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Most vertebrates, including cartilaginous fishes, maintain their plasma SO42−concentration ([SO42−]) within a narrow range of 0.2–1 mM. As seawater has a [SO42−] about 40 times higher than that of the plasma, SO42−excretion is the major role of kidneys in marine teleost fishes. It has been suggested that cartilaginous fishes also excrete excess SO42−via the kidney. However, little is known about the underlying mechanisms for SO42−transport in cartilaginous fish, largely due to the extraordinarily elaborate four-loop configuration of the nephron, which consists of at least 10 morphologically distinguishable segments. In the present study, we determined cDNA sequences from the kidney of holocephalan elephant fish ( Callorhinchus milii) that encoded solute carrier family 26 member 1 (Slc26a1) and member 6 (Slc26a6), which are SO42−transporters that are expressed in mammalian and teleost kidneys. Elephant fish Slc26a1 (cmSlc26a1) and cmSlc26a6 mRNAs were coexpressed in the proximal II (PII) segment of the nephron, which comprises the second loop in the sinus zone. Functional analyses using Xenopus oocytes and the results of immunohistochemistry revealed that cmSlc26a1 is a basolaterally located electroneutral SO42−transporter, while cmSlc26a6 is an apically located, electrogenic Cl−/SO42−exchanger. In addition, we found that both cmSlc26a1 and cmSlc26a6 were abundantly expressed in the kidney of embryos; SO42−was concentrated in a bladder-like structure of elephant fish embryos. Our results demonstrated that the PII segment of the nephron contributes to the secretion of excess SO42−by the kidney of elephant fish. Possible mechanisms for SO42−secretion in the PII segment are discussed.

Abstract Picornaviruses have emerged as promising cancer therapies due to their ability to drive cytotoxic cellular immune responses and for promoting oncolysis. These properties include preferential replication in tumor cells, the induction of strong innate and adaptive immune responses, and the ease with which their genomes can be manipulated. We have developed Theiler's murine encephalomyelitis virus (TMEV) as an immunotherapy vector that promotes strong adaptive immune responses to tumor antigens embedded within its genome. To further explore its usefulness as cancer therapy, we investigated whether direct intratumoral delivery of TMEV could promote tumor regression. We generated several picornavirus hybrids using substrains of TMEV that have unique immunopathologic characteristics, despite their extensive sequence homology. These hybrids exhibit a unique propensity to infect and replicate in melanoma. We have identified GD7-KS1, a virus that is particularly effective at replicating and infecting B16 melanoma in vitro and provides benefit as an oncolytic therapy in vivo after intratumoral injection. In addition, this virus promotes the mobilization and accumulation of CD8+ T cells within treated tumors. Altogether, these findings demonstrate that picornavirus substrains can be used to rationally design virus hybrids that promote antitumor responses and add to the known strategies identified by us and others to further enhance the therapeutic potential of vectors used to treat cancer. Mol Cancer Ther; 15(3); 523–30. ©2016 AACR.

ObjectivesTo investigate the utility and safety of the GuideLiner “mother‐and‐child” catheter system during transradial and transfemoral percutaneous coronary intervention (PCI).BackgroundIn patients with complex coronary anatomy, stent delivery can be challenging and result in procedural failure and complications. The GuideLiner is a coaxial guide extension system designed to enable deep vessel engagement and facilitate device delivery. The purpose of this study was to evaluate procedural success and safety in a series of GuideLiner‐facilitated PCI.MethodsSingle center retrospective study of PCI utilizing the GuideLiner catheter between February 2010 and October 2014. Patients who underwent PCI without GuideLiner use during the same time period were used as controls for comparison.ResultsA total of 363 cases of GuideLiner‐facilitated PCI were identified from 6,088 unique PCI procedures performed during this same time period. Patients in the GuideLiner group were older (mean age 71.5 vs. 67.8, P < 0.001) and had more multivessel disease (72% vs. 63%, P = 0.001) compared with controls. Type C lesions were present in 78% of GuideLiner cases. Procedural success resulting in successful device delivery with the GuideLiner catheter was 80.2%. Stent deformation associated with GuideLiner use occurred in 2.2% (8/363), with the incidence of this complication decreasing over device iterations. Coronary dissection attributed to GuideLiner occurred in 3.3% (12/363) and became less frequent over the study period.ConclusionsIn this consecutive series of GuideLiner supported PCI, the guide extension system enabled procedural success in the majority. A decline in device‐associated complications over time may be attributed to operator learning curve, patient selection, and improvement in catheter design. © 2015 Wiley Periodicals, Inc.

ObjectivesTo determine the feasibility of automated co‐registration of angiography and intravascular ultrasound (IVUS) to facilitate integration of these two imaging modalities in a synchronous manner.BackgroundIVUS provides cross‐sectional imaging of coronary arteries but lacks overview of the vascular territory provided by angiography. Co‐registration of angiography and IVUS would increase utility of IVUS in the clinical setting.MethodsForty‐nine consecutive patients undergoing surveillance for cardiac allograft vasculopathy with angiography and IVUS of the left anterior descending artery (LAD) were enrolled. A pre‐IVUS angiogram of the LAD was performed followed by an ECG‐triggered fluoroscopy (ECGTF) during IVUS pullback at 0.5 mm/s using an automatic pullback device. ECGTF was used to track the IVUS catheter during pullback and establish a spatial relationship to the pre‐IVUS angiogram. Angio‐IVUS co‐registration was performed with a research prototype (Siemens Healthcare, Germany) and accuracy was evaluated by distance mismatch between angiography and IVUS images at vessel bifurcations.ResultsMedian age was 54 (44.5, 67) years. The population was 82.6% male with minimal risk factors. The median (IQR) co‐registration distance mismatch measured at 108 bifurcations in 42 (85%) patients was 0.35 (0.00–1.16) mm. Seven patients were excluded due to inappropriate data acquisition (n = 3) and failure of tracking (n = 4), e.g., due to overlapping sternal wires. Estimated effective radiation dose for ECGTF was 0.09 mSv.ConclusionThis study demonstrates the feasibility of angio‐IVUS co‐registration which may be used as a clinical tool for localizing IVUS cross‐sections along an angiographic roadmap. © 2015 Wiley Periodicals, Inc.

Abstract Purpose: p38 MAPK regulates the production of cytokines in the tumor microenvironment and enables cancer cells to survive despite oncogenic stress, radiotherapy, chemotherapy, and targeted therapies. Ralimetinib (LY2228820 dimesylate) is a selective small-molecule inhibitor of p38 MAPK. This phase I study aimed to evaluate the safety and tolerability of ralimetinib, as a single agent and in combination with tamoxifen, when administered orally to patients with advanced cancer. Experimental Design: The study design consisted of a dose-escalation phase performed in a 3+3 design (Part A; n = 54), two dose-confirmation phases [Part B at 420 mg (n = 18) and Part C at 300 mg (n = 8)], and a tumor-specific expansion phase in combination with tamoxifen for women with hormone receptor–positive metastatic breast cancer refractory to aromatase inhibitors (Part D; n = 9). Ralimetinib was administered orally every 12 hours on days 1 to 14 of a 28-day cycle. Results: Eighty-nine patients received ralimetinib at 11 dose levels (10, 20, 40, 65, 90, 120, 160, 200, 300, 420, and 560 mg). Plasma exposure of ralimetinib (Cmax and AUC) increased in a dose-dependent manner. After a single dose, ralimetinib inhibited p38 MAPK–induced phosphorylation of MAPKAP-K2 in peripheral blood mononuclear cells. The most common adverse events, possibly drug-related, included rash, fatigue, nausea, constipation, pruritus, and vomiting. The recommended phase II dose was 300 mg every 12 hours as monotherapy or in combination with tamoxifen. Although no patients achieved a complete response or partial response,19 patients (21.3%) achieved stable disease with a median duration of 3.7 months, with 9 of these patients on study for ≥6 cycles. Conclusions: Ralimetinib demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer. Clin Cancer Res; 22(5); 1095–102. ©2015 AACR.

AbstractBackgroundOverexpression of p16 is associated with improved outcomes among patients with oropharyngeal carcinoma. However, its role in the outcomes of patients with nasopharyngeal cancer (NPC) remains unclear.MethodsEighty‐six patients with NPC treated at MD Anderson Cancer Center from 2000 to 2014 were identified. Epstein‐Barr virus (EBV) and human papillomavirus (HPV) status were determined by in situ hybridization (ISH) and p16 by immunohistochemical staining.ResultsEBV positivity was associated with extended overall survival (OS; median, 95.0 vs 44.9 months; p < .004), progression‐free survival (PFS; median, 80.4 vs 28.1 months; p < .013), and locoregional control (median, 104.4 vs 65.5 months; p < .043). In patients with EBV‐positive tumors, p16 overexpression correlated with improved PFS (median, 106.3 vs 27.1 months; p < .02) and locoregional control (median, 93.6 vs 64.5 months; p < .02).ConclusionP16 overexpression is associated with improved PFS and locoregional control in patients with EBV‐positive NPC. P16 expression may complement EBV status in predicting treatment outcomes for patients with NPC. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1459–E1466, 2016

This article provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward.