Risk factors for the first and second inappropriate implantable cardioverter-defibrillator therapy

Introduction: Various risk factors for the first inappropriate implantable cardioverter-defibrillator (ICD) therapy event have been reported, including a history of atrial fibrillation/atrial flutter (AF/AFL), younger age, and multiple zones. Nonetheless, which factors are concordant with real-world data has not been clarified, and risk factors for the second inappropriate ICD therapy event have not been well examined. This study aimed to clarify the risk factors for the first and second inappropriate ICD therapy events. Methods: We conducted a post-hoc secondary analysis of data from a multicenter, prospective observational study (the Nippon Storm Study) designed to clarify the risk factors for electrical storm. Results: The analysis included data from 1549 patients who received ICD or cardiac resynchronization therapy with defibrillator (CRT-D). Over a median follow-up of 28 months, 293 inappropriate ICD therapy events occurred in 153 (10.0%) patients. On multivariate Cox regression analysis, the risk factors for the first inappropriate ICD therapy event were younger age (hazard ratio [HR], 0.986; p = 0.028), AF/AFL (HR, 2.324; p = 0.002), ICD without CRT implantation (HR, 2.377; p = 0.004), and multiple zones (HR, 1.852; p = 0.010). "No-intervention" after the first inappropriate ICD therapy event was the sole risk factor for the second inappropriate ICD therapy event. Conclusions: Risk factors for the first inappropriate ICD therapy event were similar to those previously reported. Immediate intervention after the first inappropriate ICD therapy event could reduce the risk of the second inappropriate event

Non-destructively differentiating the roles of creep, wear and oxidation in long-term in vivo exposed polyethylene cups

Wear of polyethylene acetabular cups in patients of total hip arthroplasty is routinely deduced from the penetration of the femoral head into the acetabular liner as observed in the radiographs. However, the linear penetration thus measured represents the cumulative contribution of two components, one due to wear, and the other due to creep or irreversible deformation of the polyethylene structure. The erroneous attribution to wear of the entire penetration displacement of the head in the cup might lead to misinterpretation of the actual performance of acetabular cups. The aim of this study was to quantify the head displacement components due to wear and to creep, as they occur in vivo in acetabular cups, and to relate them to the oxidation state of the material by means of advanced Raman spectroscopy procedures. Throughout the investigation, we compared the behaviors on the molecular scale of acetabular cups subjected to different sterilization methods (i.e., gamma-irradiation and ethylene oxide treatment). (C) Koninklijke Brill NV, Leiden, 201

Nuclear Hormone Receptor Expression in Mouse Kidney and Renal Cell Lines

Nuclear hormone receptors (NHRs) are transcription factors that regulate carbohydrate and lipid metabolism, immune responses, and inflammation. Although several NHRs, including peroxisome proliferator-activated receptor-γ (PPARγ) and PPARα, demonstrate a renoprotective effect in the context of diabetic nephropathy (DN), the expression and role of other NHRs in the kidney are still unrecognized. To investigate potential roles of NHRs in the biology of the kidney, we used quantitative real-time polymerase chain reaction to profile the expression of all 49 members of the mouse NHR superfamily in mouse kidney tissue (C57BL/6 and db/m), and cell lines of mesangial (MES13), podocyte (MPC), proximal tubular epithelial (mProx24) and collecting duct (mIMCD3) origins in both normal and high-glucose conditions. In C57BL/6 mouse kidney cells, hepatocyte nuclear factor 4α, chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) and COUP-TFIII were highly expressed. During hyperglycemia, the expression of the NHR 4A subgroup including neuron-derived clone 77 (Nur77), nuclear receptor-related factor 1, and neuron-derived orphan receptor 1 significantly increased in diabetic C57BL/6 and db/db mice. In renal cell lines, PPARδ was highly expressed in mesangial and proximal tubular epithelial cells, while COUP-TFs were highly expressed in podocytes, proximal tubular epithelial cells, and collecting duct cells. High-glucose conditions increased the expression of Nur77 in mesangial and collecting duct cells, and liver x receptor α in podocytes. These data demonstrate NHR expression in mouse kidney cells and cultured renal cell lines and suggest potential therapeutic targets in the kidney for the treatment of DN

Prognostic significance of nonsustained ventricular tachycardia in patients receiving cardiac resynchronization therapy for primary prevention: Analysis of the Japan cardiac device treatment registry database

BackgroundWhether nonsustained ventricular tachycardia (NSVT) is a marker of increased risk of sustained ventricular tachyarrhythmias (VTAs) remains to be established in patients receiving cardiac resynchronization therapy with a defibrillator (CRT‐D) for primary prevention.MethodsAmong the follow‐up data of the Japan cardiac device treatment registry (JCDTR) with an implantation date between January 2011 and August 2015, information regarding a history of NSVT before the CRT‐D implantation for primary prevention had been registered in 269 patients. Outcomes were compared between two groups with and without NSVT: NSVT group (n = 179) and No NSVT group (n = 90).ResultsThere was no significant difference with regard to age, gender, and NYHA class between the two groups. Left ventricular ejection fraction (LVEF) was 25.6% in the NSVT group and 28.0% in the No NSVT group (P = .046). The rate of appropriate therapy at 24 months was 26.0% and 18.4% in the NSVT and No NSVT groups (P = .22), respectively. Survival free from heart failure death was reduced in the NSVT group, as compared with the No NSVT group, with the rate of 90.2% vs 97.2% at 24 months (P = .030). A multivariate analysis identified a history of NSVT, anemia, and no use of angiotensin‐converting enzyme inhibitor (ACEI) or angiotensin‐receptor blocker (ARB) as predictors of heart failure death.ConclusionsNSVT appears to be a surrogate marker of severe heart failure rather than a substrate for subsequent sustained VTAs in patients with CRT‐D for primary prevention

Sequence of the Gonium pectorale mating locus reveals a complex and dynamic history of changes in volvocine algal mating haplotypes

Citation: Hamaji, T., Mogi, Y., Ferris, P. J., Mori, T., Miyagishima, S., Kabeya, Y., . . . Nozaki, H. (2016). Sequence of the Gonium pectorale mating locus reveals a complex and dynamic history of changes in volvocine algal mating haplotypes. G3: Genes, Genomes, Genetics, 6(5), 1179-1189. doi:10.1534/g3.115.026229Additional Authors: Nozaki, H.Sex-determining regions (SDRs) or mating-type (MT) loci in two sequenced volvocine algal species, Chlamydomonas reinhardtii and Volvox carteri, exhibit major differences in size, structure, gene content, and gametolog differentiation. Understanding the origin of these differences requires investigation of MT loci from related species. Here, we determined the sequences of the minus and plus MT haplotypes of the isogamous 16-celled volvocine alga, Gonium pectorale, which is more closely related to the multicellular V. carteri than to C. reinhardtii. Compared to C. reinhardtiiMT, G. pectoraleMT is moderately larger in size, and has a less complex structure, with only two major syntenic blocs of collinear gametologs. However, the gametolog content of G. pectoraleMT has more overlap with that of V. carteriMT than with C. reinhardtiiMT, while the allelic divergence between gametologs in G. pectorale is even lower than that in C. reinhardtii. Three key sex-related genes are conserved in G. pectorale MT: GpMID and GpMTD1 in MT-, and GpFUS1 in MT+. GpFUS1 protein exhibited specific localization at the plus-gametic mating structure, indicating a conserved function in fertilization. Our results suggest that the G. pectorale-V. carteri common ancestral MT experienced at least one major reformation after the split from C. reinhardtii, and that the V. carteri ancestral MT underwent a subsequent expansion and loss of recombination after the divergence from G. pectorale. These data begin to polarize important changes that occurred in volvocine MT loci, and highlight the potential for discontinuous and dynamic evolution in SDRs. © 2016 Hamaji et al

Detection of epidermal growth factor receptor mutations in exhaled breath condensate using droplet digital polymerase chain reaction

The detection of certain oncogenic driver mutations, including those of epidermal growth factor receptor (EGFR), is essential for determining treatment strategies for advanced non‑small cell lung cancer (NSCLC). The current study assessed the feasibility of testing exhaled breath condensate (EBC) for EGFR mutations by droplet digital PCR (ddPCR). Samples were collected from 12 patients with NSCLC harboring EGFR mutations that were admitted to Okayama University Hospital between June 1, 2014 and December 31, 2017. A total of 21 EBC samples were collected using the RTube™ method and EGFR mutations (L858R, exon 19 deletions or T790M) were assessed through ddPCR analysis (EBC‑ddPCR). A total of 3 healthy volunteer samples were also tested to determine a threshold value for each mutation. Various patient characteristics were determined, including sex (3 males and 9 females), age (range 54‑81 years; median, 66 years), smoking history (10 had never smoked; 2 were former smokers), histology (12 patients exhibited adenocarcinoma), clinical stage (9 patients were stage IV; 3 exhibited post‑operative recurrence) and EGFR mutation type (4 had L858R; 8 had exon 19 deletions; 8 had T790M). EBC‑ddPCR demonstrated positive droplets in 8 of the 12 patients. The sensitivity and specificity of each mutation was as follows: 27.3 and 80.0% for EGFR L858R, 30.0 and 90.9% for EGFR Ex19del, and 22.2 and 100% for EGFR T790M. EBC‑ddPCR analysis of EGFR mutations exhibited modest sensitivity and acceptable specificity. EBC‑ddPCR is a minimally invasive and replicable procedure and may be a complementary method for EGFR testing in patients where blood or tissue sampling proves difficult

Rapid Acquisition of Alectinib Resistance in ALK-Positive Lung Cancer With High Tumor Mutation Burden

Introduction The highly selective ALK receptor tyrosine kinase (ALK) inhibitor alectinib is standard therapy for ALK-positive lung cancers; however, some tumors quickly develop resistance. Here, we investigated the mechanism associated with rapid acquisition of resistance using clinical samples. Methods Autopsied samples were obtained from lung, liver, and renal tumors from a 51-year-old male patient with advanced ALK-positive lung cancer who had acquired resistance to alectinib in only 3 months. We established an alectinib-resistant cell line (ABC-14) from pleural effusion and an alectinib/crizotinib-resistant cell line (ABC-17) and patient-derived xenograft (PDX) model from liver tumors. Additionally, we performed next-generation sequencing, direct DNA sequencing, and quantitative real-time reverse transcription polymerase chain reaction. Results ABC-14 cells harbored no ALK mutations and were sensitive to crizotinib while also exhibiting MNNG HOS transforming gene (MET) gene amplification and amphiregulin overexpression. Additionally, combined treatment with crizotinib/erlotinib inhibited cell growth. ABC-17 and PDX tumors harbored ALK G1202R, and PDX tumors metastasized to multiple organs in vivo, whereas the third-generation ALK-inhibitor, lorlatinib, diminished tumor growth in vitro and in vivo. Next-generation sequencing indicated high tumor mutation burden and heterogeneous tumor evolution. The autopsied lung tumors harbored ALK G1202R (c. 3604 G>A) and the right renal metastasis harbored ALK G1202R (c. 3604 G>C); the mutation thus comprised different codon changes. Conclusions High tumor mutation burden and heterogeneous tumor evolution might be responsible for rapid acquisition of alectinib resistance. Timely lorlatinib administration or combined therapy with an ALK inhibitor and other receptor tyrosine-kinase inhibitors might constitute a potent strategy

VEGFR2 blockade augments the effects of tyrosine kinase inhibitors by inhibiting angiogenesis and oncogenic signaling in oncogene-driven non-small-cell lung cancers

Molecular agents targeting the epidermal growth factor receptor (EGFR)-, anaplastic lymphoma kinase (ALK)- or c-ros oncogene 1 (ROS1) alterations have revolutionized the treatment of oncogene-driven non-small-cell lung cancer (NSCLC). However, the emergence of acquired resistance remains a significant challenge, limiting the wider clinical success of these molecular targeted therapies. In this study, we investigated the efficacy of various molecular targeted agents, including erlotinib, alectinib, and crizotinib, combined with anti-vascular endothelial growth factor receptor (VEGFR) 2 therapy. The combination of VEGFR2 blockade with molecular targeted agents enhanced the anti-tumor effects of these agents in xenograft mouse models of EGFR-, ALK-, or ROS1-altered NSCLC. The numbers of CD31-positive blood vessels were significantly lower in the tumors of mice treated with an anti-VEGFR2 antibody combined with molecular targeted agents compared with in those of mice treated with molecular targeted agents alone, implying the antiangiogenic effects of VEGFR2 blockade. Additionally, the combination therapies exerted more potent antiproliferative effects in vitro in EGFR-, ALK-, or ROS1-altered NSCLC cells, implying that VEGFR2 inhibition also has direct anti-tumor effects on cancer cells. Furthermore, VEGFR2 expression was induced following exposure to molecular targeted agents, implying the importance of VEGFR2 signaling in NSCLC patients undergoing molecular targeted therapy. In conclusion, VEGFR2 inhibition enhanced the anti-tumor effects of molecular targeted agents in various oncogene-driven NSCLC models, not only by inhibiting tumor angiogenesis but also by exerting direct antiproliferative effects on cancer cells. Hence, combination therapy with anti-VEGFR2 antibodies and molecular targeted agents could serve as a promising treatment strategy for oncogene-driven NSCLC