Citations

AbstractRenal agenesis is a devastating birth defect, and although genes encoding retinoic acid signaling components have been shown to be important for renal...Renal agenesis (RA) is one of the more extreme examples of congenital anomalies of the kidney and urinary tract (CAKUT). Bilateral renal agenesis is almost invariably fatal at birth, and unilateral renal agenesis can lead to future health issues including end-stage renal disease. Genetic investigations have identified several gene variants that cause RA, including EYA1, LHX1, and WT1. However, whereas compound null mutations of genes encoding α and γ retinoic acid receptors (RARs) cause RA in mice, to date there have been no reports of variants in RAR genes causing RA in humans. In this study, we carried out whole exome sequence analysis of two families showing inheritance of an RA phenotype, and in both identified a single candidate gene, GREB1L. Analysis of a zebrafish greb1l loss-of-function mutant revealed defects in the pronephric kidney just prior to death, and F0 CRISPR/Cas9 mutagenesis of Greb1l in the mouse revealed kidney agenesis phenotypes, implicating Greb1l in this disorder. GREB1L resides in a chromatin complex with RAR members, and our data implicate GREB1L as a coactivator for RARs. This study is the first to associate a component of the RAR pathway with renal agenesis in humans.

The failure of the polycystins (PCs) to function in primary cilia is thought to be responsible for autosomal dominant polycystic kidney disease (ADPKD). Primary cilia integrate multiple cellular signaling pathways, including calcium, cAMP, Wnt, and Hedgehog, which control cell proliferation and differentiation. It has been proposed that mutated PCs result in reduced intracellular calcium, which in turn upregulates cAMP, protein kinase A (PKA) signaling, and subsequently other proliferative signaling pathways. However, the role of PKA in ADPKD has not been directly ascertained in vivo, although the expression of the main regulatory subunit of PKA in cilia and other compartments (PKA-RIα, encoded by PRKAR1A) is increased in a mouse model orthologous to ADPKD. Therefore, we generated a kidney-specific knockout of Prkar1a to examine the consequences of constitutive upregulation of PKA on wild-type and Pkd1 hypomorphic ( Pkd1 RC ) backgrounds. Kidney-specific loss of Prkar1a induced renal cystic disease and markedly aggravated cystogenesis in the Pkd1 RC models. In both settings, it was accompanied by upregulation of Src, Ras, MAPK/ERK, mTOR, CREB, STAT3, Pax2 and Wnt signaling. On the other hand, Gli3 repressor activity was enhanced, possibly contributing to hydronephrosis and impaired glomerulogenesis in some animals. To assess the relevance of these observations in humans we looked for and found evidence for kidney and liver cystic phenotypes in the Carney complex, a tumoral syndrome caused by mutations in PRKAR1A. These observations expand our understanding of the pathogenesis of ADPKD and demonstrate the importance of PRKAR1A highlighting PKA as a therapeutic target in ADPKD.

AbstractBackgroundLittle is known about the optimal use of shared decision making (SDM) to guide palliative and end‐of‐life decisions in the emergency department (ED).ObjectiveThe objective was to convene a working group to develop a set of research questions that, when answered, will substantially advance the ability of clinicians to use SDM to guide palliative and end‐of‐life care decisions in the ED.MethodsParticipants were identified based on expertise in emergency, palliative, or geriatrics care; policy or patient‐advocacy; and spanned physician, nursing, social work, legal, and patient perspectives. Input from the group was elicited using a time‐staggered Delphi process including three teleconferences, an open platform for asynchronous input, and an in‐person meeting to obtain a final round of input from all members and to identify and resolve or describe areas of disagreement.ConclusionKey research questions identified by the group related to which ED patients are likely to benefit from palliative care (PC), what interventions can most effectively promote PC in the ED, what outcomes are most appropriate to assess the impact of these interventions, what is the potential for initiating advance care planning in the ED to help patients define long‐term goals of care, and what policies influence palliative and end‐of‐life care decision making in the ED. Answers to these questions have the potential to substantially improve the quality of care for ED patients with advanced illness.

Aberrant intracellular calcium levels and increased cAMP signaling contribute to the development of polycystic kidney disease (PKD). cAMP can be hydrolyzed by various phosphodiesterases (PDEs). To examine the role of cAMP hydrolysis and the most relevant PDEs in the pathogenesis of PKD, we examined cyst development in Pde1 - or Pde3 -knockout mice on the Pkd2 −/WS25 background (WS25 is an unstable Pkd2 allele). These PDEs were selected because of their importance in cross-talk between calcium and cyclic nucleotide signaling ( PDE1 ), control of cell proliferation and cystic fibrosis transmembrane conductance regulator (CFTR) –driven fluid secretion (PDE3), and response to vasopressin V2 receptor activation (both). In Pkd2 −/WS25 mice, knockout of Pde1a , Pde1c , or Pde3a but not of Pde1b or Pde3b aggravated the development of PKD and was associated with higher levels of protein kinase A–phosphorylated (Ser133) cAMP–responsive binding protein (P-CREB), activating transcription factor-1, and CREB–induced CRE modulator proteins in kidney nuclear preparations. Immunostaining also revealed higher expression of P-CREB in Pkd2−/ WS25 ; Pde1a −/− , Pkd2− /WS25 ; Pde1c −/− , and Pkd2−/ WS25 ; Pde3a −/− kidneys. The cystogenic effect of desmopressin administration was markedly enhanced in Pkd2 −/WS25 ; Pde3a −/− mice, despite PDE3 accounting for only a small fraction of renal cAMP PDE activity. These observations show that calcium- and calmodulin-dependent PDEs ( PDE1A and PDE1C ) and PDE3A modulate the development of PKD, possibly through the regulation of compartmentalized cAMP pools that control cell proliferation and CFTR–driven fluid secretion. Treatments capable of increasing the expression or activity of these PDEs may, therefore, retard the development of PKD.

Abstract Background First identified as an estrogen-inducible gene in a breast cancer cell line, LIV-1 is a multispan transmembrane protein of the solute-carrier family 39 with putative zinc transporter and metalloproteinase activity. As a downstream target of STAT3, it promotes the epithelial-to-mesenchymal transition that is important in the malignant progression to metastasis. LIV-1 is expressed in a number of cancers with the highest prevalence and level of expression in breast, prostate, and melanoma. Additionally, LIV-1 has been linked with malignant progression to metastasis and associated with lymph node involvement in breast cancer. Normal tissue expression is predominantly limited to hormonally regulated tissues, including breast and prostate. In metastatic breast cancer tissue samples, the current validated immunohistochemistry assay for LIV-1 has detected moderate to high expression in 82% of samples tested, with 88% positivity in hormone receptor-positive tumors and 73% in triple-negative tumors. SGN-LIV1A is an antibody-drug conjugate (ADC) composed of a humanized anti-LIV-1 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. In vitro, SGN-LIV1A shows target-specific internalization and cytotoxic activity against LIV-1-positive neoplastic cell lines. Significant dose-dependent tumor regression was demonstrated in mouse xenograft models. Methods The primary objective of this first-in-human phase 1, open label, multicenter study is to evaluate the safety and tolerability, and to identify the maximum tolerated dose of SGN-LIV1A using a 3+3 dose-escalation study design. Pharmacokinetics, immunogenicity, and antitumor activity will also be evaluated (ClinicalTrials.gov #NCT01969643). Enrollment to this US-based trial began in late 2013. Eligible patients are adult females who have hormone receptor-positive/HER2-negative or triple-negative metastatic breast cancer. Tumor tissue must be positive for expression of LIV-1 per central assessment. Patients must have received at least 2 prior cytotoxic regimens in the metastatic setting and have measurable disease per RECIST v1.1. Pre-existing neuropathy ≥ Grade 2 is not permitted. SGN-LIV1A is administered intravenously every 3 weeks at protocol-defined doses starting at 0.5 mg/kg. Patients who achieve an objective response or stable disease per RECIST v1.1 are eligible to continue treatment until disease progression. At the completion of dose escalation, expansion cohorts may be opened to enroll patients with specific breast cancer subtypes to further define safety and antitumor activity. Tumor biopsies are being obtained at baseline and after one cycle of treatment to evaluate the role of LIV-1 expression, target saturation, and other tumor-specific measurements in the antitumor activity of SGN-LIV1A. Citation Format: Andres Forero, Howard Burris III, Patricia LoRusso, Jennifer Specht, Kathy Miller, Monica Mita, Minetta C Liu, Shanu Modi, Lajos Pusztai, Django Sussman, Ana Kostic. SGN-LIV1A: A phase 1 trial evaluating a novel antibody-drug conjugate in patients with LIV-1-positive breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT2-3-01.

Key Points Thalidomide and prednisone maintenance after transplantation improves progression-free but not overall survival.