Activity and safety of enobosarm, a novel, oral, selective androgen receptor modulator, in androgen receptor-positive, oestrogen receptor-positive, and HER2-negative advanced breast cancer (Study G200802): a randomised, open-label, multicentre, multinational, parallel design, phase 2 trial.

BACKGROUND: The androgen receptor is a tumour suppressor in oestrogen receptor-positive breast cancer. The activity and safety of enobosarm, an oral selective androgen receptor modulator, was evaluated in women with oestrogen receptor (ER)-positive, HER2-negative, and androgen receptor (AR)-positive disease. METHODS: Women who were postmenopausal (aged ≥18 years) with previously treated ER-positive, HER2-negative, locally advanced or metastatic breast cancer with an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled in a randomised, open-label, multicentre, multinational, parallel design, phase 2 trial done at 35 cancer treatment centres in nine countries. Participants were stratified on the setting of immediately preceding endocrine therapy and the presence of bone-only metastasis and randomly assigned (1:1) to 9 mg or 18 mg oral enobosarm daily using an interactive web response system. The primary endpoint was clinical benefit rate at 24 weeks in those with centrally confirmed AR-positive disease (ie, the evaluable population). This trial is registered with ClinicalTrials.gov (NCT02463032). FINDINGS: Between Sept 10, 2015, and Nov 28, 2017, 136 (79%) of 172 patients deemed eligible were randomly assigned to 9 mg (n=72) or 18 mg (n=64) oral enobosarm daily. Of these 136 patients, 102 (75%) patients formed the evaluable population (9 mg, n=50; 18 mg, n=52). The median age was 60·5 years (IQR 52·3-69·3) in the 9 mg group and 62·5 years (54·0-69·3) in the 18 mg group. The median follow-up was 7·5 months (IQR 2·9-14·1). At 24 weeks, 16 (32%, 95% CI 20-47) of 50 in the 9 mg group and 15 (29%, 17-43) of 52 in the 18 mg group had clinical benefit. Six (8%) of 75 patients who received 9 mg and ten (16%) of 61 patients who received 18 mg had grade 3 or grade 4 drug-related adverse events, most frequently increased hepatic transaminases (three [4%] of 75 in the 9 mg group and two [3%] of 61 in the 18 mg group), hypercalcaemia (two [3%] and two [3%]), and fatigue (one [1%] and two [3%]). Four deaths (one in the 9 mg group and three in the 18 mg group) were deemed unrelated to the study drug. INTERPRETATION: Enobosarm has anti-tumour activity in patients with ER-positive, HER2-negative advanced breast cancer, showing that AR activation can result in clinical benefit, supporting further clinical investigation of selective AR activation strategies for the treatment of AR-positive, ER-positive, HER2-negative advanced breast cancer. FUNDING: GTx.

Arming androgen receptors to oppose oncogenic estrogen receptor activity in breast cancer.

Most breast cancers are driven by oncogenic activity of the estrogen receptor alpha (ER). Resistance to ER target therapies is the major cause of breast cancer death. Recently, there has been renewed interest in targeting the androgen receptor (AR) to treat ER-driven breast cancers. Herein, we discuss evidence for an AR agonist, not antagonist, treatment strategy.

Insulin receptor substrate-1 (IRS-1) mediates progesterone receptor-driven stemness and endocrine resistance in oestrogen receptor+ breast cancer.

BACKGROUND: Progesterone receptors (PR) are potent modifiers of endocrine responses. In aberrant signalling cancer contexts, phosphorylation events dramatically alter steroid hormone receptor action. METHODS: The transcriptomes of primary tumours and metastases in mice harbouring ER+ breast cancer patient-derived xenografts (PDXs) were analysed following single-cell RNAseq. In vitro assays were employed to delineate mechanisms of endocrine resistance and stemness. RESULTS: A 16-gene phospho-Ser294 PR (p-PR) signature predicted poor outcome in ER+ breast cancer. Relative to primary PDX tumours, metastatic lesions expressed abundant p-PR and exhibited an activated PR gene programme with elevated expression of PGR and IRS-1. Breast cancer models of activated PR lost the expression of IGF1R and acquired insulin hypersensitivity with tamoxifen insensitivity. Activated p-PR+ breast cancer cells formed increased tumourspheres with enlarged ALDH+ and CD24-/CD44 populations. E2 induced PR/IRS-1 interaction and exchange of IGF1Rß for IRS-1 in p-PR-containing transcriptional complexes. Inhibition of IRS-1 or IR and inducible IRS-1 knockdown reduced tumourspheres. Endocrine-resistant models of luminal B breast cancer induced p-PR in 3D cultures and required PR and IRS-1 for tumoursphere formation. CONCLUSIONS: Phospho-PR-B cooperates with IRS-1 to promote outgrowth of endocrine-resistant and stem-like breast cancer cells. Targeting phospho-PR/IRS-1 crosstalk may block the emergence of endocrine resistance.

Glucocorticoid receptors are required effectors of TGFß1-induced p38 MAPK signaling to advanced cancer phenotypes in triple-negative breast cancer.

BACKGROUND: Altered signaling pathways typify breast cancer and serve as direct inputs to steroid hormone receptor sensors. We previously reported that phospho-Ser134-GR (pS134-GR) species are elevated in triple-negative breast cancer (TNBC) and cooperate with hypoxia-inducible factors, providing a novel avenue for activation of GR in response to local or cellular stress. METHODS: We probed GR regulation by factors (cytokines, growth factors) that are rich within the tumor microenvironment (TME). TNBC cells harboring endogenous wild-type (wt) or S134A-GR species were created by CRISPR/Cas knock-in and subjected to transwell migration, invasion, soft-agar colony formation, and tumorsphere assays. RNA-seq was employed to identify pS134-GR target genes that are regulated both basally (intrinsic) or by TGFß1 in the absence of exogenously added GR ligands. Regulation of selected basal and TGFß1-induced pS134-GR target genes was validated by qRT-PCR and chromatin immunoprecipitation assays. Bioinformatics tools were used to probe public data sets for expression of pS134-GR 24-gene signatures. RESULTS: In the absence of GR ligands, GR is transcriptionally activated via p38-dependent phosphorylation of Ser134 as a mechanism of homeostatic stress-sensing and regulated upon exposure of TNBC cells to TME-derived agents. The ligand-independent pS134-GR transcriptome encompasses TGFß1 and MAPK signaling gene sets associated with TNBC cell survival and migration/invasion. Accordingly, pS134-GR was essential for TNBC cell anchorage-independent growth in soft-agar, migration, invasion, and tumorsphere formation, an in vitro readout of cancer stemness properties. Both pS134-GR and expression of the MAPK-scaffolding molecule 14-3-3ζ were essential for a functionally intact p38 MAPK signaling pathway downstream of MAP3K5/ASK1, indicative of a feedforward signaling loop wherein self-perpetuated GR phosphorylation enables cancer cell autonomy. A 24-gene pS134-GR-dependent signature induced by TGFß1 predicts shortened overall survival in breast cancer patients. CONCLUSIONS: Phospho-S134-GR is a critical downstream effector of p38 MAPK signaling and TNBC migration/invasion, survival, and stemness properties. Our studies define a ligand-independent role for GR as a homeostatic "sensor" of intrinsic stimuli as well as extrinsic factors rich within the TME (TGFß1) that enable potent activation of the p38 MAPK stress-sensing pathway and nominate pS134-GR as a therapeutic target in aggressive TNBC.

Reticulon-1 and Reduced Migration toward Chemoattractants by Macrophages Differentiated from the Bone Marrow of Ultraviolet-Irradiated and Ultraviolet-Chimeric Mice.

The ability of macrophages to respond to chemoattractants and inflammatory signals is important for their migration to sites of inflammation and immune activity and for host responses to infection. Macrophages differentiated from the bone marrow (BM) of UV-irradiated mice, even after activation with LPS, migrated inefficiently toward CSF-1 and CCL2. When BM cells were harvested from UV-irradiated mice and transplanted into naive mice, the recipient mice (UV-chimeric) had reduced accumulation of elicited monocytes/macrophages in the peritoneal cavity in response to inflammatory thioglycollate or alum. Macrophages differentiating from the BM of UV-chimeric mice also had an inherent reduced ability to migrate toward chemoattractants in vitro, even after LPS activation. Microarray analysis identified reduced reticulon-1 mRNA expressed in macrophages differentiated from the BM of UV-chimeric mice. By using an anti-reticulon-1 Ab, a role for reticulon-1 in macrophage migration toward both CSF-1 and CCL2 was confirmed. Reticulon-1 subcellular localization to the periphery after exposure to CSF-1 for 2.5 min was shown by immunofluorescence microscopy. The proposal that reduced reticulon-1 is responsible for the poor inherent ability of macrophages to respond to chemokine gradients was supported by Western blotting. In summary, skin exposure to erythemal UV radiation can modulate macrophage progenitors in the BM such that their differentiated progeny respond inefficiently to signals to accumulate at sites of inflammation and immunity.

UV Irradiation of Skin Enhances Glycolytic Flux and Reduces Migration Capabilities in Bone Marrow-Differentiated Dendritic Cells.

A systemic immunosuppression follows UV irradiation of the skin of humans and mice. In this study, dendritic cells (DCs) differentiating from the bone marrow (BM) of UV-irradiated mice had a reduced ability to migrate toward the chemokine (C-C motif) ligand 21. Fewer DCs also accumulated in the peritoneal cavity of UV-chimeric mice (ie, mice transplanted with BM from UV-irradiated mice) after injection of an inflammatory stimulus into that site. We hypothesized that different metabolic states underpin altered DC motility. Compared with DCs from the BM of nonirradiated mice, those from UV-irradiated mice produced more lactate, consumed more glucose, and had greater glycolytic flux in a bioenergetics stress test. Greater expression of 3-hydroxyanthranilate 3,4-dioxygenase was identified as a potential contributor to increased glycolysis. Inhibition of 3-hydroxyanthranilate 3,4-dioxygenase by 6-chloro-dl-tryptophan prevented both increased lactate production and reduced migration toward chemokine (C-C motif) ligand 21 by DCs differentiated from BM of UV-irradiated mice. UV-induced prostaglandin E2 has been implicated as an intermediary in the effects of UV radiation on BM cells. DCs differentiating from BM cells pulsed in vitro for 2 hours with dimethyl prostaglandin E2 were functionally similar to those from the BM of UV-irradiated mice. Reduced migration of DCs to lymph nodes associated with increased glycolytic flux may contribute to their reduced ability to initiate new immune responses in UV-irradiated mice.

Balloon angioplasty versus Viabahn stent graft for treatment of failing or thrombosed prosthetic hemodialysis grafts.

OBJECTIVE: To compare the results of stent graft placement to balloon angioplasty for the treatment of stenosis at the venous anastomosis of failing and thrombosed prosthetic hemodialysis grafts. METHODS: This prospective, multicenter trial included 293 patients randomized (1:1) to the stent graft (n = 145) or balloon angioplasty (n = 148) group for treatment of stenosis at the venous anastomosis of dysfunctional (n = 164) or thrombosed (n = 129) hemodialysis grafts. The primary study end point was target lesion primary patency at 6 months; participants were followed for up to 24 months. Primary patency of the access circuit was a secondary end point. Statistical analysis of effectiveness was performed using both the intent-to-treat population and the effectiveness-per-protocol (EPP) populations for primary patency end points. Statistical analysis of additional effectiveness end points was performed using the EPP population. RESULTS: The 6-month target lesion primary patency was statistically greater in the stent graft group than the balloon angioplasty group (intent-to-treat, 51.6% vs 34.2% [P = .006]; EPP, 52.9% vs 35.5% [P = .008]). Compared with the angioplasty group, the stent graft group increased the median time from the index procedure to the next intervention on the target lesion by 95 days (203 vs 108 days). Patients with dysfunctional (stenotic) grafts had higher target lesion primary patency compared with patients with thrombosed grafts regardless of treatment (EPP, stent graft, 64.6% vs 36.1% and balloon angioplasty, 45.8% vs 23.5%). When compared with angioplasty, using a stent graft for treatment of a venous anastomotic stenosis of a thrombosed graft increased the 6-month target lesion primary patency by 53.6% (EPP, 36.1% vs 23.5%). CONCLUSIONS: When compared with balloon angioplasty, a stent graft provided superior target lesion primary patency at 6 months for treatment of venous anastomotic stenoses of dysfunctional and thrombosed prosthetic hemodialysis grafts.

Selective inhibition of CDK9 in triple negative breast cancer.

Targeted therapy for triple-negative breast cancers (TNBC) remains a clinical challenge due to tumour heterogeneity. Since TNBC have key features of transcriptionally addicted cancers, targeting transcription via regulators such as cyclin-dependent kinase 9 (CDK9) has potential as a therapeutic strategy. Herein, we preclinically tested a new selective CDK9 inhibitor (CDDD11-8) in TNBC using cell line, patient-derived organoid, and patient-derived explant models. In vitro, CDDD11-8 dose-dependently inhibited proliferation (IC50 range: 281-734 nM), induced cell cycle arrest, and increased apoptosis of cell lines, which encompassed the three major molecular subtypes of TNBC. On target inhibition of CDK9 activity was demonstrated by reduced RNAPII phosphorylation at a CDK9 target peptide and down-regulation of the MYC and MCL1 oncogenes at the mRNA and protein levels in all cell line models. Drug induced RNAPII pausing was evident at gene promoters, with strongest pausing at MYC target genes. Growth of five distinct patient-derived organoid models was dose-dependently inhibited by CDDD11-8 (IC50 range: 272-771 nM), including three derived from MYC amplified, chemo-resistant TNBC metastatic lesions. Orally administered CDDD11-8 also inhibited growth of mammary intraductal TNBC xenograft tumours with no overt toxicity in vivo (mice) or ex vivo (human breast tissues). In conclusion, our studies indicate that CDK9 is a viable therapeutic target in TNBC and that CDDD11-8, a novel selective CDK9 inhibitor, has efficacy in TNBC without apparent toxicity to normal tissues.

The androgen receptor interacts with GATA3 to transcriptionally regulate a luminal epithelial cell phenotype in breast cancer.

BACKGROUND: The androgen receptor (AR) is a tumor suppressor in estrogen receptor (ER) positive breast cancer, a role sustained in some ER negative breast cancers. Key factors dictating AR genomic activity in a breast context are largely unknown. Herein, we employ an unbiased chromatin immunoprecipitation-based proteomic technique to identify endogenous AR interacting co-regulatory proteins in ER positive and negative models of breast cancer to gain new insight into mechanisms of AR signaling in this disease. RESULTS: The DNA-binding factor GATA3 is identified and validated as a novel AR interacting protein in breast cancer cells irrespective of ER status. AR activation by the natural ligand 5α-dihydrotestosterone (DHT) increases nuclear AR-GATA3 interactions, resulting in AR-dependent enrichment of GATA3 chromatin binding at a sub-set of genomic loci. Silencing GATA3 reduces but does not prevent AR DNA binding and transactivation of genes associated with AR/GATA3 co-occupied loci, indicating a co-regulatory role for GATA3 in AR signaling. DHT-induced AR/GATA3 binding coincides with upregulation of luminal differentiation genes, including EHF and KDM4B, established master regulators of a breast epithelial cell lineage. These findings are validated in a patient-derived xenograft model of breast cancer. Interaction between AR and GATA3 is also associated with AR-mediated growth inhibition in ER positive and ER negative breast cancer. CONCLUSIONS: AR and GATA3 interact to transcriptionally regulate luminal epithelial cell differentiation in breast cancer regardless of ER status. This interaction facilitates the tumor suppressor function of AR and mechanistically explains why AR expression is associated with less proliferative, more differentiated breast tumors and better overall survival in breast cancer.

Fibrin sheath and its relation to subsequent events after tunneled dialysis catheter exchange.

The use of tunneled catheters (TDC) for chronic hemodialysis is frequent and often fails due to fibrin or thrombus and infection. We hypothesized that the presence of fibrin sheath in TDC increases the risk for subsequent catheter malfunction and infection. We did a retrospective review of TDC exchanges and de novo placements from January 2005 to September 2011. Demographic data, information about the catheter procedure, and radiological data were collected. Final outcome analysis included 168 procedure events. Three groups of catheter procedures were identified: catheter exchange without a fibrin sheath (CE), catheter exchange with a treated fibrin sheath (CEF), and de novo catheter placements (DCP). Fibrin sheath incidence was 47%. In the CEF group, there was no statistical difference in the incidence of subsequent infections or dysfunctions (7% and 60%, respectively), when compared with the CE group (9% and 43%, respectively), (p=0.3). Mean time to subsequent dysfunction or infection was similar for CEF and CE (135 vs. 136 days, p-value, 0.98). Fibrin sheaths are common and should be evaluated when performing TDC exchange. If the fibrin sheath is treated, there is no increased incidence in subsequent catheter dysfunction or infection compared with patients without a fibrin sheath.

Predicting post renal biopsy complications.

At our institution, kidney biopsies are performed by an interventional nephrologist with standardized guidelines using real-time ultrasound. We hypothesized that patient factors could predict post biopsy complications. We did a retrospective review of 100 patients who underwent renal biopsy. Prebiopsy data obtained included demographics, blood pressure, laboratory studies, and kidney size. Biopsy procedure information was also recorded. Complications and post biopsy imaging was noted. A minor complication was defined as one not requiring intervention while a major complication required interventions like readmission or blood transfusion. The average age was 47 years, 41 were men, 51 were black, 30 had diabetes, 42 were obese, and 81 had hypertension. Twenty-six patients had a complication; 14 minor and 12 major including 1 nephrectomy. Factors predictive of a complication were thrombocytopenia (p=0.002) and inpatient status (p=0.04). Drop in hemoglobin at 6 hours was moderately sensitive and specific for a bleeding complication with an ROC of 0.723. Thrombocytopenia and inpatient status are risk factors for complications after renal biopsy. Serum creatinine, obesity, blood pressure, kidney size, needle size, and number of passes were not predictive of a major complication in our study.

Association of maturation period blood pressure with dialysis access patency.

Problematic dialysis vascular access is a major health issue. The purpose of this study was to evaluate for potentially modifiable factors associated with access patency, particularly, the association of early postoperative, or maturation period, blood pressure with patency. A retrospective review was performed of patients who had undergone placement of an arteriovenous fistula or graft. Demographic, operative, and postoperative factors were evaluated for possible association with access primary patency using univariate and multivariate Cox regression analyses. Seventy-three patients over a 3-year review period were examined. Overall analysis showed a significant association of absence of peripheral vascular disease, aspirin use, and absence of previous permanent dialysis access with higher primary patency rates. Fistula subgroup analysis showed that higher blood pressure during the maturation period relative to preoperative blood pressure was associated with lower patency rates. For grafts, race was significantly associated with patency, with blacks having higher patency rates than whites. Multiple clinical factors were found to have a significant association with dialysis access primary patency. The finding of an association of maturation period blood pressure with fistula patency suggests that the maturation period environment, specifically hemodynamics during this time, may play an important role in dialysis access patency.

The role of stents in hemodialysis vascular access.

Vascular access is the Achilles' heel of dialysis therapy among patient with end stage kidney disease. The development of neointimal hyperplasia and subsequent stenosis is common in vascular access and is associated with significant morbidity. Percutaneous transluminal angioplasty using balloon inflation was the standard therapy of these lesions. However, the balloon-based approaches were associated with poor vascular access patency rate necessitating new inventions. It is within this context that different types of stents were developed in order to improve the overall dialysis vascular access functionality. In this article, we review the available literature regarding the use of stents in treating dialysis vascular access stenotic lesions. Further, we review the major clinical trials of stent use in different anatomic locations and in different clinical scenarios.

PICC line management among patients with chronic kidney disease.

More than 1 million peripherally inserted central catheters (PICC) are placed annually in the US and are used to provide convenient vascular access for a variety of reasons including long term antibiotic treatment, chemotherapy, parenteral nutrition, and blood draws. Although they are relatively easy to place and inexpensive, PICC line use is associated with many complications such as phlebitis/thrombophlebitis, venous thrombosis, catheter-related infection, wound infection, and central vein stenosis. These complications are far more deleterious for patients with chronic kidney disease (CKD) whose lives depend on a functioning hemodialysis access once they reach end stage kidney disease (ESKD). Despite recent guidelines to avoid PICC lines in CKD and ESKD patients, clinical use remains high. There is an ongoing urgency to educate and inform health care providers and the CKD patients themselves in preserving their venous real estate. In this article, we review AV access and PICC line background, complications associated with PICC lines in the CKD population, and recommendations for alternatives to placing a PICC line in this vulnerable patient population.

Glucocorticoid Receptors Drive Breast Cancer Cell Migration and Metabolic Reprogramming via PDK4.

Corticosteroids act on the glucocorticoid receptor (GR; NR3C1) to resolve inflammation and are routinely prescribed to breast cancer patients undergoing chemotherapy treatment to alleviate side effects. Triple-negative breast cancers (TNBCs) account for 15% to 20% of diagnoses and lack expression of estrogen and progesterone receptors as well as amplified HER2, but they often express high GR levels. GR is a mediator of TNBC progression to advanced metastatic disease; however, the mechanisms underpinning this transition to more aggressive behavior remain elusive. We previously showed that tissue/cellular stress (hypoxia, chemotherapies) as well as factors in the tumor microenvironment (transforming growth factor ß [TGF-ß], hepatocyte growth factor [HGF]) activate p38 mitogen-activated protein kinase (MAPK), which phosphorylates GR on Ser134. In the absence of ligand, pSer134-GR further upregulates genes important for responses to cellular stress, including key components of the p38 MAPK pathway. Herein, we show that pSer134-GR is required for TNBC metastatic colonization to the lungs of female mice. To understand the mechanisms of pSer134-GR action in the presence of GR agonists, we examined glucocorticoid-driven transcriptomes in CRISPR knock-in models of TNBC cells expressing wild-type or phospho-mutant (S134A) GR. We identified dexamethasone- and pSer134-GR-dependent regulation of specific gene sets controlling TNBC migration (NEDD9, CSF1, RUNX3) and metabolic adaptation (PDK4, PGK1, PFKFB4). TNBC cells harboring S134A-GR displayed metabolic reprogramming that was phenocopied by pyruvate dehydrogenase kinase 4 (PDK4) knockdown. PDK4 knockdown or chemical inhibition also blocked cancer cell migration. Our results reveal a convergence of GR agonists (ie, host stress) with cellular stress signaling whereby pSer134-GR critically regulates TNBC metabolism, an exploitable target for the treatment of this deadly disease.

Role of AI and Radiomic Markers in Early Diagnosis of Renal Cancer and Clinical Outcome Prediction: A Brief Review.

Globally, renal cancer (RC) is the 10th most common cancer among men and women. The new era of artificial intelligence (AI) and radiomics have allowed the development of AI-based computer-aided diagnostic/prediction (AI-based CAD/CAP) systems, which have shown promise for the diagnosis of RC (i.e., subtyping, grading, and staging) and prediction of clinical outcomes at an early stage. This will absolutely help reduce diagnosis time, enhance diagnostic abilities, reduce invasiveness, and provide guidance for appropriate management procedures to avoid the burden of unresponsive treatment plans. This survey mainly has three primary aims. The first aim is to highlight the most recent technical diagnostic studies developed in the last decade, with their findings and limitations, that have taken the advantages of AI and radiomic markers derived from either computed tomography (CT) or magnetic resonance (MR) images to develop AI-based CAD systems for accurate diagnosis of renal tumors at an early stage. The second aim is to highlight the few studies that have utilized AI and radiomic markers, with their findings and limitations, to predict patients' clinical outcome/treatment response, including possible recurrence after treatment, overall survival, and progression-free survival in patients with renal tumors. The promising findings of the aforementioned studies motivated us to highlight the optimal AI-based radiomic makers that are correlated with the diagnosis of renal tumors and prediction/assessment of patients' clinical outcomes. Finally, we conclude with a discussion and possible future avenues for improving diagnostic and treatment prediction performance.

Luminal breast cancer identity is determined by loss of glucocorticoid receptor activity.

Glucocorticoid receptor (GR) is a transcription factor that plays a crucial role in cancer biology. In this study, we utilized an in silico-designed GR activity signature to demonstrate that GR relates to the proliferative capacity of numerous primary cancer types. In breast cancer, the GR activity status determines luminal subtype identity and has implications for patient outcomes. We reveal that GR engages with estrogen receptor (ER), leading to redistribution of ER on the chromatin. Notably, GR activation leads to upregulation of the ZBTB16 gene, encoding for a transcriptional repressor, which controls growth in ER-positive breast cancer and associates with prognosis in luminal A patients. In relation to ZBTB16's repressive nature, GR activation leads to epigenetic remodeling and loss of histone acetylation at sites proximal to cancer-driving genes. Based on these findings, epigenetic inhibitors reduce viability of ER-positive breast cancer cells that display absence of GR activity. Our findings provide insights into how GR controls ER-positive breast cancer growth and may have implications for patients' prognostication and provide novel therapeutic candidates for breast cancer treatment.

A vascular access coordinator improves the prevalent fistula rate.

The Centers for Medicare and Medicaid Services set the prevalent arteriovenous fistula (AVF) rate of 66% as a national standard. To test the hypothesis that the use of a clinical vascular access coordinator could increase the rate of AVF in a large Nephrology group practice, we implemented an aggressive, multidisciplinary vascular access improvement program led by a trained vascular access coordinator (VAC). In early 2009, we established protocols, approved by all physicians, for the care of vascular access and implemented by a nurse VAC. We retrospectively reviewed Network vascular access data reports from January 2008 through December 2010. The data show that after the implementation of a comprehensive access program led by a VAC, the prevalent AVF rate increased from 50% to 65%. The number of grafts decreased while the percentage of dialysis catheters used for more than 90 days was cut in half. These data suggest that despite an unchanged catheter rate at dialysis initiation, the use of a VAC implementing an aggressive, multidisciplinary access program can significantly increase the AVF rate while decreasing grafts and prevalent catheter use.

Dialysis vascular access management by interventional nephrology programs at University Medical Centers in the United States.

The development of interventional nephrology has undoubtedly led to an improvement in patient care at many facilities across the United States. However, these services have traditionally been offered by interventional nephrologists in the private practice arena. While interventional nephrology was born in the private practice setting, several academic medical centers across the United States have now developed interventional nephrology programs. University Medical Centers (UMCs) that offer interventional nephrology face challenges, such as smaller dialysis populations, limited financial resources, and real or perceived political "turf" issues." Despite these hurdles, several UMCs have successfully established interventional nephrology as an intricate part of a larger nephrology program. This has largely been accomplished by consolidating available resources and collaborating with other specialties irrespective of the size of the dialysis population. The collaboration with other specialties also offers an opportunity to perform advanced procedures, such as application of excimer laser and endovascular ultrasound. As more UMCs establish interventional nephrology programs, opportunities for developing standardized training centers will improve, resulting in better quality and availability of nephrology-related procedures, and providing an impetus for research activities.

Breast Tumor Kinase (Brk/PTK6) Mediates Advanced Cancer Phenotypes via SH2-Domain Dependent Activation of RhoA and Aryl Hydrocarbon Receptor (AhR) Signaling.

Protein tyrosine kinase 6 (PTK6; also called Brk) is overexpressed in 86% of patients with breast cancer; high PTK6 expression predicts poor outcome. We reported PTK6 induction by HIF/GR complexes in response to either cellular or host stress. However, PTK6-driven signaling events in the context of triple-negative breast cancer (TNBC) remain undefined. In a mouse model of TNBC, manipulation of PTK6 levels (i.e., via knock-out or add-back) had little effect on primary tumor volume, but altered lung metastasis. To delineate the mechanisms of PTK6 downstream signaling, we created kinase-dead (KM) and kinase-intact domain structure mutants of PTK6 via in-frame deletions of the N-terminal SH3 or SH2 domains. While the PTK6 kinase domain contributed to soft-agar colony formation, PTK6 kinase activity was entirely dispensable for cell migration. Specifically, TNBC models expressing a PTK6 variant lacking the SH2 domain (SH2-del PTK6) were unresponsive to growth factor-stimulated cell motility relative to SH3-del, KM, or wild-type PTK6 controls. Reverse-phase protein array revealed that while intact PTK6 mediates spheroid formation via p38 MAPK signaling, the SH2 domain of PTK6 limits this biology, and instead mediates TNBC cell motility via activation of the RhoA and/or AhR signaling pathways. Inhibition of RhoA and/or AhR blocked TNBC cell migration as well as the branching/invasive morphology of PTK6+/AhR+ primary breast tumor tissue organoids. Inhibition of RhoA also enhanced paclitaxel cytotoxicity in TNBC cells, including in a taxane-refractory TNBC model. IMPLICATIONS: The SH2-domain of PTK6 is a potent effector of advanced cancer phenotypes in TNBC via RhoA and AhR, identified herein as novel therapeutic targets in PTK6+ breast tumors.