyes with improved PSD at follow-up 3 was significantly greater in the surgical eyes compared with controls (P = .02). CONCLUSIONS: Short-term enhancement of central and peripheral VF sensitivity occurs after surgical reduction of IOP in glaucomatous eyes and may represent a potential biomarker for retinal ganglion cell response to therapeutic interventions in glaucoma.

Maintaining the accuracy of the (60)Co calibration service at the ARPANSA post source replacement in 2010.

The Australian Radiation Protection and Nuclear Safety Agency (ARPANSA) maintains a (60)Co teletherapy source primarily for the calibration of therapy dosemeters. The source and encapsulating head were replaced in early 2010 with an Eldorado 78 head and new (60)Co source. In this article we present the results of ongoing accuracy and stability measurements since the replacement. A number of formal and informal indirect comparisons have been carried out with laboratories holding primary and secondary standards for (60)Co. ARPANSA chambers have also been calibrated at international primary standard laboratories allowing comparison of calibration coefficients and thus (60)Co absorbed dose standards. (60)Co calibration coefficients supplied by manufacturers of chambers were compared to those measured at the ARPANSA when this calibration was traceable to a primary standard. ARPANSA also participates in an annual international mailed dosimetry audit conducted by the International Atomic Energy Agency. The results thus far demonstrate that the absorbed doses to water delivered by the new ARPANSA (60)Co source are consistent with international doses within the stated uncertainties.

Direct calibration in megavoltage photon beams using Monte Carlo conversion factor: validation and clinical implications.

The Australian Radiation Protection and Nuclear Safety Agency (ARPANSA) has established a method for ionisation chamber calibrations using megavoltage photon reference beams. The new method will reduce the calibration uncertainty compared to a (60)Co calibration combined with the TRS-398 energy correction factor. The calibration method employs a graphite calorimeter and a Monte Carlo (MC) conversion factor to convert the absolute dose to graphite to absorbed dose to water. EGSnrc is used to model the linac head and doses in the calorimeter and water phantom. The linac model is validated by comparing measured and modelled PDDs and profiles. The relative standard uncertainties in the calibration factors at the ARPANSA beam qualities were found to be 0.47% at 6 MV, 0.51% at 10 MV and 0.46% for the 18 MV beam. A comparison with the Bureau International des Poids et Mesures (BIPM) as part of the key comparison BIPM.RI(I)-K6 gave results of 0.9965(55), 0.9924(60) and 0.9932(59) for the 6, 10 and 18 MV beams, respectively, with all beams within 1σ of the participant average. The measured kQ values for an NE2571 Farmer chamber were found to be lower than those in TRS-398 but are consistent with published measured and modelled values. Users can expect a shift in the calibration factor at user energies of an NE2571 chamber between 0.4-1.1% across the range of calibration energies compared to the current calibration method.

Regulation of external genitalia development by concerted actions of FGF ligands and FGF receptors.

Members of the fibroblast growth factor (FGF) family play diverse roles during the development and patterning of various organs. In human and mice, 22 FGFs and four receptors derived from several splice variants are present. Redundant expression and function of FGF genes in organogenesis have been reported, but their roles in embryonic external genitalia, genital tubercle (GT), development have not been studied in detail. To address the role of FGF during external genitalia development, we have analyzed the expression of FGF genes (Fgf8, 9, 10) and receptor genes (Fgfr1, r2IIIb, r2IIIc) in GT of mice. Furthermore, Fgf10 and Fgfr2IIIb mutant mice were analyzed to elucidate their roles in embryonic external genitalia development. Fgfr2IIIb was expressed in urethral plate epithelium during GT development. Fgfr2IIIb mutant mice display urethral dysmorphogenesis. Marker gene analysis for urethral plate and bilateral mesenchymal formation suggests the existence of epithelial-mesenchymal interaction during urethral morphogenesis. Therefore, FGF10/FGFR2IIIb signals seem to constitute a developmental cascade for such morphogenesis.

A hypusine-eIF5A-PEAK1 switch regulates the pathogenesis of pancreatic cancer.

Deregulation of protein synthesis is a hallmark of cancer cell proliferation, survival, and metastatic progression. eIF5A1 and its highly related isoform eIF5A2 are translation initiation factors that have been implicated in a range of human malignancies, but how they control cancer development and disease progression is still poorly understood. Here, we investigated how eIF5A proteins regulate pancreatic ductal adenocarcinoma (PDAC) pathogenesis. eIF5A proteins are the only known proteins regulated by a distinct posttranslational modification termed hypusination, which is catalyzed by two enzymes, deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). The highly selective nature of the hypusine modification and its amenability to pharmacologic inhibition make eIF5A proteins attractive therapeutic targets. We found that the expression and hypusination of eIF5A proteins are upregulated in human PDAC tissues and in premalignant pancreatic intraepithelial neoplasia tissues isolated from Pdx-1-Cre: LSL-KRAS(G12D) mice. Knockdown of eIF5A proteins in PDAC cells inhibited their growth in vitro and orthotopic tumor growth in vivo, whereas amplification of eIF5A proteins increased PDAC cell growth and tumor formation in mice. Small-molecule inhibitors of DHPS and DOHH both suppressed eIF5A hypusination, preventing PDAC cell growth. Interestingly, we found that eIF5A proteins regulate PDAC cell growth by modulating the expression of PEAK1, a nonreceptor tyrosine kinase essential for PDAC cell growth and therapy resistance. Our findings suggest that eIF5A proteins utilize PEAK1 as a downstream effector to drive PDAC pathogenesis and that pharmacologic inhibition of the eIF5A-hypusine-PEAK1 axis may provide a novel therapeutic strategy to combat this deadly disease.

CRIPTO/GRP78 signaling maintains fetal and adult mammary stem cells ex vivo.

Little is known about the extracellular signaling factors that govern mammary stem cell behavior. Here, we identify CRIPTO and its cell-surface receptor GRP78 as regulators of stem cell behavior in isolated fetal and adult mammary epithelial cells. We develop a CRIPTO antagonist that promotes differentiation and reduces self-renewal of mammary stem cell-enriched populations cultured ex vivo. By contrast, CRIPTO treatment maintains the stem cell phenotype in these cultures and yields colonies with enhanced mammary gland reconstitution capacity. Surface expression of GRP78 marks CRIPTO-responsive, stem cell-enriched fetal and adult mammary epithelial cells, and deletion of GRP78 from adult mammary epithelial cells blocks their mammary gland reconstitution potential. Together, these findings identify the CRIPTO/GRP78 pathway as a developmentally conserved regulator of fetal and adult mammary stem cell behavior ex vivo, with implications for the stem-like cells found in many cancers.