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.

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.

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.

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.

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.

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.

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.

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.

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.

High-Throughput Imaging Assay for Drug Screening of 3D Prostate Cancer Organoids.

New treatments are required for advanced prostate cancer; however, there are fewer preclinical models of prostate cancer than other common tumor types to test candidate therapeutics. One opportunity to increase the scope of preclinical studies is to grow tissue from patient-derived xenografts (PDXs) as organoid cultures. Here we report a scalable pipeline for automated seeding, treatment and an analysis of the drug responses of prostate cancer organoids. We established organoid cultures from 5 PDXs with diverse phenotypes of prostate cancer, including castrate-sensitive and castrate-resistant disease, as well as adenocarcinoma and neuroendocrine pathology. We robotically embedded organoids in Matrigel in 384-well plates and monitored growth via brightfield microscopy before treatment with poly ADP-ribose polymerase inhibitors or a compound library. Independent readouts including metabolic activity and live-cell imaging-based features provided robust measures of organoid growth and complementary ways of assessing drug efficacy. Single organoid analyses enabled in-depth assessment of morphological differences between patients and within organoid populations and revealed that larger organoids had more striking changes in morphology and composition after drug treatment. By increasing the scale and scope of organoid experiments, this automated assay complements other patient-derived models and will expedite preclinical testing of new treatments for prostate cancer.

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.

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.

New Directions in Ensuring Catheter Safety.

Tunneled dialysis catheters remain the most common vascular access used to initiate hemodialysis. Unfortunately, their use is associated with higher morbidity and mortality when compared with arteriovenous fistulae or grafts. Different types of catheters with different designs and material properties function differently. Additional devices and medications can be used to decrease the rates of infection and thrombosis. The current available tunneled dialysis catheters remain far from the desired goal and innovation in the field of dialysis vascular access remains in dire need.

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.

A multimodal computer-aided diagnostic system for precise identification of renal allograft rejection: Preliminary results.

PURPOSE: Early assessment of renal allograft function post-transplantation is crucial to minimize and control allograft rejection. Biopsy - the gold standard - is used only as a last resort due to its invasiveness, high cost, adverse events (e.g., bleeding, infection, etc.), and the time for reporting. To overcome these limitations, a renal computer-assisted diagnostic (Renal-CAD) system was developed to assess kidney transplant function. METHODS: The developed Renal-CAD system integrates data collected from two image-based sources and two clinical-based sources to assess renal transplant function. The imaging sources were the apparent diffusion coefficients (ADCs) extracted from 47 diffusion-weighted magnetic resonance imaging (DW-MRI) scans at 11 different b-values (b0, b50, b100, ..., b1000 s/mm 2 ), and the transverse relaxation rate (R2*) extracted from 30 blood oxygen level-dependent MRI (BOLD-MRI) scans at 5 different echo times (TEs = 2, 7, 12, 17, and 22 ms). Serum creatinine (SCr) and creatinine clearance (CrCl) were the clinical sources for kidney function evaluation. The Renal-CAD system initially performed kidney segmentation using the level-set method, followed by estimation of the ADCs from DW-MRIs and the R2* from BOLD-MRIs. ADCs and R2* estimates from 30 subjects that have both types of scans were integrated with their associated SCr and CrCl. The integrated biomarkers were then used as our discriminatory features to train and test a deep learning-based classifier, namely stacked autoencoders (SAEs) to differentiate non-rejection (NR) from acute rejection (AR) renal transplants. RESULTS: Using a leave-one-subject-out cross-validation approach along with SAEs, the Renal-CAD system demonstrated 93.3% accuracy, 90.0% sensitivity, and 95.0% specificity in differentiating AR from NR. Robustness of the Renal-CAD system was also confirmed by the area under the curve value of 0.92. Using a stratified tenfold cross-validation approach, the Renal-CAD system demonstrated its reproducibility and robustness by a diagnostic accuracy of 86.7%, sensitivity of 80.0%, specificity of 90.0%, and AUC of 0.88. CONCLUSION: The obtained results demonstrate the feasibility and efficacy of accurate, noninvasive identification of AR at an early stage using the Renal-CAD system.

90 YEARS OF PROGESTERONE: Steroid receptors as MAPK signaling sensors in breast cancer: let the fates decide.

Steroid hormone receptors (SRs) are classically defined as ligand-activated transcription factors that function as master regulators of gene programs important for a wide range of processes governing adult physiology, development, and cell or tissue homeostasis. A second function of SRs includes the ability to activate cytoplasmic signaling pathways. Estrogen (ER), androgen (AR), and progesterone (PR) receptors bind directly to membrane-associated signaling molecules including mitogenic protein kinases (i.e. c-SRC and AKT), G-proteins, and ion channels to mediate context-dependent actions via rapid activation of downstream signaling pathways. In addition to making direct contact with diverse signaling molecules, SRs are further fully integrated with signaling pathways by virtue of their N-terminal phosphorylation sites that act as regulatory hot-spots capable of sensing the signaling milieu. In particular, ER, AR, PR, and closely related glucocorticoid receptors (GR) share the property of accepting (i.e. sensing) ligand-independent phosphorylation events by proline-directed kinases in the MAPK and CDK families. These signaling inputs act as a 'second ligand' that dramatically impacts cell fate. In the face of drugs that reliably target SR ligand-binding domains to block uncontrolled cancer growth, ligand-independent post-translational modifications guide changes in cell fate that confer increased survival, EMT, migration/invasion, stemness properties, and therapy resistance of non-proliferating SR+ cancer cell subpopulations. The focus of this review is on MAPK pathways in the regulation of SR+ cancer cell fate. MAPK-dependent phosphorylation of PR (Ser294) and GR (Ser134) will primarily be discussed in light of the need to target changes in breast cancer cell fate as part of modernized combination therapies.

Inhibition of the SRC Kinase HCK Impairs STAT3-Dependent Gastric Tumor Growth in Mice.

Persistent activation of the latent transcription factor STAT3 is observed in gastric tumor epithelial and immune cells and is associated with a poor patient prognosis. Although targeting STAT3-activating upstream kinases offers therapeutically viable targets with limited specificity, direct inhibition of STAT3 remains challenging. Here we provide functional evidence that myeloid-specific hematopoietic cell kinase (HCK) activity can drive STAT3-dependent epithelial tumor growth in mice and is associated with alternative macrophage activation alongside matrix remodeling and tumor cell invasion. Accordingly, genetic reduction of HCK expression in bone marrow-derived cells or systemic pharmacologic inhibition of HCK activity suppresses alternative macrophage polarization and epithelial STAT3 activation, and impairs tumor growth. These data validate HCK as a molecular target for the treatment of human solid tumors harboring excessive STAT3 activity.

A DEEP LEARNING-BASED CAD SYSTEM FOR RENAL ALLOGRAFT ASSESSMENT: DIFFUSION, BOLD, AND CLINICAL BIOMARKERS.

Recently, studies for non-invasive renal transplant evaluation have been explored to control allograft rejection. In this paper, a computer-aided diagnostic system has been developed to accommodate with an early-stage renal transplant status assessment, called RT-CAD. Our model of this system integrated multiple sources for a more accurate diagnosis: two image-based sources and two clinical-based sources. The image-based sources included apparent diffusion coefficients (ADCs) and the amount of deoxygenated hemoglobin (R2*). More specifically, these ADCs were extracted from 47 diffusion weighted magnetic resonance imaging (DW-MRI) scans at 11 different b-values (b0, b50, b100, …, b1000 s/mm2), while the R2* values were extracted from 30 blood oxygen level-dependent MRI (BOLD-MRI) scans at 5 different echo times (2ms, 7ms, 12ms, 17ms, and 22ms). The clinical sources included serum creatinine (SCr) and creatinine clearance (CrCl). First, the kidney was segmented through the RT-CAD system using a geometric deformable model called a level-set method. Second, both ADCs and R2* were estimated for common patients (N = 30) and then were integrated with the corresponding SCr and CrCl. Last, these integrated biomarkers were considered the discriminatory features to be used as trainers and testers for future deep learning-based classifiers such as stacked auto-encoders (SAEs). We used a k-fold cross-validation criteria to evaluate the RT-CAD system diagnostic performance, which achieved the following scores: 93.3%, 90.0%, and 95.0% in terms of accuracy, sensitivity, and specificity in differentiating between acute renal rejection (AR) and non-rejection (NR). The reliability and completeness of the RT-CAD system was further accepted by the area under the curve score of 0.92. The conclusions ensured that the presented RT-CAD system has a high reliability to diagnose the status of the renal transplant in a non-invasive way.

A Novel CNN-Based CAD System for Early Assessment of Transplanted Kidney Dysfunction.

This paper introduces a deep-learning based computer-aided diagnostic (CAD) system for the early detection of acute renal transplant rejection. For noninvasive detection of kidney rejection at an early stage, the proposed CAD system is based on the fusion of both imaging markers and clinical biomarkers. The former are derived from diffusion-weighted magnetic resonance imaging (DW-MRI) by estimating the apparent diffusion coefficients (ADC) representing the perfusion of the blood and the diffusion of the water inside the transplanted kidney. The clinical biomarkers, namely: creatinine clearance (CrCl) and serum plasma creatinine (SPCr), are integrated into the proposed CAD system as kidney functionality indexes to enhance its diagnostic performance. The ADC maps are estimated for a user-defined region of interest (ROI) that encompasses the whole kidney. The estimated ADCs are fused with the clinical biomarkers and the fused data is then used as an input to train and test a convolutional neural network (CNN) based classifier. The CAD system is tested on DW-MRI scans collected from 56 subjects from geographically diverse populations and different scanner types/image collection protocols. The overall accuracy of the proposed system is 92.9% with 93.3% sensitivity and 92.3% specificity in distinguishing non-rejected kidney transplants from rejected ones. These results demonstrate the potential of the proposed system for a reliable non-invasive diagnosis of renal transplant status for any DW-MRI scans, regardless of the geographical differences and/or imaging protocol.

Phosphorylated Progesterone Receptor Isoforms Mediate Opposing Stem Cell and Proliferative Breast Cancer Cell Fates.

Progesterone receptors (PRs) are key modifiers of estrogen receptor (ER) target genes and drivers of luminal breast cancer progression. Total PR expression, rather than isoform-specific PR expression, is measured in breast tumors as an indicator of functional ER. We identified phenotypic differences between PR-A and PR-B in luminal breast cancer models with a focus on tumorsphere biology. Our findings indicated that PR-A is a dominant driver of cancer stem cell (CSC) expansion in T47D models, and PR-B is a potent driver of anchorage-independent proliferation. PR-A+ tumorspheres were enriched for aldehyde dehydrogenase (ALDH) activity, CD44+/CD24-, and CD49f+/CD24- cell populations relative to PR-B+ tumorspheres. Progestin promoted heightened expression of known CSC-associated target genes in PR-A+ but not PR-B+ cells cultured as tumorspheres. We report robust phosphorylation of PR-A relative to PR-B Ser294 and found that this residue is required for PR-A-induced expression of CSC-associated genes and CSC behavior. Cells expressing PR-A S294A exhibited impaired CSC phenotypes but heightened anchorage-independent cell proliferation. The PR target gene and coactivator, FOXO1, promoted PR phosphorylation and tumorsphere formation. The FOXO1 inhibitor (AS1842856) alone or combined with onapristone (PR antagonist), blunted phosphorylated PR, and tumorsphere formation in PR-A+ and PR-B+ T47D, MCF7, and BT474 models. Our data revealed unique isoform-specific functions of phosphorylated PRs as modulators of distinct and opposing pathways relevant to mechanisms of late recurrence. A clear understanding of PR isoforms, phosphorylation events, and the role of cofactors could lead to novel biomarkers of advanced tumor behavior and reveal new approaches to pharmacologically target CSCs in luminal breast cancer.