bluuebunny/crossref_metadata_2025 huggingface dataset:
CPAP Treatment Adherence in Women with Obstructive Sleep Apnea
Authors: Libman E. , Bailes S. , Fichten C. S. , Rizzo D. , Creti L. , Baltzan M. , Grad R. , Pavilanis A. , Tran D.-L. , Conrod K. , Amsel R.
Published: March 2017

Untreated obstructive sleep apnea (OSA) has numerous negative health-related consequences. Continuous positive airway pressure (CPAP) is generally considered the treatment of choice for OSA, but rates of nonadherence are high. It is believed that OSA is more prevalent among men; therefore understanding how OSA presents among women is limited and treatment adherence has received little research attention. For this study, 29 women were recruited from primary care offices. They completed a questionnaire battery and underwent a night of nocturnal polysomnography (PSG) followed by a visit with a sleep specialist. Women diagnosed with OSA were prescribed CPAP; 2 years later CPAP adherence was evaluated. Results show that approximately half the sample was adherent. There were no significant differences between adherent and nonadherent women on OSA severity; however CPAP adherent women had worse nocturnal and daytime functioning scores at the time of diagnosis. Moreover, when the seven nocturnal and daytime variables were used as predictors in a discriminant analysis, they could predict 87% of adherent and 93% of the nonadherent women. The single most important predictor was nonrefreshing sleep. We discuss the implications of the findings for identifying women in primary care with potential OSA and offer suggestions for enhancing treatment adherence.
An Approach to Developing Local Climate Change Environmental Public Health Indicators in a Rural District
Authors: Houghton Adele , Austin Jessica , Beerman Abby , Horton Clayton
Published: March 2017

Climate change represents a significant and growing threat to population health. Rural areas face unique challenges, such as high rates of vulnerable populations; economic uncertainty due to their reliance on industries that are vulnerable to climate change; less resilient infrastructure; and lower levels of access to community and emergency services than urban areas. This article fills a gap in public health practice by developing climate and health environmental public health indicators for a local public health department in a rural area. We adapted the National Environmental Public Health Tracking Network’s framework for climate and health indicators to a seven-county health department in Western Kentucky. Using a three-step review process, we identified primary climate-related environmental public health hazards for the region (extreme heat, drought, and flooding) and a suite of related exposure, health outcome, population vulnerability, and environmental vulnerability indicators. Indicators that performed more poorly at the county level than at the state and national level were defined as “high vulnerability.” Six to eight high vulnerability indicators were identified for each county. The local health department plans to use the results to enhance three key areas of existing services: epidemiology, public health preparedness, and community health assessment.
A Different Perspective for Management of Diabetes Mellitus: Controlling Viral Liver Diseases
Authors: Zhao Yingying , Xing Huichun
Published: March 2017

Knowing how to prevent and treat diabetes mellitus (DM) earlier is essential to improving outcomes. Through participating in synthesis and catabolism of glycogen, the liver helps to regulate glucose homeostasis. Viral related liver diseases are associated with glycometabolism disorders, which means effective management of viral liver diseases may be a therapeutic strategy for DM. The present article reviews the correlation between DM and liver diseases to give an update of the management of DM rooted by viral liver diseases.
Antioxidative and Anti‐Inflammatory Activities of Galloyl Derivatives and Antidiabetic Activities of Acer ginnala
Authors: Park Kwan Hee , Yoon Kyu Hyeong , Yin Jun , Le Thi Tam , Ahn Hye Sin , Yoon Seong Hye , Lee Min Won
Published: March 2017

Chromatographic isolation of the 80% MeOH extract of Acer ginnala (AG) yielded seven galloyl derivatives: gallic acid (1), ginnalin B (2), acertannin (3), maplexin D (4), maplexin E (5), quercetin‐3‐O‐(2′′‐galloyl)‐α‐L‐rhamnopyranoside (6), and kaempferol‐3‐O‐(2′′‐galloyl)‐α‐L‐rhamnopyranoside (7). This is the first study to report the isolation of compounds 4 and 5 from AG. Galloyl derivatives 3–7 exhibited potent radical scavenging activities, with 5 and 7 showing particularly strong inhibitory activities against nitric oxide production in lipopolysaccharides‐ (LPS‐) stimulated RAW264.7 cells. In addition, oral administration of AG extract (500 mg/kg b.w.) improved symptoms of hyperglycemia and blunted the increases in serum GOT/GPT levels in a rat model of streptozotocin‐induced diabetes. These results suggest that galloyl derivatives (1–7) are antioxidant and anti‐inflammatory agents and that AG extract has potential as a functional material or novel herbal medicine for treating diabetes mellitus.
Efficient Data Mining Algorithms for Screening Potential Proteins of Drug Target
Authors: Wang Qi , Huang JinCai , Feng YangHe , Fei JiaWei
Published: March 2017

The past few decades have witnessed the boom in pharmacology as well as the dilemma of drug development. Playing a crucial role in drug design, the screening of potential human proteins of drug targets from open access database with well‐measured physical and chemical properties is a task of challenge but significance. In this paper, the screening of potential drug target proteins (DTPs) from a fine collected dataset containing 5376 unlabeled proteins and 517 known DTPs was researched. Our objective is to screen potential DTPs from the 5376 proteins. Here we proposed two strategies assisting the construction of dataset of reliable nondrug target proteins (NDTPs) and then bagging of decision trees method was employed in the final prediction. Such two‐stage algorithms have shown their effectiveness and superior performance on the testing set. Both of the algorithms maintained higher recall ratios of DTPs, respectively, 93.5% and 97.4%. In one turn of experiments, strategy1‐based bagging of decision trees algorithm screened about 558 possible DTPs while 1782 potential DTPs were predicted in the second algorithm. Besides, two strategy‐based algorithms showed the consensus of the predictions in the results, with approximately 442 potential DTPs in common. These selected DTPs provide reliable choices for further verification based on biomedical experiments.
IL33 Promotes Colon Cancer Cell Stemness via JNK Activation and Macrophage Recruitment
Authors: Fang Min , Li Yongkui , Huang Kai , Qi Shanshan , Zhang Jian , Zgodzinski Witold , Majewski Marek , Wallner Grzegorz , Gozdz Stanislaw , Macek Pawel , Kowalik Artur , Pasiarski Marcin , Grywalska Ewelina , Vatan Linda , Nagarsheth Nisha , Li Wei , Zhao Lili , Kryczek Ilona , Wang Guobin , Wang Zheng , Zou Weiping , Wang Lin
Published: March 2017

The expression and biological role of IL33 in colon cancer is poorly understood. In this study, we show that IL33 is expressed by vascular endothelial cells and tumor cells in the human colon cancer microenvironment. Administration of human IL33 and overexpression of murine IL33 enhanced human and murine colon cancer cell growth in vivo, respectively. IL33 stimulated cell sphere formation and prevented chemotherapy-induced tumor apoptosis. Mechanistically, IL33 activated core stem cell genes NANOG, NOTCH3, and OCT3/4 via the ST2 signaling pathway, and induced phosphorylation of c-Jun N terminal kinase (JNK) activation and enhanced binding of c-Jun to the promoters of the core stem cell genes. Moreover, IL33 recruited macrophages into the cancer microenvironment and stimulated them to produce prostaglandin E2, which supported colon cancer stemness and tumor growth. Clinically, tumor IL33 expression associated with poor survival in patients with metastatic colon cancer. Thus, IL33 dually targets tumor cells and macrophages and endows stem-like qualities to colon cancer cells to promote carcinogenesis. Collectively, our work reveals an immune-associated mechanism that extrinsically confers cancer cell stemness properties. Targeting the IL33 signaling pathway may offer an opportunity to treat patients with metastatic cancer. Cancer Res; 77(10); 2735–45. ©2017 AACR.
NR1D1 Recruitment to Sites of DNA Damage Inhibits Repair and Is Associated with Chemosensitivity of Breast Cancer
Authors: Ka Na-Lee , Na Tae-Young , Na Hyelin , Lee Min-Ho , Park Han-Su , Hwang Sewon , Kim Il Yong , Seong Je Kyung , Lee Mi-Ock
Published: March 2017

DNA repair capacity is critical for survival of cancer cells upon therapeutic DNA damage and thus is an important determinant of susceptibility to chemotherapy in cancer patients. In this study, we identified a novel function of nuclear receptor NR1D1 in DNA repair, which enhanced chemosensitivity in breast cancer cells. NR1D1 inhibited both nonhomologous end joining and homologous recombination double-strand breaks repair, and delayed the clearance of γH2AX DNA repair foci that formed after treatment of doxorubicin. PARylation of NR1D1 by PARP1 drove its recruitment to damaged DNA lesions. Deletion of the ligand binding domain of NR1D1 that interacted with PARP1, or treatment of 6-(5H)-phenanthridinone, an inhibitor of PARP1, suppressed the recruitment of NR1D1 to DNA damaged sites, indicating PARylation as a critical step for the NR1D1 recruitment. NR1D1 inhibited recruitment of the components of DNA damage response complex such as SIRT6, pNBS1, and BRCA1 to DNA lesions. Downregulation of NR1D1 in MCF7 cells resulted in resistance to doxorubicin, both in vitro and in vivo. Analysis of four public patient data sets indicated that NR1D1 expression correlates positively with clinical outcome in breast cancer patients who received chemotherapy. Our findings suggest that NR1D1 and its ligands provide therapeutic options that could enhance the outcomes of chemotherapy in breast cancer patients. Cancer Res; 77(9); 2453–63. ©2017 AACR.
Defining Cancer Subpopulations by Adaptive Strategies Rather Than Molecular Properties Provides Novel Insights into Intratumoral Evolution
Authors: Ibrahim-Hashim Arig , Robertson-Tessi Mark , Enriquez-Navas Pedro M. , Damaghi Mehdi , Balagurunathan Yoganand , Wojtkowiak Jonathan W. , Russell Shonagh , Yoonseok Kam , Lloyd Mark C. , Bui Marilyn M. , Brown Joel S. , Anderson Alexander R.A. , Gillies Robert J. , Gatenby Robert A.
Published: March 2017

Ongoing intratumoral evolution is apparent in molecular variations among cancer cells from different regions of the same tumor, but genetic data alone provide little insight into environmental selection forces and cellular phenotypic adaptations that govern the underlying Darwinian dynamics. In three spontaneous murine cancers (prostate cancers in TRAMP and PTEN mice, pancreatic cancer in KPC mice), we identified two subpopulations with distinct niche construction adaptive strategies that remained stable in culture: (i) invasive cells that produce an acidic environment via upregulated aerobic glycolysis; and (ii) noninvasive cells that were angiogenic and metabolically near-normal. Darwinian interactions of these subpopulations were investigated in TRAMP prostate cancers. Computer simulations demonstrated invasive, acid-producing (C2) cells maintain a fitness advantage over noninvasive, angiogenic (C3) cells by promoting invasion and reducing efficacy of immune response. Immunohistochemical analysis of untreated tumors confirmed that C2 cells were invariably more abundant than C3 cells. However, the C2 adaptive strategy phenotype incurred a significant cost due to inefficient energy production (i.e., aerobic glycolysis) and depletion of resources for adaptations to an acidic environment. Mathematical model simulations predicted that small perturbations of the microenvironmental extracellular pH (pHe) could invert the cost/benefit ratio of the C2 strategy and select for C3 cells. In vivo, 200 mmol/L NaHCO3 added to the drinking water of 4-week-old TRAMP mice increased the intraprostatic pHe by 0.2 units and promoted proliferation of noninvasive C3 cells, which remained confined within the ducts so that primary cancer did not develop. A 0.2 pHe increase in established tumors increased the fraction of C3 cells and signficantly diminished growth of primary and metastatic tumors. In an experimental tumor construct, MCF7 and MDA-MB-231 breast cancer cells were coinjected into the mammary fat pad of SCID mice. C2-like MDA-MB-231 cells dominated in untreated animals, but C3-like MCF7 cells were selected and tumor growth slowed when intratumoral pHe was increased. Overall, our data support the use of mathematical modeling of intratumoral Darwinian interactions of environmental selection forces and cancer cell adaptive strategies. These models allow the tumor to be steered into a less invasive pathway through the application of small but selective biological force. Cancer Res; 77(9); 2242–54. ©2017 AACR.
Effective Cancer Risk Communication to Prevent Disparities in the Era of Precision Medicine
Authors: Joseph G , Pasick RJ , Schillinger D , Luce J , Cheng JKY , Guerra C
Published: March 2017

As genetics and genomics become part of mainstream Medicine, these advances have the potential to reduce or exacerbate health disparities. Gaps in effective communication (where all parties share the same meaning) are widely recognized as a major contributor to health disparities. The purpose of this study was to examine cancer genetic counselor-patient communication, to assess its effectiveness from the patient perspective, and to pilot intervention strategies to improve it. We used multiple inductive methods, including standard ethnographic techniques to systematically observe and audio-record genetic counseling sessions, and qualitative interviews with observed patients using the audio recordings to stimulate recall and probe specific aspects of the communication. Data analyses were conducted using grounded theory. We observed 64 English-, 35 Spanish- and 25 Cantonese- speaking public hospital patients (n = 124) and 10 Genetic Counselors in 170 appointments, and interviewed 49 patients who had been offered testing. We identified a fundamental mismatch between the information provided by genetic counselors and the information desired and meaningful to patients. Several components of the communication that contributed to this mismatch and often resulted in ineffective communication included: (1) too much information; (2) complex terminology and conceptually difficult presentation of information; (3) information perceived as not relevant by the patient; (4) unintentional inhibition of patient engagement and question-asking; (5) vague discussions of screening and prevention recommendations. To address these communication barriers, we adapted from other fields of Medicine to the genetic counseling context and pilot tested evidence-based strategies for effective communication with limited literacy patients. Our findings indicate a need to transform the standard model of hereditary cancer risk communication. The increasing access of diverse populations to genetic services, high rates of limited health literacy in the US, and growing complexity of genetic information have created a perfect storm. If not directly addressed, this convergence can be expected to exacerbate health disparities in the genomic age.
Identifying Patient Smoking History for Cessation and Lung Cancer Screening through Mining Electronic Health Records
Authors: Onega T , Nutter EL , Sargent J , Doherty JA , Hassanpour S
Published: March 2017

Electronic health records (EHRs) contain information about tobacco use, but smoking status and history are often inadequately captured, resulting in missed opportunities for smoking cessation intervention and lung cancer screening decision-making. Informatics methods can improve ascertainment of smoking behaviors through development of a tobacco use registry from EHRs. Methods: Using structured data and free text from our local EHR, we developed two support vector machine (SVM) models to classify smoking status (never, former, current) and smoking history (never, pack-years, cigarettes per day, years smoked). We trained and tested these models on 758 clinical notes from the Epic-based EHR of the Dartmouth-Hitchcock health system; the training set had 479 notes and the test set 280. Notes were eligible if a patient was: ≥21 years old with a clinical encounter in the EHR from 1/1/15-9/1/16. We assessed the models' performance through precision (probability that retrieved element is relevant), recall (probability that relevant element is retrieved), and the F1-score (harmonic mean of precision and recall). We also tested the models on publicly available data from the National Centers for Biomedical Computing (i2b2) Results: Of the 280 test records, 22% were current smokers, 19% former, and 59% never smokers. Accuracy assessment of our models showed: precision = 68% and recall = 85% for smoking status and for smoking history; precision = 66% and recall = 94%. The F1-scores for smoking status and history were 65% and 74%, respectively. The majority of correctly classified smokers also had one or more smoking history element ascertained with our model. Of those individuals correctly classified as never smokers (n = 98) only two were misclassified as having a smoking history. When testing our models on i2b2 data, our F1-score was 92%. Review of misclassified records indicates that deep learning refinements to our current machine learning approach will improve performance measures. Conclusion: Machine learning models applied to our Epic EHR consistently identifies smoking history. Creating a tobacco use registry from the EHR is feasible and with advanced algorithms, will help target patients for cancer control efforts, such as smoking cessation and lung cancer screening.
Premenopausal Breast Cancer: Exercise and Leukocyte Telomere Length
Authors: Oakley-Girvan I , Pitteri S , Canchola A , Sellmeyer D , Palesh O , Stewart S , Hsieh C-L , Bloom J
Published: March 2017

Leukocyte telomere length (LTL) may function as a marker of health, the immune system and cancer survival. We evaluated whether premenopausal breast cancer survivors (PBCS) that successfully increased exercise levels also increased LTL. This study is the first to describe LTLs in a population-based sample of PBCS before and after an exercise intervention. We analyzed LTL before and after the Exercise for Bone Health Intervention, a randomized, controlled trial of 273 premenopausal women 55 years of age or younger at diagnosis that started the intervention within 2 years of receipt of initial chemotherapy. This pilot analysis included 60 women with the greatest increase in exercise from pre to post intervention. Those with longer LTLs at pre-intervention (PRE) had LTLs that grew shorter during the study, however, they still had longer LTLs at post-intervention (POST) than those who started with shorter LTLs. The group whose LTLs shortened the most during the study were those with longer LTLs and more exercise at PRE, ANOVA across four levels P = 0.030. In multivariable regression models of LTL change adjusted for age and LTL at PRE, factors that were independently associated with LTLs that became shorter were older age (P = 0.017), longer telomeres at PRE (P = 0.0004), higher levels of exercise (P = 0.013), higher income (P = 0.011), feeling down-hearted and blue (P = 0.003), higher levels of sociability (P = 0.015), more chronic medical conditions (P = 0.018), and higher levels of insulin-like grown factor-1 at POST (P = 0.003). While this is a pilot sub-study and requires additional confirmation, we postulate that women accustomed to exercising and being highly sociable pre-diagnosis may have experienced a greater impact on their lifestyles post-diagnosis resulting in a more rapid rate of LTL shortening. We hypothesize that time to return to LTL homeostasis for YBCS may be dependent upon a combination of physical health and psychosocial networks pre and post diagnosis and the immune system may be an important modifier. Further studies combining new technology to improve the capture of exercise and psychosocial well-being, and monitor levels of inflammation are needed to determine whether lifestyle interventions can be used to impact biomarkers of health in YBCS.
FDA Drug Approval: Elotuzumab in Combination with Lenalidomide and Dexamethasone for the Treatment of Relapsed or Refractory Multiple Myeloma
Authors: Gormley Nicole J. , Ko Chia-Wen , Deisseroth Albert , Nie Lei , Kaminskas Edvardas , Kormanik Natasha , Goldberg Kirsten B. , Farrell Ann T. , Pazdur Richard
Published: March 2017

On November 30, 2015, the FDA approved elotuzumab (Empliciti; Bristol-Myers Squibb) in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who received one to three prior therapies. FDA approval was based primarily on the results of a phase III, randomized, open-label, multicenter trial, CA204004, which evaluated elotuzumab in combination with lenalidomide and dexamethasone (E-Ld) compared with lenalidomide and dexamethasone (Ld) alone in patients with relapsed or refractory multiple myeloma. Coprimary endpoints were progression-free survival (PFS) and overall response rate (ORR). The key secondary endpoint was overall survival, but these data were not mature at the time of clinical database cutoff. The trial demonstrated a statistically significant improvement in PFS, with an estimated HR of 0.70 for E-Ld over Ld [95% confidence interval (CI), 0.57–0.85; P = 0.0004). Estimated median PFS was 19.4 months in the E-Ld arm and 14.9 months in the Ld arm. ORR was 75.8% in the E-Ld arm compared with 65.5% in the Ld arm. Serious adverse reactions were reported in 65% of patients in the E-Ld arm compared with 57% in the Ld arm. The FDA approved elotuzumab with the following warnings and precautions: infusion reactions, infections, second primary malignancies, hepatotoxicity, and interference with the determination of complete response. Clin Cancer Res; 23(22); 6759–63. ©2017 AACR.
Role of Autophagy in Angiogenesis Induced by a High-Glucose Condition in RF/6A Cells
Authors: Du Jun-Hui , Li Xia , Li Rong , Cheng Bai-Xiang , Kuerbanjiang Manzila , Ma Le
Published: March 2017

Purpose: To study the effect of autophagy on vitality, migration, and tube formation of RF/6A cells under the condition of D-glucose. Methods: Cultured RF/6A cells were randomly divided into 4 groups (control, low glucose, high glucose, and high glucose with 3-methyladenine [3-MA]). Autophagy-related proteins (Atg7, p62, and LC3) were monitored. Cell vitality, cell migration, tube formation, reactive oxygen species (ROS) production, and apoptosis were assessed. Results: Cell vitality significantly decreased and cell migration and tube formation significantly increased in the high-glucose group (p < 0.05). Pretreatment with 3-MA significantly increased cell viability and inhibited cell migration and tube formation (p < 0.05). ROS production increased in the high-glucose group and decreased in the high-glucose with N-acetylcysteine (NAC) group (p < 0.05). The level of apoptosis increased in the high-glucose group, while it was reduced in the high-glucose with 3-MA group. Conclusion: Autophagy maybe participates in the formation of retinal neovascularization induced by high glucose.
Autoimmune Diabetes and Thyroiditis Complicating Treatment with Nivolumab
Authors: Li Li , Masood Awais , Bari Shahla , Yavuz Sahzene , Grosbach Alan B.
Published: March 2017

Programmed cell death-1 (PD-1) ligand inhibitors have gained popularity in the treatment of advanced non-small-cell lung cancer. The immune system is regulated by stimulatory and inhibitory signaling and aims to achieve the balance between activation and inhibition. Treatment with immune checkpoint inhibitors enhances immune response, but is also known to diminish immune tolerance and increase autoimmune toxicity. Here we present a case of a patient with advanced squamous cell lung cancer who developed type I diabetes and thyroiditis after treatment with PD-1 checkpoint inhibitor nivolumab. The presence of autoimmune diabetes mellitus and thyroiditis were confirmed by markedly elevated titers of the glutamic acid decarboxylase autoantibody and thyroid peroxidase antibody, respectively. This report serves to heighten awareness of potential autoimmune toxicities related to anti-PD-1 therapy, especially as these toxicities are manageable if identified in a timely manner.
Clinical Presentation of Cutaneous Leishmaniasis caused by Leishmania major
Authors: Remadi Latifa , Haouas Najoua , Chaara Dhekra , Slama Darine , Chargui Najla , Dabghi Radhia , Jbeniani Henda , Mezhoud Habib , Babba Hamouda
Published: March 2017

Background/Aims: The diagnosis of cutaneous leishmaniasis (CL) is based on the microscopic detection of amastigote, isolation of the parasite, or the detection of Leishmania DNA. Nevertheless, since these techniques are time consuming and not usually available in many endemic countries, the diagnosis remains clinical. Consequently, such disease may be overlooked because of its similarity to other skin diseases. The aim of this study is to describe the clinical polymorphism of CL caused by Leishmaniamajor.Methods: A cross-sectional survey was carried out on 166 patients. Diagnoses were made by both microscopic examination of stained tissue-scraping smears and PCR. The Leishmania species was identified by restriction enzyme analysis of the ribosomal internal transcribed spacer 1 region. The clinical polymorphism was analyzed only for patients with a positive diagnosis for CL and L. major as the identified species. Results and Conclusion: Of the 166 patients, 75 patients fit the inclusion criteria. Twelve different types of CL caused by L. major were defined. The most common type was the ulcero-crusted form followed by the papulonodular form and the impetigenous form. The ulcerated, mucocutaneous, lupoid, and sporotricoid forms were less common. The eczematiform, erysipeloid, verrucous, psoriasiform, and pseudotumoral types were represented by a single case. Zoonotic CL caused by L. major can simulate many other skin diseases, which may lead to a significant spread of this disease and increases in morbidity and drug resistance. This large polymorphism may be the result of a complex association between the genetics of the parasite and the immune response of the host.
Discontinuation of Peritoneal Dialysis after Late Initiation of Eculizumab in a Case of Familial Atypical Hemolytic-Uremic Syndrome: A Case Report
Authors: Alonso Valente Rafael , García Rodríguez Giannina Elena , García Marcote Yanina , Fidalgo Díaz Manuel , Becerra Mosquera Vanesa , Novoa García Daniel , Cordal Martínez Teresa , Díaz Rodríguez Cándido
Published: March 2017

Background: Atypical hemolytic-uremic syndrome is caused by a thrombotic microangiopathy and manifests itself with hemolytic anemia, thrombocytopenia, and organ ischemia. Its etiology is a mutation affecting the genes encoding for proteins of the complement system. Early treatment with eculizumab (8.6 months from the moment of presentation), a humanized monoclonal antibody against complement, is shown to be effective in controlling symptoms and reversing organ damage. We present a patient with a mutation not previously described in the literature. Late treatment with eculizumab resulted in a good therapeutic response, eliminating the need for peritoneal dialysis. Case Presentation: A 34-year-old woman showed symptoms and laboratory findings consistent with atypical hemolytic-uremic syndrome. Genetic analysis revealed an unusual mutation of the complement regulatory gene not seen previously. Due to unavailability of eculizumab at the time of presentation, conventional treatment was started with poor response. Late initiation of eculizumab resulted in discontinuation of peritoneal dialysis and yielded a good and sustained clinical response. Conclusions: This case shows that eculizumab treatment for patients with atypical hemolytic-uremic syndrome, even when initiated many months after beginning on dialysis, might offer substantial benefits and improve the patients’ quality of life.
Isodicentric Philadelphia Chromosome: A Rare Chromosomal Aberration in Imatinib-Resistant Chronic Myelogenous Leukemia Patients - Case Report with Review of the Literature
Authors: Ramachandran Krishna C. , Narayanan Geetha , Nair Sreejith G. , Thambi Sugeeth M. , Kamala Lekshmi H. , Gopinath Preethi , Sreedharan Hariharan
Published: March 2017

The BCR-ABL1 fusion gene derived from the Philadelphia chromosome, resulting from a classical translocation event t(9;22)(q34.13;q11.23), is responsible for the pathogenesis of chronic myeloid leukemia (CML) in more than 90% of the patients. The isoderivative chromosome 22, ider(22), and relative amplification or duplication of the BCR-ABL1 gene have been considered as one of the major reasons associated with the resistance to chemotherapy with imatinib mesylate, but the data remain unclear. GTG-banding together with FISH were performed to identify the presence of the ider(22) chromosome. Reverse transcription-polymerase chain reaction (RT-PCR) for the detection of BCR-ABL1 fusion transcripts and BCR-ABL1 kinase domain mutation analysis were carried out in this study. Conventional and molecular cytogenetic analysis on metaphase chromosomes confirmed the presence of ider(22) chromosomes in both patients. Molecular characterization revealed the presence of a 210-kDa BCR-ABL1 type b3a2 and lack of mutations at the kinase domain region on the fusion product in both patients. The occurrence of the ider(22) chromosome could be considered as an important marker correlated with the aggressive progression of CML as well as the emergence of drug-resistant cell clones.
Xp22.31 Microdeletion due to Microhomology-Mediated Break-Induced Replication in a Boy with Contiguous Gene Deletion Syndrome
Authors: Nagai Koki , Shima Hirohito , Kamimura Miki , Kanno Junko , Suzuki Erina , Ishiguro Akira , Narumi Satoshi , Kure Shigeo , Fujiwara Ikuma , Fukami Maki
Published: March 2017

The Xp22.31 region is characterized by a low frequency of interspersed repeats and a low GC content. Submicroscopic deletions at Xp22.31 involving STS and ANOS1 (alias KAL1) underlie X-linked ichthyosis and Kallmann syndrome, respectively. Of the known microdeletions at Xp22.31, a common approximately 1.5-Mb deletion encompassing STS was ascribed to nonallelic homologous recombination, while 2 ANOS1-containing deletions were attributed to nonhomologous end-joining. However, the genomic bases of other microdeletions within the Xp22.31 region remain to be elucidated. Here, we identified a 2,735,696-bp deletion encompassing STS and ANOS1 in a boy with X-linked ichthyosis and Kallmann syndrome. The breakpoints of the deletion were located within Alu repeats and shared 2-bp microhomology. The fusion junction was not associated with nucleotide stretches, and the breakpoint-flanking regions harbored no palindromes or noncanonical DNA motifs. These results indicate that microhomology-mediated break-induced replication (MMBIR) can cause deletions at Xp22.31, resulting in contiguous gene deletion syndrome. It appears that interspersed repeats without other known rearrangement-inducing DNA features or high GC contents are sufficient to stimulate MMBIR at Xp22.31.
Disease Progression Modeling to Evaluate the Effects of Enzyme Replacement Therapy on Kidney Function in Adult Patients with the Classic Phenotype of Fabry Disease
Authors: Nowak Albina , Koch Gilbert , Huynh-Do Uyen , Siegenthaler Martin , Marti Hans-Peter , Pfister Marc
Published: March 2017

Background/Aims: Fabry disease (FD) is a rare inherited lysosomal storage disease with common and serious kidney complications. Enzyme replacement therapies (ERT) with agalsidase-α and -β were investigated to characterize their therapeutic effect on kidney function in FD patients with Classic phenotype. Methods: The prospective FD cohort consisted of 98 genetically confirmed patients (females, n = 61, males, n = 37). The median [interquartile range] follow-up time (time difference from first to last visit) was 9 [6, 12] years. The median age of ERT start was 36 [21 – 54] years for females and 39 [28 – 49] years for males. Results: A disease progression model was developed to (i) characterize the time course of estimated glomerular filtration rate (eGFR) and (ii) evaluate therapeutic effects of ERT on kidney function. Change in eGFR over time was best described by the linear model. Females had stable kidney function with and without ERT (eGFR slopes of -0.07 ml/min/1.73m^2 per year and 0.52 ml/min/1.73m^2 per year, respectively). Males with ERT showed an eGFR decrease of -3.07 ml/min/1.73m^2 per year. Conclusion: Mathematical disease progression modeling indicates that there is no clear therapeutic effect of ERT on kidney function in adult patients with Classic Phenotype of FD. Interpretation of these findings should take into account that the study is not randomized and lacks a placebo controlled group. Further investigations are warranted to clarify whether earlier ERT initiation before 18 years of age, higher ERT dose or more intensive therapies can preserve kidney function.
Microarray Analysis Reveals Increased Expression of Matrix Metalloproteases and Cytokines of Interleukin-20 Subfamily in the Kidneys of Neonate Rats Underwent Unilateral Ureteral Obstruction: A Potential Role of IL-24 in the Regulation of Inflammation and Tissue Remodeling
Authors: Pap Domonkos , Sziksz Erna , Kiss Zoltán , Rokonay Réka , Veres-Székely Apor , Lippai Rita , Takács István Márton , Kis Éva , Fekete Andrea , Reusz György , Vannay Adam , Szabó Attila J.
Published: March 2017

Background/Aims: Congenital obstructive nephropathy (CON) is the main cause of pediatric chronic kidney diseases leading to renal fibrosis. High morbidity and limited treatment opportunities of CON urge the better understanding of the underlying molecular mechanisms. Methods: To identify the differentially expressed genes, microarray analysis was performed on the kidney samples of neonatal rats underwent unilateral ureteral obstruction (UUO). Microarray results were then validated by real-time RT-PCR and bioinformatics analysis was carried out to identify the relevant genes, functional groups and pathways involved in the pathomechanism of CON. Renal expression of matrix metalloproteinase (MMP)-12 and interleukin (IL)-24 were evaluated by real-time RT-PCR, flow cytometry and immunohistochemical analysis. Effect of the main profibrotic factors on the expression of MMP-12 and IL-24 was investigated on HK-2 and HEK-293 cell lines. Finally, the effect of IL-24 treatment on the expression of pro-inflammatory cytokines and MMPs were tested in vitro. Results: Microarray analysis revealed 880 transcripts showing >2.0-fold change following UUO, enriched mainly in immune response related processes. The most up-regulated genes were MMPs and members of IL-20 cytokine subfamily, including MMP-3, MMP-7, MMP-12, IL-19 and IL-24. We found that while TGF-β treatment inhibits the expression of MMP-12 and IL-24, H2O2 or PDGF-B treatment induce the epithelial expression of MMP-12. We demonstrated that IL-24 treatment decreases the expression of IL-6 and MMP-3 in the renal epithelial cells. Conclusions: This study provides an extensive view of UUO induced changes in the gene expression profile of the developing kidney and describes novel molecules, which may play significant role in the pathomechanism of CON.
Distinctive expression signatures of serum microRNAs in ischaemic stroke and transient ischaemic attack patients
Authors: Wang Cheng , Song Jia-xi , Lv Qiu-shi , Pan Hao , Zhang Chun-ni , Wu Jia , Fan Chun-li , Ma Li-juan , Liu Ting , Wang Jun-jun
Published: March 2017

Circulating microRNAs (miRNAs) have recently emerged as promising biomarkers for ischaemic stroke (IS). However, the expression patterns of specific miRNAs in transient ischaemic attack (TIA) patients have not been investigated. Their predictive values for the presence of IS and TIA and their relationships to the neurological deficit severity of IS and the subsequent stroke risk after TIA remain unclear exactly. In this study, 754 miRNAs were initially screened by the TaqMan Low Density Array (TLDA) in two pooled serum samples from 50 IS patients and 50 controls. Markedly altered miRNAs were subsequently validated by individual quantitative reverse-transcription PCR (qRT-PCR) assays first in the same cohort of TLDA and further confirmed in another larger cohort including 177 IS, 81 TIA patients and 42 controls. Consequently, TLDA screening showed that 71 miRNAs were up-regulated and 49 miRNAs were down-regulated in IS patients. QRT-PCR validation confirmed that serum levels of miR-23b-3p, miR-29b-3p, miR-181a-5p and miR-21–5p were significantly increased in IS patients. Strikingly, serum levels of miR-23b-3p, miR-29b-3p and miR-181a-5p were also significantly elevated in TIA patients. Furthermore, up-regulated miR-23b-3p, miR-29b-3p and miR-21–5p could clearly differentiate between IS and TIA patients. Logistic regression and receiver-operating characteristic curve analyses demonstrated that these altered miRNAs may function as predictive and discriminative biomarkers for IS and TIA, and their distinctive expression signatures may contribute to assessing neurological deficit severity of IS and subsequent stroke risk after TIA.

Supplementary Material to this article is available online at www.thrombosis-online.com.
Identification of a functional genetic variant driving racially dimorphic platelet gene expression of the thrombin receptor regulator, PCTP
Authors: Kong Xianguo , Simon Lukas , Holinstat Michael , Shaw Chad , Bray Paul , Edelstein Leonard
Published: March 2017

Platelet activation in response to stimulation of the Protease Activated Receptor 4 (PAR4) receptor differs by race. One factor that contributes to this difference is the expression level of Phosphatidylcholine Transfer Protein (PCTP), a regulator of platelet PAR4 function. We have conducted an expression Quantitative Trait Locus (eQTL) analysis that identifies single nucleotide polymorphisms (SNPs) linked to the expression level of platelet genes. This analysis revealed 26 SNPs associated with the expression level of PCTP at genome-wide significance (p < 5×10–8). Using annotation from ENCODE and other public data we prioritised one of these SNPs, rs2912553, for functional testing. The allelic frequency of rs2912553 is racially-dimorphic, in concordance with the racially differential expression of PCTP. Reporter gene assays confirmed that the single nucleotide change caused by rs2912553 altered the transcriptional potency of the surrounding genomic locus. Electromobility shift assays, luciferase assays, and overexpression studies indicated a role for the megakaryocytic transcription factor GATA1. In summary, we have integrated multi-omic data to identify and functionalise an eQTL. This, along with the previously described relationship between PCTP and PAR4 function, allows us to characterise a genotype-phenotype relationship through the mechanism of gene expression.
Mortality and cancer after 12 versus 30 months dual antiplatelet therapy
Authors: Cabrera-Fuentes Hector , Lee Kwangmin , Cho Young , Park Kyungil , Park Tae , Kim Young , Yoon Sung-Cheol , Serebruany Victor , Kim Moo
Published: March 2017

The optimal duration and cancer risks of antiplatelet therapy following percutaneous coronary intervention (PCI) are unclear. We compared cancer and all-cause mortality after dual antiplatelet therapy (DAPT) for the combination of clopidogrel and aspirin (ASA) versus ASA alone over 18 months follow-up in event-free patients at 12 months DAPT from the Health Insurance Review and Assessment (HIRA) dataset via the Korean Outcomes Registry Evaluating Antithrombotics (KOREA). We selected PCI patients who were event free for 12 months and maintained a consistent antiplatelet regimen for 18 more months. The primary endpoints were any cancer and all-cause mortality at 30 months follow-up after PCI. From 320,351 screened post-PCI patient HIRA records, we excluded 294,413 and qualified 25,938, constituting DAPT (n=10,992) and ASA (n=14,946) groups. The Propensity Score Matching (PSM), and Inverse Probability of Treatment Weighting (IPTW) revealed no significant differences in background demographics and clinical characteristics for DAPT versus ASA patients. At 30-months post-PCI, after massive (>91 %) exclusions, cancer risk was higher for continuous DAPT [455 (4.15 %) vs 606 (4.04 %); HR=1.221; 95 %CI: 1.061–1.405; p=0.005], which remained significant by PSM (p=0.006) or IPTW (p=0.007), while all-cause mortality was similar [136 (1.24 %) vs 192 (1.28 %) HR=0.999; 95 %CI: 0.736–1.135; p=0.993]. This analysis suggests a potential mild excess cancer risk, but no mortality benefit in Korean post-PCI patients treated with DAPT for an additional 18 months beyond conventional 12 months DAPT. These data are not supporting continuing DAPT for more than one year in East Asians. Analysing cancer types and assessing potential cancer association with bleeding are warranted.
Quality of Care at Hospitals Identified as Outliers in Publicly Reported Mortality Statistics for Percutaneous Coronary Intervention
Authors: Waldo Stephen W. , McCabe James M. , Kennedy Kevin F. , Zigler Corwin M. , Pinto Duane S. , Yeh Robert W.
Published: March 2017

Background:

Public reporting of percutaneous coronary intervention (PCI) outcomes may create disincentives for physicians to provide care for critically ill patients, particularly at institutions with worse clinical outcomes. We thus sought to evaluate the procedural management and in-hospital outcomes of patients treated for acute myocardial infarction before and after a hospital had been publicly identified as a negative outlier.

Methods:

Using state reports, we identified hospitals that were recognized as negative PCI outliers in 2 states (Massachusetts and New York) from 2002 to 2012. State hospitalization files were used to identify all patients with an acute myocardial infarction within these states. Procedural management and in-hospital outcomes were compared among patients treated at outlier hospitals before and after public report of outlier status. Patients at nonoutlier institutions were used to control for temporal trends.

Results:

Among 86 hospitals, 31 were reported as outliers for excess mortality. Outlier facilities were larger, treating more patients with acute myocardial infarction and performing more PCIs than nonoutlier hospitals (
P
<0.05 for each). Among 507 672 patients with acute myocardial infarction hospitalized at these institutions, 108 428 (21%) were treated at an outlier hospital after public report. The likelihood of PCI at outlier (relative risk [RR], 1.13; 95% confidence interval [CI], 1.12–1.15) and nonoutlier institutions (RR, 1.13; 95% CI, 1.11–1.14) increased in a similar fashion (interaction
P
=0.50) after public report of outlier status. The likelihood of in-hospital mortality decreased at outlier institutions (RR, 0.83; 95% CI, 0.81–0.85) after public report, and to a lesser degree at nonoutlier institutions (RR, 0.90; 95% CI, 0.87–0.92; interaction
P
<0.001). Among patients that underwent PCI, in-hospital mortality decreased at outlier institutions after public recognition of outlier status in comparison with prior (RR, 0.72; 9% CI, 0.66–0.79), a decline that exceeded the reduction at nonoutlier institutions (RR, 0.87; 95% CI, 0.80–0.96; interaction
P
<0.001).

Conclusions:

Large hospitals with higher clinical volume are more likely to be designated as negative outliers. The rates of percutaneous revascularization increased similarly at outlier and nonoutlier institutions after report of outlier status. After outlier designation, in-hospital mortality declined at outlier institutions to a greater extent than was observed at nonoutlier facilities.
Time in Therapeutic Range and Outcomes After Warfarin Initiation in Newly Diagnosed Atrial Fibrillation Patients With Renal Dysfunction
Authors: Szummer Karolina , Gasparini Alessandro , Eliasson Staffan , Ärnlöv Johan , Qureshi Abdul Rashid , Bárány Peter , Evans Marie , Friberg Leif , Carrero Juan Jesus
Published: March 2017

Background

It is unknown whether renal dysfunction conveys poor anticoagulation control in warfarin‐treated patients with atrial fibrillation and whether poor anticoagulation control associates with the risk of adverse outcomes in these patients.

Methods and Results

This was an observational study from the Stockholm CREatinine Measurements (SCREAM) cohort including all newly diagnosed atrial fibrillation patients initiating treatment with warfarin (n=7738) in Stockholm, Sweden, between 2006 and 2011. Estimated glomerular filtration rate (eGFR; mL/min per 1.73 m
2
) was calculated from serum creatinine. Time‐in‐therapeutic range (TTR) was assessed from international normalized ratio (INR) measurements up to warfarin cessation, adverse event, or end of follow‐up (2 years). Adverse events considered a composite of intracranial hemorrhage, ischemic stroke, myocardial infarction, or death. During median 254 days, TTR was 83%, based on median 21 INR measurements per patient. TTR was 70% among patients with eGFR <30, around 10% lower than in those with normal renal function. During observation, adverse events occurred in 4.0% of patients, and those with TTR ≤75% were at higher adverse event risk. This was independent of patient characteristics, comorbidities, number of INR tests, days exposed to warfarin, and, notably, independent of eGFR: adjusted odds ratio (OR) 1.84 (95% CI, 1.41–2.40) for TTR 75% to 60% and adjusted OR 2.09 (1.59–2.74) for TTR <60%. No interaction was observed between eGFR and TTR in association to adverse events (
P
=0.2).

Conclusion

Severe chronic kidney disease (eGFR <30) patients with atrial fibrillation have worse INR control while on warfarin. An optimal TTR (>75%) is associated with lower risk of adverse events, independently of underlying renal function.
Individual Differences and Long-term Consequences of tDCS-augmented Cognitive Training
Authors: Katz Benjamin , Au Jacky , Buschkuehl Martin , Abagis Tessa , Zabel Chelsea , Jaeggi Susanne M. , Jonides John
Published: March 2017

A great deal of interest surrounds the use of transcranial direct current stimulation (tDCS) to augment cognitive training. However, effects are inconsistent across studies, and meta-analytic evidence is mixed, especially for healthy, young adults. One major source of this inconsistency is individual differences among the participants, but these differences are rarely examined in the context of combined training/stimulation studies. In addition, it is unclear how long the effects of stimulation last, even in successful interventions. Some studies make use of follow-up assessments, but very few have measured performance more than a few months after an intervention. Here, we utilized data from a previous study of tDCS and cognitive training [Au, J., Katz, B., Buschkuehl, M., Bunarjo, K., Senger, T., Zabel, C., et al. Enhancing working memory training with transcranial direct current stimulation. Journal of Cognitive Neuroscience, 28, 1419–1432, 2016] in which participants trained on a working memory task over 7 days while receiving active or sham tDCS. A new, longer-term follow-up to assess later performance was conducted, and additional participants were added so that the sham condition was better powered. We assessed baseline cognitive ability, gender, training site, and motivation level and found significant interactions between both baseline ability and motivation with condition (active or sham) in models predicting training gain. In addition, the improvements in the active condition versus sham condition appear to be stable even as long as a year after the original intervention.