bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract IA14: Lessons from modeling neural tumors in mice
Authors: Xie Xuan-Hua , Alcantara Sheila , Laks Dan , Shi Yufeng , Parada Luis F.
Published: May 2018

We have used genetically engineered mouse models to study GBM. In particular, through mutation of glioma relevant genes (P53; Pten; Nf1) we have examined the scope of the cell of origin for these tumors. We find that as cells in the adult neural stem cell lineage progress, their capacity to undergo glioma formation is largely compromised though cellular phenotypes arise as a consequence of mutation. We find that in the subventricular zone, only quiescent stem cells and early progenitors can readily form GBM following mutation. Our search for additional cells of origin has further identified additional source cells for these tumors. GBM can arise from the OPC lineage following the same mutations, and these tumors have a distinct signature that can be identified among the TCGA GBM data sets. Thus the cell of origin is constrained to stem-like cells and tumor characteristics include signatures revealing the lineage of origin. We have further examined the properties of tumor growth and transplantation and find that these tumors grow in hierarchical fashion with a relatively small and quiescent cell population at the apex. These “cancer stem cells” can be identified and isolated. New single-cell sequencing technology promises to reveal many previous secrets from these cells. Understanding how a stem cell transforms into a cancer stem cell may provide novel approaches for therapeutic targeting.

Citation Format: Xuan-Hua Xie, Sheila Alcantara, Dan Laks, Yufeng Shi, Luis F. Parada. Lessons from modeling neural tumors in mice [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr IA14.
Abstract PR11: Investigating lung cancer cells-of-origin using three-dimensional organoid cultures
Authors: Wong Kwok-Kin , Kim Carla , Brainson Christine Fillmore
Published: May 2018

There are many distinct epithelial cell types in the adult lung that could give rise to non-small cell lung cancer. These cell types include tracheal basal stem cells, tracheal club cells, distal lung bronchioalveolar stem cells (BASCs), and distal lung alveolar type 2 cells (AT2). My laboratory is using mouse models to test directly which lung stem and progenitor cells are most fit to serve as cells-of-origin of lung adenocarcinoma and lung squamous cell carcinoma. Previously, we demonstrated that tracheal club cells and BASCs are the likely cells-of-origin for KRASG12D; Lkb1-null adenosquamous tumors. The same strategy is now being used to test which cells can give rise to adenocarcinomas using the LSL:EGFRT90M/L858R (LSL=lox-stop-lox) mouse strain, or squamous cell carcinoma using the Lkb1flox/flox; Ptenflox/flox mouse strain. Briefly, tracheas and lungs from Cre-naïve mice are enzymatically dissociated, and fluorescence activated cell sorting (FACS) is used to enrich for four distinct populations: NGFR+/Sca1+ tracheal basal cells, NGFR-/Sca1+ tracheal club cells, Sca1+ distal lung BASCs, and Sca1- distal lung AT2 cells. Each population is then incubated with either adeno-GFP control virus or adeno-Cre virus to induce EGFR T790M/L858R expression or delete both alleles of Lkb1 and Pten. Three dimensional air-liquid-interface cultures are then used to expand the populations as organoids. For EGFR organoids, both basal and club cells give rise to larger, faster-growing bronchiolar organoids after EGFR is induced. AT2 cells similarly give rise to much larger alveolar organoids after EGFR induction, and BASCs change from giving rise to both bronchiolar and alveolar organoids to nearly exclusively alveolar. For Lkb1/Pten organoids, all four populations can tolerate deletion of the two genes, but it is only the basal cell and club cell organoids that progress to a squamous morphology in vitro. While both BASC and AT2 organoids continue to grow, they appear phenotypically normal. Transplant assays to assess malignancy and RNA-seq and ChIP-seq studies to explore gene transcription and epigenetic changes are under way. These experiments will shed light on the cells of the adult lung that give rise to genotype-specific tumors, and will aid us to better classify lung cancer heterogeneity from a cell-of-origin perspective.

Citation Format: Kwok-Kin Wong, Carla Kim, Christine Fillmore Brainson. Investigating lung cancer cells-of-origin using three-dimensional organoid cultures [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr PR11.
Subcellular Localization of Antigen in Keratinocytes Dictates Delivery of CD4+ T-cell Help for the CTL Response upon Therapeutic DNA Vaccination into the Skin
Authors: Bąbała Nikolina , Bovens Astrid , de Vries Evert , Iglesias-Guimarais Victoria , Ahrends Tomasz , Krummel Matthew F. , Borst Jannie , Bins Adriaan D.
Published: May 2018

In a mouse model of therapeutic DNA vaccination, we studied how the subcellular localization of vaccine protein impacts antigen delivery to professional antigen-presenting cells and efficiency of CTL priming. Cytosolic, membrane-bound, nuclear, and secretory versions of ZsGreen fluorescent protein, conjugated to MHC class I and II ovalbumin (OVA) epitopes, were expressed in keratinocytes by DNA vaccination into the skin. ZsGreen-OVA versions reached B cells in the skin-draining lymph node (dLN) that proved irrelevant for CTL priming. ZsGreen-OVA versions were also actively transported to the dLN by dendritic cells (DC). In the dLN, vaccine proteins localized to classical (c)DCs of the migratory XCR1+ and XCR− subtypes, and—to a lesser extent—to LN-resident cDCs. Secretory ZsGreen-OVA induced the best antitumor CTL response, even though its delivery to cDCs in the dLN was significantly less efficient than for other vaccine proteins. Secretory ZsGreen-OVA protein proved superior in CTL priming, because it led to in vivo engagement of antigen-loaded XCR1+, but not XCR1−, cDCs. Secretory ZsGreen-OVA also maximally solicited CD4+ T-cell help. The suboptimal CTL response to the other ZsGreen-OVA versions was improved by engaging costimulatory receptor CD27, which mimics CD4+ T-cell help. Thus, in therapeutic DNA vaccination into the skin, mere inclusion of helper epitopes does not ensure delivery of CD4+ T-cell help for the CTL response. Targeting of the vaccine protein to the secretory route of keratinocytes is required to engage XCR1+ cDC and CD4+ T-cell help and thus to promote CTL priming. Cancer Immunol Res; 6(7); 835–47. ©2018 AACR.
IL22 Promotes Kras-Mutant Lung Cancer by Induction of a Protumor Immune Response and Protection of Stemness Properties
Authors: Khosravi Nasim , Caetano Mauricio S. , Cumpian Amber M. , Unver Nese , De la Garza Ramos Cynthia , Noble Oscar , Daliri Soudabeh , Hernandez Belinda J. , Gutierrez Berenice A. , Evans Scott E. , Hanash Samir , Alekseev Andrei M. , Yang Yi , Chang Seon Hee , Nurieva Roza , Kadara Humam , Chen Jichao , Ostrin Edwin J. , Moghaddam Seyed Javad
Published: May 2018

Somatic KRAS mutations are the most common oncogenic variants in lung cancer and are associated with poor prognosis. Using a Kras-induced lung cancer mouse model, CC-LR, we previously showed a role for inflammation in lung tumorigenesis through activation of the NF-κB pathway, along with induction of interleukin 6 (IL6) and an IL17-producing CD4+ T-helper cell response. IL22 is an effector molecule secreted by CD4+ and γδ T cells that we previously found to be expressed in CC-LR mice. IL22 mostly signals through the STAT3 pathway and is thought to act exclusively on nonhematopoietic cells with basal IL22 receptor (IL22R) expression on epithelial cells. Here, we found that higher expression of IL22R1 in patients with KRAS-mutant lung adenocarcinoma was an independent indicator of poor recurrence-free survival. We then showed that genetic ablation of Il22 in CC-LR mice (CC-LR/IL22KO mice) caused a significant reduction in tumor number and size. This was accompanied by significantly lower tumor cell proliferation, angiogenesis, and STAT3 activation. Il22 ablation was also associated with significant reduction in lung-infiltrating inflammatory cells and expression of protumor inflammatory cytokines. Conversely, this was accompanied with increased antitumor Th1 and cytotoxic CD8+ T-cell responses, while suppressing the protumor immunosuppressive T regulatory cell response. In CC-LR/IL22KO mice, we found significantly reduced expression of core stemness genes and the number of prototypical SPC+CCSP+ stem cells. Thus, we conclude that IL22 promotes Kras-mutant lung tumorigenesis by driving a protumor inflammatory microenvironment with proliferative, angiogenic, and stemness contextual cues in epithelial/tumor cells. Cancer Immunol Res; 6(7); 788–97. ©2018 AACR.
Comparison between Nonmydriatic Spectral Domain Optical Coherence Tomography and Conventional Ophthalmologic Examination in Detecting Adult Macular Pathology
Authors: Mehanna Carl-Joe , Abdul Fattah Maamoun , Ghazi Nicola , Sheheitli Huda , Haddad Sandra S. , Haddad Randa S. , Salti Haytham I.
Published: May 2018

Objective: To compare nonmydriatic spectral domain optical coherence tomography (NMOCT) to comprehensive ophthalmologic evaluation (COE) in detecting adult macular abnormalities. Methods: This is a single-reader observational pilot study of adults older than 50 years with no known ophthalmologic problems to assess the correlation between NMOCT and COE in detecting macular abnormalities classified as epiretinal, intraretinal, subretinal, or a combination thereof. Subjects underwent NMOCT of the macula followed by COE which included a dilated fundus examination and ancillary tests as needed. Results: A total of 771 eyes of 406 patients were included. Cohen’s kappa coefficient of agreement between NMOCT and COE for detecting any abnormality was high (0.90, p < 0.0001), with NMOCT having an overall sensitivity of 82.65% and specificity of 98.97%. Sensitivities and specificities of NMOCT in detecting each category of macular abnormalities were as follows: epiretinal (86.36%, 99.73%), intraretinal (80.00%, 99.58%), and subretinal (88.89%, 99.73%), respectively. Conclusion: NMOCT is a promising tool for detecting adult macular abnormalities.
Intrauterine Growth Restriction Affects Cerebellar Granule Cells in the Developing Guinea Pig Brain
Authors: Tolcos Mary , McDougall Annie , Shields Amy , Chung Yoonyoung , O’Dowd Rachael , Turnley Ann , Wallace Megan , Rees Sandra
Published: May 2018

Intrauterine growth restriction (IUGR) can lead to adverse neurodevelopmental sequelae in postnatal life. However, the effects of IUGR on the cerebellum are still to be fully elucidated. A major determinant of growth and development of the cerebellum is proliferation and subsequent migration of cerebellar granule cells. Our objective was to determine whether IUGR, induced by chronic placental insufficiency (CPI) in guinea pigs, results in abnormal cerebellar development due to deficits suggestive of impaired granule cell proliferation and/or migration. CPI was induced by unilateral ligation of the uterine artery at mid-gestation, producing growth-restricted (GR) foetuses at 52 and 60 days of gestation (dg), and neonates at 1 week postnatal age (term approx. 67 dg). Controls were from sham-operated animals. In GR foetuses compared with controls at 52 dg, the external granular layer (EGL) width and internal granular layer (IGL) area were similar. In GR foetuses compared with controls at 60 dg: (a) the EGL width was greater (p < 0.005); (b) the IGL area was smaller (p < 0.005); (c) the density of Ki67-negative (postmitotic) granule cells in the EGL was greater (p < 0.01); (d) the somal area of Purkinje cells was reduced (p < 0.005), and (e) the linear density of Bergmann glia was similar. The EGL width in GR foetuses at 60 dg was comparable to that of 52 dg control and GR foetuses. The pattern of p27-immunoreactivity in the EGL was the inverse of Ki67-immunoreactivity at both foetal ages; there was no difference between control and GR foetuses at either age in the width of p27-immunoreactivity, or in the percentage of the EGL width that it occupied. In the molecular layer of GR neonates compared with controls there was an increase in the areal density of granule cells (p < 0.05) and in the percentage of migrating to total number of granule cells (p < 0.01) at 1 week but not at 60 dg (p > 0.05). Thus, we found no specific evidence that IUGR affects granule cell proliferation, but it alters the normal program of migration to the IGL and, in addition, the development of Purkinje cells. Such alterations will likely affect the development of appropriate circuitry and have implications for cerebellar function.
Patterns of Infancy Growth and Metabolic Hormonal Profile Are Different in Very-Low-Birth-Weight Preterm Infants Born Small for Gestational Age Compared to Those Born Appropriate for Gestational Age
Authors: Hernandez María Isabel , Rossel Katherine , Peña Veronica , Garcia Mirna , Cavada Gabriel , Avila Alejandra , Iñiguez German , Mericq Verónica
Published: May 2018

Background/Aims: An increased preterm birth survival rate is associated with long-term neurological and metabolic risks; thus, our aim was to evaluate whether early patterns of infancy anthropometry and metabolic hormonal profile differ in preterm infants born small for gestational age (SGA) or appropriate for gestational age (AGA) from birth to 36 months of corrected age (CA). Methods: We recruited 110 very-low-birth-weight (VLBW) preterm infants (AGA = 60 and SGA = 50) with a mean birth weight of –2.39 ± 0.77 versus 0.57 ± 0.54 standard deviation scores (SDS) (p < 0.01) and birth length of –2.1 ± 1.05 versus –0.44 ± 0.82 SDS (p < 0.01), respectively. Anthropometry and blood sampling for insulin, insulin-like growth factor (IGF)-II, IGF-I, and leptin were performed for up to 3 years. Results: All neonates increased their weight, length, and head circumference SDS during the early inpatient period. Up to 90% reached a normal length within this period. The IGF-II, insulin, and glycemia concentrations changed in parallel with weight. In the first year of CA, only SGA infants gained weight and height SDS. The homoeostatic model assessment had a trend toward higher values in SGA infants at 24 and 36 months (p = 0.06 and p = 0.07). Conclusion: Being SGA is the strongest predictor of early recovery of height in VLBW preterm infants. Follow-up will allow us to determine whether the differences in the growth patterns of VLBW preterm infants by birth weight SDS persist.
Voice and Swallowing Outcomes after Hyoid Suspension Surgery in Patients with Obstructive Sleep Apnea
Authors: Askar Sherif M. , Quriba Amal S. , Hassan Elham M. , Awad Ali M. , Bessar Ahmad A.
Published: May 2018

Objective: The role of hyoidthyroidpexia (HTP) surgery in the management of patients with obstructive sleep apnea (OSA) is well described with good reported outcomes. The effect of HTP on other laryngeal functions is not well discussed. This study was designed to evaluate voice and swallowing outcomes after HTP. Patients and Methods: This study was applied on a selected group of OSA patients. HTP (as a sole procedure) was performed in 17 patients and 14 patients had simultaneous palatal procedures (e.g., anterior palatoplasty). Pre- and postoperative assessment of voice and swallowing were done. Results: Comparison between pre- and postoperative results of voice and swallowing measures revealed a nonsignificant difference. Conclusion: HTP (as a sole technique or as part of a multilevel intervention) could help with airway collapse and might be considered a safe, simple, and effective technique in the management of selected patients experiencing OSA. In addition, it seems to have no hazardous effect on either the voice or swallowing function of patients.
C-proSP-B: A Possible Biomarker for Pulmonary Diseases?
Authors: Kahn Nicolas , Rossler Anne-Kathrin , Hornemann Katrin , Muley Thomas , Grünig Ekkehard , Schmidt Werner , Herth Felix J.F. , Kreuter Michael
Published: May 2018

Background: Detection of surfactant proteins A and D (SP-A and SP-D) in the serum of patients with pulmonary diseases is thought to reflect an injury of the alveolar epithelial barrier and as such serve as a biomarker for these diseases. However, the data for SP-B are limited. Objectives: The aim of this feasibility study was to assess whether immature SP-B pre-proteins might have value as a possible biomarker for pulmonary diseases. Methods: In serum samples from patients with different chronic lung diseases (interstitial lung diseases [ILDs], chronic obstructive pulmonary disease, asthma, lung cancer, pulmonary hypertension, inflammation, patients on ventilator support; total n = 283), C-proSP-B was measured using an electrochemiluminescence immunoassay based on mouse monoclonal anti-C-proSP-B antibodies. Levels were correlated to lung functional and clinical parameters. Results: The highest C-proSP-B levels were detected in the serum of idiopathic pulmonary fibrosis (IPF) patients. In a multivariate analysis, C-proSP-B levels were able to discriminate IPF patients from patients with all other pulmonary diseases (p < 0.0001). No significant correlations were found between C-proSP-B levels and lung function, smoking history, or disease extent. Conclusions: SP-B pre-proteins might serve as a biomarker in pulmonary diseases with alveolar or interstitial damage such as ILDs, especially in IPF. Their role in the long-term monitoring of such diseases has to be clarified further.
Circulating Biomarkers for Cholangiocarcinoma
Authors: Loosen Sven H. , Vucur Mihael , Trautwein Christian , Roderburg Christoph , Luedde Tom
Published: May 2018

Background: Cholangiocarcinoma (CCA) represents the second most common primary liver malignancy. The incidence rate has constantly increased over the last decades and CCA patients face a dismal prognosis with a 5-year survival rate of less than 5% for advanced stage of disease. Surgical tumor resection has remained the only potentially curative treatment option in daily practice but is often not feasible due to advanced disease stage at initial diagnosis. Summary: The early detection of cholangiocarcinoma is essential to provide patients with a potentially curative treatment. Furthermore, prognostic biomarkers represent a valuable tool to offer patients a tailored therapeutic approach in accordance to their life expectancy. The clinically most established biomarker carbohydrate antigen 19–9 shows only a limited diagnostic and prognostic power, encouraging the evaluation of novel biomarkers for cholangiocarcinoma in the last years. Key Massage: In this review, we assess currently available and potential future biomarkers for the diagnosis and prognosis of cholangicarcinoma.
Hepatocellular Carcinoma with Irregular Rim-Like Arterial Phase Hyperenhancement: More Aggressive Pathologic Features
Authors: Rhee Hyungjin , An Chansik , Kim Hye-Young , Yoo Jeong Eun , Park Young Nyun , Kim Myeong-Jin
Published: May 2018

Background and Aims: The purpose of our study was to examine the histopathologic characteristics of hepatocellular carcinoma (HCC) with irregular rim-like arterial phase enhancement (IRE), which has been reported to be associated with more aggressive tumor behavior. Methods: We investigated 84 pathologically confirmed HCCs in 84 patients who underwent curative hepatic resection after gadoxetate-enhanced magnetic resonance imaging between January 2008 and February 2013. Two abdominal radiologists independently reviewed these images and classified HCCs into two categories: HCC showing IRE (IRE-HCC) and HCC showing hypoenhancement or diffuse arterial enhancement (non-IRE-HCC). Twenty-two HCCs were classified as IRE-HCCs, and 51 were classified as non-IRE-HCCs concordantly by both reviewers. The remaining 11 HCCs, on whose radiologic classifications the reviewers disagreed, were classified as HCCs with intermediate enhancement patterns. The HCC clinicopathologic characteristics and patient outcomes were then compared. Results: IRE-HCCs showed more frequent microvascular invasion (91 vs. 35%), lower microvascular density (246.5 vs. 426.5/mm2), higher proportions of sinusoid-like microvascular pattern (55 vs. 0%) and macrotrabecular pattern (45 vs. 0%), and larger areas of tumor necrosis (15 vs. 0%) and fibrous stroma (8.3 vs. 2.1%) than non-IRE-HCCs. IRE-HCCs also expressed higher levels of immunomarkers of hypoxia (carbonic anhydrase IX, 64 vs. 8%) and stemness (EpCAM, 50 vs. 20%). p values were < 0.001 for all comparisons except for EpCAM (p = 0.026). HCCs with intermediate enhancement patterns showed mixed/intermediate pathologic features from both IRE- and non-IRE-HCCs. IRE-HCC patients showed poorer 5-year disease-free survival after curative resection than non-IRE-HCC patients (p = 0.005). Conclusions: IRE-HCCs demonstrate aggressive histopathologic features, including more hypoxic and fibrotic tumor microenvironments and increased stemness, compared to non-IRE-HCCs. IRE might therefore serve as a noninvasive imaging biomarker for aggressive HCC.
Effectiveness End Points in Real-World Studies on Biological Therapies in Psoriasis: Systematic Review with Focus on Drug Survival
Authors: Costanzo Antonio , Malara Giovanna , Pelucchi Claudio , Fatiga Francesco , Barbera Giovanna , Franchi Andrea , Galeone Carlotta
Published: May 2018

Psoriasis is a complex and chronic disease, and, in most cases, therapies are required during all patients’ lifetime. The efficacy and safety profiles of biological therapies are well established, but their effectiveness is still open to discussion. We performed a systematic review to summarize how the effectiveness of biological therapies for psoriasis is measured in real-world studies and to understand whether drug survival, a recent alternative outcome to clinical ones, is a recurrent and valid outcome of effectiveness. In March 2017, we searched for quantitative epidemiological data of psoriasis treatments using PubMed/Medline and EMBASE, and we included 65 publications. The retrospective study design (37%) was most frequent, followed by prospective registries (29%), prospective studies (19%), and retrospective administrative databases/claims. Drug survival was reported in over 60% of prospective registries and retrospective studies, and less frequently in prospective studies. A general consensus emerged in the definition of drug survival as the time patients remain under treatment with a specific therapy, and in its interpretation as an overall marker of treatment success and treatment adherence, as it represents simultaneously information on drug efficacy, drug safety, and patient satisfaction. In conclusion, notwithstanding some limitations, drug survival is a useful measurement of biological therapy effectiveness for psoriasis in daily practice. Its major advantage is that it can be computed also in already collected databases without any specific clinical information on psoriasis. This outcome, combined with evidence on clinical markers of effectiveness, can contribute to better understanding the performance of this expensive class of drugs.
Comorbidities Are Associated with Altered Health Services Use in Multiple Sclerosis: A Prospective Cohort Study
Authors: McKay Kyla A. , Marrie Ruth Ann , Fisk John D. , Patten Scott B. , Tremlett Helen
Published: May 2018

Background: Persons with multiple sclerosis (MS) use health resources with greater frequency than the general population. However, little is known regarding which patient characteristics might contribute. Objective: The study aimed to evaluate characteristics associated with healthcare use in MS patients. Methods: Consecutive MS clinic attendees were recruited (September–November 2010), with clinical, demographic, and patient-completed questionnaires collected at 3 visits over 2 years. Linkage with administrative data (hospital, physician, and pharmacy records) provided healthcare use outcomes until December 31, 2013. Findings were reported as adjusted rate ratios (adjRRs) using negative binomial regression. Results: A total of 340 MS patients with a mean (SD) age of 48.4 (12.0) years and subsequent follow-up of 3.1 (0.34) years were included. Fatigue and high physical comorbidity count (≥3 vs. none) were significantly associated with higher rates of physician encounters (adjRRs: 1.37 and 1.52, respectively), prescriptions filled (adjRRs: 1.25 and 1.40), and hospitalizations (adjRRs: 4.02 and 3.45). In addition, anxiety, disruptive pain, and perceived functional cognitive difficulties were associated with higher rates of physician encounters and prescriptions dispensed (adjRR ranged from 1.28 to 1.48). Discussion: The presence of fatigue and higher physical comorbidity burden were associated with higher rates of health services use. Findings have implications for those examining healthcare burden or organizing health services for persons with MS.
Perineal Wound Closure Using Biological Mesh Following Extralevator Abdominoperineal Excision
Authors: Baloch Naseer , Nilsson Per J. , Nordenvall Caroline , Abraham-Nordling Mirna
Published: May 2018

Aims: This study aimed to describe the short-term perineal healing rates in patients with perineal reconstruction using a biological mesh following extralevator abdominoperineal excision (elAPE). Methods: In a retrospective, descriptive single-centre cohort study, 88 consecutive patients treated with elAPE and perineal closure using a biological mesh between January 2011 and December 2015 were reviewed. All available data from electronic hospital records was collected. Patients were followed for 1 year following surgery and perineal wound status assessed at 3 months and at 1 year. Results: In total, 63 patients were male and all but 8 patients were treated for primary rectal cancer. All patients but 3 had received radiotherapy prior to surgery. Multivisceral excisions were performed in 19 patients. Omentoplasty was performed in 55 patients and 3 different types of meshes were used during the study period. At 3 months, 58 patients (66%) had a healed perineum. No association was detected between patient, tumour or perioperative characteristics and perineal wound status at 3 months. At 1 year, 4 patients were deceased and among the remaining 84, the perineal wound was healed in 77 patients (92%). Conclusion: The use of biological meshes in perineal reconstruction following elAPE is feasible and safe, and the perineal wound is healed in the majority of the patients within 3 months.
Bidirectional Connections between Depression and Ataxia Severity in Spinocerebellar Ataxia Type 3 Patients
Authors: Lin Min-Ting , Yang Jin-Shan , Chen Ping-Ping , Qian Mei-Zhen , Lin Hui-Xia , Chen Xiao-Ping , Shang Xian-Jin , Wang Dan-Ni , Chen Yu-Chao , Jiang Bin , Chen Yi-Jun , Chen Wan-Jin , Wang Ning , Gan Shi-Rui
Published: May 2018

Background: Spinocerebellar ataxia type 3 (SCA3), which is the most common subtype of SCA worldwide, exhibits common neuropsychological symptoms such as depression. However, the contribution of depression to the severity of SCA3 has not yet been thoroughly investigated. Methods: The present study investigated the prevalence of depression using Beck depression inventory in 104 molecularly conﬁrmed SCA3 patients from China. The putative risk factors for depression and whether the depression could affect the severity of ataxia were established by multivariable linear regression models. Results: The frequency of depression in the study subjects was 57.69% (60/104), which was higher than that in SCA3 patients from a subset of other populations. The gender (p = 0.03) and severity (p < 0.01) of ataxia were those risk factors that could affect depression. Conversely, depression (p < 0.01) together with the duration (p < 0.01) of SCA3 could also play a positive role in the severity of ataxia. Conclusions: The extremely common depression results from motor disability caused by ataxia; it also affects the disease severity of SCA3. These findings suggested that depression was a part of neurodegeneration in SCA3 and necessitated intensive focus and interventions while caring for SCA3 patients.
Neutrophil-Lymphocyte Ratio Predicts Functional and Safety Outcomes after Endovascular Treatment for Acute Ischemic Stroke
Authors: Duan Zhenhui , Wang Huaiming , Wang Zhen , Hao Yonggang , Zi Wenjie , Yang Dong , Zhou Zhiming , Liu Wenhua , Lin Min , Shi Zhonghua , Lv Penghua , Wan Yue , Xu Gelin , Xiong Yunyun , Zhu Wusheng , Liu Xinfeng ,   on behalf of the ACTUAL Investigators
Published: May 2018

Background and Objective: Endovascular treatment (EVT) is proven to be safe and effective for treating acute large vessel occlusion stroke (LVOS). The neutrophil-lymphocyte ratio (NLR) reflects systemic inflammation, which plays an important role in the process of treating ischemic stroke. This study aims to explore the relationship between NLR and the clinical outcomes of LVOS patients undergoing EVT. Methods: Patients were selected from the EVT for acUte Anterior circuLation (ACTUAL) ischemic stroke registry. The laboratory data (neutrophil count, lymphocyte count) before EVT were collected. Poor functional outcome was defined as modified Rankin Scale (mRS) of 3–6 at 3 months. Multivariable logistic regression analyses were performed to explore the relationship of NLR with functional outcome, symptomatic intracranial hemorrhage (sICH), and mortality. Results: We eventually included 616 patients (median of age, 66 years; 40.3% female). There were 350 (56.7%) patients achieving mRS of 3–6 at 3 months, 98 (15.9%) patients with sICH, and the mortality at 3 months was 24.8% (153/616). Baseline NLR was independently associated with poor functional outcome (OR 1.58; 95% CI 1.02–2.45; p = 0.039) and sICH (OR 1.84; 95% CI 1.09–3.11; p = 0.023) but showed a trend for predicting 3-month mortality (OR 1.57; 95% CI 0.94–2.65; p = 0.088). Conclusions: NLR independently predicts 3-month functional outcome and sICH but the existence of a trend association with mortality after EVT for acute anterior circulation LVOS patients.
Does the Pituitary Gland Volume Change in Polycystic Ovary Syndrome?
Authors: Bozkurt Koseoglu Sezen , Dinc Elibol Funda
Published: May 2018

Aims: Polycystic ovary syndrome (PCOS) is the commonest cause of menstrual irregularity and hirsutism during reproductive age. We hypothesized in the alterations in the pituitary gland in PCOS. Methods: We measured the volume of the pituitary gland in 39 PCOS patients and 42 age-matched healthy controls using 0.35 mm thick T1-weighted sagittal cranial images. Serum levels of estradiol (E2), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were measured on days 3–5 of the menstrual cycle of the participants. Results: There was a significant difference in terms of LH, FSH, and LH/FSH ratio (p < 0.05) between groups. Mean pituitary gland volume (PGV) was 4.1 ± 1.36 mm3 for the study group and 3.4 ± 0.77 mm3 for the control group. PGV was statistically significantly higher in PCOS group than the control group (p < 0.05). There was no correlation between hormone levels and PGVs in groups. Conclusion: Enlarged pituitary volume in PCOS may be due to excessive LH release.
Microvesicles from Human Adipose Tissue-Derived Mesenchymal Stem Cells as a New Protective Strategy in Osteoarthritic Chondrocytes
Authors: Tofiño-Vian Miguel , Guillén Maria Isabel , Pérez del Caz María Dolores , Silvestre Antonio , Alcaraz María José
Published: May 2018

Background/Aims: Chronic inflammation contributes to cartilage degeneration during the progression of osteoarthritis (OA). Adipose tissue-derived mesenchymal stem cells (AD-MSC) show great potential to treat inflammatory and degradative processes in OA and have demonstrated paracrine effects in chondrocytes. In the present work, we have isolated and characterized the extracellular vesicles from human AD-MSC to investigate their role in the chondroprotective actions of these cells. Methods: AD-MSC were isolated by collagenase treatment from adipose tissue from healthy individuals subjected to abdominal lipectomy surgery. Microvesicles and exosomes were obtained from conditioned medium by filtration and differential centrifugation. Chondrocytes from OA patients were used in primary culture and stimulated with 10 ng/ml interleukin(IL)-1β in the presence or absence of AD-MSC microvesicles, exosomes or conditioned medium. Protein expression was investigated by ELISA and immunofluorescence, transcription factor-DNA binding by ELISA, gene expression by real-time PCR, prostaglandin E2 (PGE2) by radioimmunoassay, and matrix metalloproteinase (MMP) activity and nitric oxide (NO) production by fluorometry. Results: In OA chondrocytes stimulated with IL-1β, microvesicles and exosomes reduced the production of inflammatory mediators tumor necrosis factor-α, IL-6, PGE2 and NO. The downregulation of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 would lead to the decreased PGE2 production while the effect on NO could depend on the reduction of inducible nitric oxide synthase expression. Treatment of OA chondrocytes with extracellular vesicles also decreased the release of MMP activity and MMP-13 expression whereas the production of the anti-inflammatory cytokine IL-10 and the expression of collagen II were significantly enhanced. The reduction of inflammatory and catabolic mediators could be the consequence of a lower activation of nuclear factor-κB and activator protein-1. The upregulation of annexin A1 specially in MV may contribute to the anti-inflammatory and chondroprotective effects of AD-MSC. Conclusions: Our data support the interest of AD-MSC extracellular vesicles to develop new therapeutic approaches in joint conditions.
Prognostic Factors of Renal Involvement in Systemic Sclerosis
Authors: Rosato Edoardo , Gigante Antonietta , Barbano Biagio , Gasperini Maria Ludovica , Cianci Rosario , Muscaritoli Maurizio
Published: May 2018

Background/Aims: Renal involvement is common in systemic sclerosis (SSc), including asymptomatic reduction of glomerular filtration rate (GFR), increased renal resistance indices, scleroderma renal crisis (SRC) and ANCA-associated vasculitis. The aim was to evaluate type and evolution of renal involvement for a period of five years. Methods: 121 SSc patients (100 F, 21 M) with mean age of 54.9 ± 13.8, disease duration of 9 ± 6 years, of which 62 had a diffused form and 59 limited form were enrolled. All patients were screened annually for renal function by laboratory examination, ultrasound and color Doppler ultrasound of renal arteries. Results: Over the five-year observation period, 6 SRC (3 M, 3 F) occurred, four of which required dialysis. One patient developed ANCA-related proliferative glomerulonephritis and the other one acute tubular necrosis. The remaining 113 patients had a preserved renal function (serum creatinine 0.75 ± 0.24 mg/dl, GFR 93.8 ± 20 ml/min, 24h proteinuria 0.20 ± 0.15 g). Doppler indices of intrarenal arterial stiffness increased with progression of capillaroscopic damage and with presence of digital ulcers. A negative correlation was observed between estimated GFR and pulsatile index (p< 0,05, r=-0.198), resistive index(p< 0,01, r=0.267), S/D ratio (p< 0,01, r=-0.237). Conclusion: In SSc patients, renal function was normal for 4.1 years despite the presence of increased intrarenal arterial stiffness. SRC was observed in 4.9% of SSc patients. In SSc patients, a periodic follow-up based on clinical and laboratory evaluation, colorDoppler ultrasound and, in some cases, renal biopsy is required to evaluate renal involvement.
5-Aminolevulinic Acid-Mediated Sonodynamic Therapy Alleviates Atherosclerosis via Enhancing Efferocytosis and Facilitating a Shift in the Th1/Th2 Balance Toward Th2 Polarization
Authors: Yang Yang , Liu Yuanyuan , Chen Xi , Gong Jie , Huang Zhen , Wang Wei , Shi Yuanqi , Wang Yu , Yao Jianting , Shen Zhaoqian , Tian Zhen , Jin Hong , Tian Ye
Published: May 2018

Background/Aims: We and other groups have demonstrated that 5-aminolevulinic acid (ALA)-mediated sonodynamic therapy (ALA-SDT) induces macrophage and foam cell apoptosis and stabilizes atherosclerosis (AS) plaques in animal models. Lymphocytes also play vital roles in the development of AS. The primary purpose of the present study was to investigate the effects of ALA-SDT on T helper (Th) cell fate and function, Th subset differentiation, and atherosclerotic lesion stability. Methods: We utilized ALA-SDT on Western diet-fed apoE-/-mice in vivo and human Jurkat cells in vitro. Hematoxylin and eosin staining and TUNEL assays were used to evaluate the atherosclerotic plaque size and apoptosis within the atheroma. ALA induced cytotoxicity on cultured Jurkat cells was determined with CCK-8 assay. To address the mechanisms, levels of intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and mitochondrial permeability transition pore (MPTP) opening were evaluated by staining with fluorescent probes. Western blot analysis and confocal microscopy were used to analyze the protein levels of caspases, Bax and cytochrome c and the release of cytochrome c. Cell apoptosis and necrosis and phagocytosis were examined by flow cytometry. ELISAs and immunofluorescent staining were used to assess the corresponding cytokine levels and Th subset cell numbers within the atheroma. Results: Our studies revealed that ALA-SDT significantly enhanced CD4+ cell apoptosis and macrophage-mediated phagocytosis and hence reduced the necrotic core size. ALA-SDT activated the mitochondrial apoptotic signaling pathway with minimal necrosis in Jurkat cells. ALA-SDT inhibited the Th1 response and enhanced the Th2 response. These effects of ALA-SDT were mediated primarily through the generation of ROS. Conclusion: ALA-SDT alleviates AS by enhancing cytotoxic effects on Th cells, subsequently stimulating efferocytosis and facilitating a shift in the Th1/Th2 balance toward Th2 cells, a discovery that might help elucidate the mechanism underlying SDT as a potential treatment to prevent atherothrombotic events.
The Influence of Hyperlipidemia on Endothelial Function of FPN1 Tek-Cre Mice and the Intervention Effect of Tetramethylpyrazine
Authors: Sun Ming-Yue , Zhang Miao , Chen Shui-Ling , Zhang Shu-Ping , Guo Chun-Yu , Wang Jing-Shang , Liu Xin , Miao Yang , Yin Hui-Jun
Published: May 2018

Background/Aims: Systemic iron homeostasis is strictly governed in mammals; however, disordered iron metabolism (such as excess iron burden) is recognized as a risk factor for various types of diseases including AS (Atherosclerosis). The hepcidin-ferroportin axis plays the key role in regulation of iron homeostasis and modulation of this signaling could be a potential therapeutic strategy in the treatment of these diseases. TMP (Tetramethylpyrazine) has been reported to have therapeutical effect on AS. Here, we aimed to investigate the effect of iron overload under hyperlipidemia condition on the endothelial injury, inflammation and oxidative stress by employing FPN1 Tek-cre mouse model with or without TMP intervention. Methods: Subjects for this study were 80 FPN1 Tek-cre mice and 40 C57BL/6 mice and we randomly divided them into six groups: Group N: C57BL/6 mice with normal diet, Group M: C57BL/6 mice with high-fat diet, Group FN: FPN1 Tek-cre mice with normal diet, Group FNT: FPN1 Tek-cre mice with normal diet and TMP injection, Group FM: FPN1 Tek-cre mice with high-fat diet, Group FMT: FPN1 Tek-cre mice with high-fat diet and TMP injection. After seven days of treatment, blood samples were obtained to detect the levels of blood lipids, Hepcidin, NO, ET-1, ROS, MDA, SOD, IL-1, IL-6 and TNF-α respectively. The liver and aorta were used for testing the lipid deposition by using hematoxylin and eosin(HE). Results: Hyperlipidemia could cause iron overload in the aorta and increased serum hepcidin level, particularly in FPN1 Tek-cre mice, and can be reversed by TMP intervention. Knockout of Fpn1 induced increase of serum hepcidin, exacerbated endothelial dysfunction, oxidative stress and inflammatory response, particularly under hyperlipidemia condition. TMP intervention attenuated these processes. Conclusions: Our study signifies the potential application of certain natural compounds to ameliorating iron disorders induced by hyperlipidemia and protecting on endothelial function through modulation of hepcidin-ferroportin signaling.
Inhalation of Hydrogen of Different Concentrations Ameliorates Spinal Cord Injury in Mice by Protecting Spinal Cord Neurons from Apoptosis, Oxidative Injury and Mitochondrial Structure Damages
Authors: Chen Xiao , Cui Jin , Zhai Xiao , Zhang Jun , Gu Zhengrong , Zhi Xin , Weng Weizong , Pan Panpan , Cao Liehu , Ji Fang , Wang Zhiwei , Su Jiacan
Published: May 2018

Background/Aims: Hydrogen selectively neutralizes reactive oxygen species (ROS) and ameliorates various ROS-induced injuries. Spinal cord injury (SCI) is a serious injury to the central nervous system, and secondary SCI is closely related to excessive ROS generation. We hypothesized that hydrogen inhalation ameliorates SCI, and the mechanism of action may be related to the protective effects of hydrogen against oxidative stress, apoptosis, and mitochondrial damage. Methods: Mechanically injured spinal cord neurons were incubated with different concentrations of hydrogen in vitro. Immunofluorescence staining and transmission electron microscopy were used to confirm the protective effects of hydrogen. ROS and related proteins were detected with dihydroethidium fluorescence staining, enzyme-linked immunosorbent assays, and western blotting. Terminal deoxynucleotidyl transferase dUTP nick end labeling assays, flow cytometry, and western blotting were used to detect neuronal apoptosis. ATP concentrations, Janus Green B staining, and mitochondrial permeability transition pore (mPTP) status were assessed to investigate mitochondrial damage. RNA sequencing was performed to screen potential target genes of hydrogen application. Hydrogen was administered to mice after spinal cord contusion injury was established for 42 days. The Basso Mouse Scale (BMS) and footprint analyses were used to assess locomotor functions, and immunofluorescence staining of the injured spinal cord segments was performed to detect oxidative stress status. Results: Spinal cord neurons were preserved by hydrogen administration after mechanical injury in a dose-dependent manner. ROS generation, oxidative stress injury-related markers, and the number of apoptotic neurons were significantly reduced after hydrogen treatment. The ATP production and mPTP function in injured neurons were preserved by hydrogen incubation. The expression levels of Cox8b, Cox6a2, Cox7a1, Hspb7, and Atp2a1 were inhibited by hydrogen treatment. BMS scores and the footprint assessment of mice with SCI were improved by hydrogen inhalation. Conclusions: Hydrogen inhalation (75%) ameliorated SCI in vivo and attenuated neuronal mechanical injuries in vitro, and its protective effect on spinal cord neurons was exerted in a dose-dependent manner. The underlying mechanisms included reducing ROS generation and oxidative stress, inhibiting neuronal apoptosis, and restoring mitochondrial construction and function. Cox8b, Cox6a2, Cox7a1, Hspb7, and Atp2a1 were identified as potential target genes of hydrogen treatment.
Identification and Verification of Candidate Genes Regulating Neural Stem Cells Behavior Under Hypoxia
Authors: Shi Zhongju , Wei Zhijian , Li Jiahe , Yuan Shiyang , Pan Bin , Cao Fujiang , Zhou Hengxing , Zhang Yan , Wang Yao , Sun Shiwei , Kong Xiaohong , Feng Shiqing
Published: May 2018

Background/Aims: Neural stem cells (NSCs) reside in a hypoxic environment, and hypoxia plays an important role in their development and differentiation. This study aimed to explore the underlying mechanisms by which hypoxia affects NSC behavior. Methods: In the current study, we downloaded the gene expression dataset GSE68572 and identified the differentially expressed genes (DEGs) by analyzing high-throughput gene expression in hypoxic and normoxic NSCs. Subsequently, we analyzed these data using a combined bioinformatics approach and predicted the microRNAs (miRNAs) targeting the key gene using miRNA databases. Quantitative real-time PCR (qRT-PCR) was used to validate the expression of the top five DEGs. Results: In total, 1347 genes were identified as DEGs. We identified the predominant gene ontology categories and Kyoto Encyclopedia of Genes and Genomes pathways that were significantly over-represented in the hypoxic NSCs. A protein–protein interaction network he identification of miRNAs and their putative targets may offer new diagnostic and therapeutic strategies for liver cancer the top 10 core genes. Vascular endothelial growth factor A (VEGFA) had the highest degree and may be the key gene concerning NSC behavior under hypoxia. Further validation of the top five DEGs by qRT-PCR demonstrated that four DEGs were significantly higher and one DEG was significantly lower in the hypoxic group than in the control group. Seven miRNAs were predicted and proved to target VEGFA. Conclusion: This preliminary study can prompt the understanding of the molecular mechanisms by which hypoxia has an impact on NSC behavior and can help to optimize stem cell therapies for central nervous system injuries and diseases.
Central Precocious Puberty Caused by a Heterozygous Deletion in the MKRN3 Promoter Region
Authors: Macedo Delanie B. , França Monica M. , Montenegro Luciana R. , Cunha-Silva Marina , Bessa Danielle S. , Abreu Ana Paula , Kaiser Ursula B. , Mendonca Berenice B. , Jorge Alexander A.L. , Brito Vinicius N. , Latronico Ana Claudia
Published: May 2018

Context: Loss-of-function mutations in the coding region of MKRN3, a maternally imprinted gene at chromosome 15q11.2, are a common cause of familial central precocious puberty (CPP). Whether MKRN3 alterations in regulatory regions can cause CPP has not been explored to date. We aimed to investigate potential pathogenic variants in the promoter region of MKRN3 in patients with idiopathic CPP. Patients/Methods: A cohort of 110 patients with idiopathic CPP was studied. Family history of precocious sexual development was present in 25%. Mutations in the coding region of MKRN3 were excluded in all patients. Genomic DNA was extracted from peripheral blood leukocytes, and 1,100 nucleotides (nt) of the 5′-regulatory region of MKRN3 were amplified and sequenced. Luciferase assays were performed in GT1–7 cells transiently transfected with plasmids containing mutated and wild-type MKRN3 promoter. Results: We identified a rare heterozygous 4-nt deletion (c.-150_-147delTCAG; –38 to –41 nt upstream to the transcription start site) in the proximal promoter region of MKRN3 in a girl with CPP. In silico analysis predicted that this deletion would lead to the loss of a binding site for a downstream res­ponsive element antagonist modulator (DREAM), a potential transcription factor for MKRN3 and GNRH1 expression. Luciferase assays demonstrated a significant reduction of MKRN3 promoter activity in transfected cells with a c.-150_- 147delTCAG construct plasmid in both homozygous and heterozygous states when compared with cells transfected with the corresponding wild-type MKRN3 promoter region. Conclusion: A rare genetic alteration in the regulatory region of MKRN3 causes CPP.
Rastros metodológicos para poéticas híbridas: da crítica genética, entre provocações (auto)etnográficas, à cartografia
Authors: Lírio Vinícius
Published: May 2018

Este estudo apresenta uma rede de rastros das abordagens metodológicas utilizadas pelo autor em suas pesquisas de mestrado e doutorado e na sua atual investigação. Estas têm em comum o fato de partirem de processos criativos no teatro contemporâneo. Articulam-se, aqui, princípios da Crítica Genética, das abordagens etnográfica e autoetnográfica e do método cartográfico. A partir da sistematização dessa trama, busca-se compartilhar possíveis caminhos, seus rastros e as articulações destes na atual pesquisa do autor, no sentido de mapear poéticas híbridas.