bluuebunny/crossref_metadata_2025 huggingface dataset:
Pulmonary Hilar Tumor: An Unusual Presentation of Sclerosing Hemangioma
Authors: Hung Jui-Hung , Hsueh Ching , Liao Chiung-Ying , Ho Shang-Yun , Huang Yuan-Chun
Published: September 2016

Pulmonary sclerosing hemangioma is an uncommon benign tumor of the lung; however, on rare occasions it can arise from the pulmonary hilar region. Herein, we report a 53-year-old female patient who presented with a round opacity in the right upper lung field on a radiograph. Chest computed tomography scanning revealed a 3.1 cm mass in the right pulmonary hilum. Thoracoscopic tumor excision was subsequently performed. On pathohistologic study, the tumor was well defined and composed of round stromal cells and surface cells arranged in a papillary, sclerotic, solid, and hemorrhagic pattern. In immunochemical study, the round cells were positive for thyroid transcription factor-1 (TTF-1) and epithelial membrane antigen (EMA) and negative for cytokeratin. The surface cells were positive for TTF-1, EMA, and cytokeratin. Therefore, a final diagnosis of sclerosing hemangioma was confirmed. In conclusion, pulmonary sclerosing hemangioma is uncommon and rare in the pulmonary hilar region. CT scanning is useful to determine its benignity, although imaging features are not specific for a definite differential diagnosis from other pulmonary tumors. Therefore, tissue diagnosis is usually necessary, and pulmonary sclerosing hemangioma should be listed in the differential diagnoses of pulmonary hilar tumors.
Quantification of Cell-Free DNA in Red Blood Cell Units in Different Whole Blood Processing Methods
Authors: Shih Andrew W. , Bhagirath Vinai C. , Heddle Nancy M. , Acker Jason P. , Liu Yang , Eikelboom John W. , Liaw Patricia C.
Published: September 2016

Background. Whole blood donations in Canada are processed by either the red cell filtration (RCF) or whole blood filtration (WBF) methods, where leukoreduction is potentially delayed in WBF. Fresh WBF red blood cells (RBCs) have been associated with increased in-hospital mortality after transfusion. Cell-free DNA (cfDNA) is released by neutrophils prior to leukoreduction, degraded during RBC storage, and is associated with adverse patient outcomes. We explored cfDNA levels in RBCs prepared by RCF and WBF and different storage durations. Methods. Equal numbers of fresh (stored ≤14 days) and older RBCs were sampled. cfDNA was quantified by spectrophotometry and PicoGreen. Separate regression models determined the association with processing method and storage duration and their interaction on cfDNA. Results. cfDNA in 120 RBC units (73 RCF, 47 WBF) were measured. Using PicoGreen, WBF units overall had higher cfDNA than RCF units (p=0.0010); fresh WBF units had higher cfDNA than fresh RCF units (p=0.0093). Using spectrophotometry, fresh RBC units overall had higher cfDNA than older units (p=0.0031); fresh WBF RBCs had higher cfDNA than older RCF RBCs (p=0.024). Conclusion. Higher cfDNA in fresh WBF was observed compared to older RCF blood. Further study is required for association with patient outcomes.
Tumor-Intrinsic PD-L1 Signals Regulate Cell Growth, Pathogenesis, and Autophagy in Ovarian Cancer and Melanoma
Authors: Clark Curtis A. , Gupta Harshita B. , Sareddy Gangadhara , Pandeswara Srilakshmi , Lao Shunhua , Yuan Bin , Drerup Justin M. , Padron Alvaro , Conejo-Garcia José , Murthy Kruthi , Liu Yang , Turk Mary Jo , Thedieck Kathrin , Hurez Vincent , Li Rong , Vadlamudi Ratna , Curiel Tyler J.
Published: September 2016

PD-L1 antibodies produce efficacious clinical responses in diverse human cancers, but the basis for their effects remains unclear, leaving a gap in the understanding of how to rationally leverage therapeutic activity. PD-L1 is widely expressed in tumor cells, but its contributions to tumor pathogenicity are incompletely understood. In this study, we evaluated the hypothesis that PD-L1 exerts tumor cell–intrinsic signals that are critical for pathogenesis. Using RNAi methodology, we attenuated PD-L1 in the murine ovarian cell line ID8agg and the melanoma cell line B16 (termed PD-L1lo cells), which express basal PD-L1. We observed that PD-L1lo cells proliferated more weakly than control cells in vitro. As expected, PD-L1lo cells formed tumors in immunocompetent mice relatively more slowly, but unexpectedly, they also formed tumors more slowly in immunodeficient NSG mice. RNA sequencing analysis identified a number of genes involved in autophagy and mTOR signaling that were affected by PD-L1 expression. In support of a functional role, PD-L1 attenuation augmented autophagy and blunted the ability of autophagy inhibitors to limit proliferation in vitro and in vivo in NSG mice. PD-L1 attenuation also reduced mTORC1 activity and augmented the antiproliferative effects of the mTORC1 inhibitor rapamycin. PD-L1lo cells were also relatively deficient in metastasis to the lung, and we found that anti-PD-L1 administration could block tumor cell growth and metastasis in NSG mice. This therapeutic effect was observed with B16 cells but not ID8agg cells, illustrating tumor- or compartmental-specific effects in the therapeutic setting. Overall, our findings extend understanding of PD-L1 functions, illustrate nonimmune effects of anti-PD-L1 immunotherapy, and suggest broader uses for PD-L1 as a biomarker for assessing cancer therapeutic responses. Cancer Res; 76(23); 6964–74. ©2016 AACR.
ZIC5 Drives Melanoma Aggressiveness by PDGFD-Mediated Activation of FAK and STAT3
Authors: Satow Reiko , Nakamura Tomomi , Kato Chiaki , Endo Miku , Tamura Mana , Batori Ryosuke , Tomura Shiori , Murayama Yumi , Fukami Kiyoko
Published: September 2016

Insights into mechanisms of drug resistance could extend the efficacy of cancer therapy. To probe mechanisms in melanoma, we performed siRNA screening of genes that mediate the development of neural crest cells, from which melanocytes are derived. Here, we report the identification of ZIC5 as a mediator of melanoma drug resistance. ZIC5 is a transcriptional suppressor of E-cadherin expressed highly in human melanoma. ZIC5 enhanced melanoma cell proliferation, survival, drug resistance, in vivo growth and metastasis. Microarray analysis revealed that ZIC5 downstream signaling included PDGFD and FAK activation, which contributes to drug resistance by enhancing STAT3 activation. Silencing of ZIC5 or PDGFD enhanced the apoptotic effects of BRAF inhibition and blocked survival of melanoma cells resistant to BRAF inhibitors. Furthermore, inhibition of FAK or STAT3 suppressed expression of ZIC5, which was positively regulated by PDGFD, FAK, and STAT3 in a positive feedback loop. Taken together, our results identify ZIC5 and PDGFD as candidate therapeutic targets to overcome drug resistance in melanoma. Cancer Res; 77(2); 366–77. ©2016 AACR.
SPINK6 Promotes Metastasis of Nasopharyngeal Carcinoma via Binding and Activation of Epithelial Growth Factor Receptor
Authors: Zheng Li-Sheng , Yang Jun-Ping , Cao Yun , Peng Li-Xia , Sun Rui , Xie Ping , Wang Meng-Yao , Meng Dong-Fang , Luo Dong-Hua , Zou Xiong , Chen Ming-Yuan , Mai Hai-Qiang , Guo Ling , Guo Xiang , Shao Jian-Yong , Huang Bi-Jun , Zhang Wei , Qian Chao-Nan
Published: September 2016

Nasopharyngeal carcinoma has the highest rate of metastasis among head and neck cancers, and distant metastasis is the major reason for treatment failure. The underlying molecular mechanisms of nasopharyngeal carcinoma metastasis are not fully understood. Here, we report the identification of serine protease inhibitor Kazal-type 6 (SPINK6) as a functional regulator of nasopharyngeal carcinoma metastasis via EGFR signaling. SPINK6 mRNA was upregulated in tumor and highly metastatic nasopharyngeal carcinoma cells. Immunohistochemical staining of 534 nasopharyngeal carcinomas revealed elevated SPINK6 expression as an independent unfavorable prognostic factor for overall, disease-free, and distant metastasis–free survival. Ectopic SPINK6 expression promoted in vitro migration and invasion as well as in vivo lymph node metastasis and liver metastasis of nasopharyngeal carcinoma cells, whereas silencing SPINK6 exhibited opposing effects. SPINK6 enhanced epithelial–mesenchymal transition by activating EGFR and the downstream AKT pathway. Inhibition of EGFR with a neutralizing antibody or erlotinib reversed SPINK6-induced nasopharyngeal carcinoma cell migration and invasion. Erlotinib also inhibited SPINK6-induced metastasis in vivo. Notably, SPINK6 bound to the EGFR extracellular domain independent of serine protease–inhibitory activity. Overall, our results identified a novel EGFR-activating mechanism in which SPINK6 has a critical role in promoting nasopharyngeal carcinoma metastasis, with possible implications as a prognostic indicator in nasopharyngeal carcinoma patients. Cancer Res; 77(2); 579–89. ©2016 AACR.
Molecular Subtypes of Breast Cancer: Long-term Incidence Trends and Prognostic Differences
Authors: Valla Marit , Vatten Lars Johan , Engstrøm Monica Jernberg , Haugen Olav Anton , Akslen Lars Andreas , Bjørngaard Johan Håkon , Hagen Anne Irene , Ytterhus Borgny , Bofin Anna Mary , Opdahl Signe
Published: September 2016

Background: Secular trends in incidence and prognosis of molecular breast cancer subtypes are poorly described. We studied long-term trends in a population of Norwegian women born 1886–1977.

Methods: A total of 52,949 women were followed for breast cancer incidence, and 1,423 tumors were reclassified into molecular subtypes using IHC and in situ hybridization. We compared incidence rates among women born 1886–1928 and 1929–1977, estimated age-specific incidence rate ratios (IRR), and performed multiple imputations to account for unknown subtype. Prognosis was compared for women diagnosed before 1995 and in 1995 or later, estimating cumulative risk of death and HRs.

Results: Between 50 and 69 years of age, incidence rates of Luminal A and Luminal B (HER2−) were higher among women born in 1929 or later, compared with before 1929 [IRRs 50–54 years; after imputations: 3.5; 95% confidence interval (CI), 1.8–6.9 and 2.5; 95% CI, 1.2–5.2, respectively], with no clear differences for other subtypes. Rates of death were lower in women diagnosed in 1995 or later, compared to before 1995, for Luminal A (HR 0.4; 95% CI, 0.3–0.5), Luminal B (HER2−; HR 0.5; 95% CI, 0.3–0.7), and Basal phenotype (HR 0.4; 95% CI, 0.2–0.9).

Conclusions: We found a strong secular incidence increase restricted to Luminal A and Luminal B (HER2−) subtypes, combined with a markedly improved prognosis for these subtypes and for the Basal phenotype.

Impact: This study documents a clear secular increase in incidence and a concomitant improved prognosis for specific molecular breast cancer subtypes. Cancer Epidemiol Biomarkers Prev; 25(12); 1625–34. ©2016 AACR.
Is Pelvic Inflammatory Disease a Risk Factor for Ovarian Cancer?
Authors: Rasmussen Christina B. , Jensen Allan , Albieri Vanna , Andersen Klaus K. , Kjaer Susanne K.
Published: September 2016

Background: Pelvic inflammatory disease (PID) has been proposed as a risk factor for ovarian cancer. However, the existing literature on the association between PID and ovarian cancer risk is inconclusive, and only few cohort studies have been conducted.

Methods: Using nationwide Danish registries, we conducted a population-based cohort study including all women from the birth cohorts 1940 to 1970 in Denmark during 1978–2012 (n = 1,318,929) to investigate the association between PID and subsequent risk of epithelial ovarian cancer. Among women in the cohort, 81,281 women were diagnosed with PID and 5,356 women developed ovarian cancer during follow-up through 2012. Cox regression models were used to estimate HRs and 95% confidence intervals (CI) for the association between PID and ovarian cancer, both overall and according to histotype.

Results: For ovarian cancer overall, we observed no association with PID (HR, 1.05; 95% CI, 0.92–1.20). However, in histotype-specific analyses, we found a statistically significantly increased risk of serous ovarian cancer among women with PID (HR, 1.19; 1.00–1.41; P = 0.047). Conversely, PID was not convincingly associated with risk of any of the other histotypes of ovarian cancer.

Conclusions: PID was associated with a modestly increased risk of serous ovarian cancer, but not other histotypes.

Impact: Our results indicate that PID is not a strong risk factor for ovarian cancer. Whether PID is slightly associated with risk of serous ovarian cancer has to be confirmed in other studies. Cancer Epidemiol Biomarkers Prev; 26(1); 104–9. ©2016 AACR.
Novel ABCG2 Antagonists Reverse Topotecan-Mediated Chemotherapeutic Resistance in Ovarian Carcinoma Xenografts
Authors: Ricci Jerec W. , Lovato Debbie M. , Severns Virginia , Sklar Larry A. , Larson Richard S.
Published: September 2016

Chemotherapeutic resistance remains a challenge in the treatment of ovarian carcinoma, especially in recurrent disease. Despite the fact that most patients with newly diagnosed tumors attain complete remission following cytoreductive surgery and chemotherapy, ovarian carcinoma has a recurrence rate that exceeds 75%. The ATP-binding cassette family G member 2 (ABCG2) efflux protein has been described as one mechanism that confers multiple-drug resistance to solid tumors and contributes to topotecan resistance in ovarian carcinoma. In fact, one clinical trial demonstrated ABCG2 expression in all patients with primary or recurrent ovarian carcinoma. On the basis of our previous work, we hypothesized that three compounds (CID44640177, CID1434724, and CID46245505), which represent a new piperazine-substituted pyrazolo[1,5]pyrimidine substructure class of ABCG2-specific antagonists, would restore chemosensitivity to drug-resistant ovarian cancer in vitro and in vivo. To address the treatment difficulties associated with chemotherapeutic resistance in ovarian cancer, we combined each compound (CID44640177, CID1434724, and CID46245505) with topotecan and administered the mixture to chemoresistant Igrov1/T8 ovarian cancer cells in vitro and Igrov1/T8 xenografts in CB-17 SCID mice. We found that only nanomolar concentrations of each ABCG2 inhibitor in combination with topotecan were required to restore chemosensitivity to Igrov1/T8 cells in vitro. In vivo, substantial tumor reduction was achieved with each compound in 4 days, with CID1434724 causing the largest reduction in excess of 60%. No signs of secondary toxic effects were observed with the ABCG2 antagonists. These novel compounds should be viewed as promising drug candidates to reverse ABCG2-mediated chemoresistance. Mol Cancer Ther; 15(12); 2853–62. ©2016 AACR.
Integrated Genetic, Epigenetic, and Transcriptional Profiling Identifies Molecular Pathways in the Development of Laterally Spreading Tumors
Authors: Hesson Luke B. , Ng Benedict , Zarzour Peter , Srivastava Sameer , Kwok Chau-To , Packham Deborah , Nunez Andrea C. , Beck Dominik , Ryan Regina , Dower Ashraf , Ford Caroline E. , Pimanda John E. , Sloane Mathew A. , Hawkins Nicholas J. , Bourke Michael J. , Wong Jason W.H. , Ward Robyn L.
Published: September 2016

Laterally spreading tumors (LST) are colorectal adenomas that develop into extremely large lesions with predominantly slow progression to cancer, depending on lesion subtype. Comparing and contrasting the molecular profiles of LSTs and colorectal cancers offers an opportunity to delineate key molecular alterations that drive malignant transformation in the colorectum. In a discovery cohort of 11 LSTs and paired normal mucosa, we performed a comprehensive and unbiased screen of the genome, epigenome, and transcriptome followed by bioinformatics integration of these data and validation in an additional 84 large, benign colorectal lesions. Mutation rates in LSTs were comparable with microsatellite-stable colorectal cancers (2.4 vs. 2.6 mutations per megabase); however, copy number alterations were infrequent (averaging only 1.5 per LST). Frequent genetic, epigenetic, and transcriptional alterations were identified in genes not previously implicated in colorectal neoplasia (ANO5, MED12L, EPB41L4A, RGMB, SLITRK1, SLITRK5, NRXN1, ANK2). Alterations to pathways commonly mutated in colorectal cancers, namely, the p53, PI3K, and TGFβ pathways, were rare. Instead, LST-altered genes converged on axonal guidance, Wnt, and actin cytoskeleton signaling. These integrated omics data identify molecular features associated with noncancerous LSTs and highlight that mutation load, which is relatively high in LSTs, is a poor predictor of invasive potential.

Implications: The novel genetic, epigenetic, and transcriptional changes associated with LST development reveal important insights into why some adenomas do not progress to cancer. The finding that LSTs exhibit a mutational load similar to colorectal carcinomas has implications for the validity of molecular biomarkers for assessing cancer risk. Mol Cancer Res; 14(12); 1217–28. ©2016 AACR.
ECM Composition and Rheology Regulate Growth, Motility, and Response to Photodynamic Therapy in 3D Models of Pancreatic Ductal Adenocarcinoma
Authors: Cramer Gwendolyn M. , Jones Dustin P. , El-Hamidi Hamid , Celli Jonathan P.
Published: September 2016

Pancreatic ductal adenocarcinoma is characterized by prominent stromal involvement, which plays complex roles in regulating tumor growth and therapeutic response. The extracellular matrix (ECM)-rich stroma associated with this disease has been implicated as a barrier to drug penetration, although stromal depletion strategies have had mixed clinical success. It remains less clear how interactions with ECM, acting as a biophysical regulator of phenotype, not only a barrier to drug perfusion, regulate susceptibilities and resistance to specific therapies. In this context, an integrative approach is used to evaluate invasive behavior and motility in rheologically characterized ECM as determinants of chemotherapy and photodynamic therapy (PDT) responses. We show that in 3D cultures with ECM conditions that promote invasive progression, response to PDT is markedly enhanced in the most motile ECM-infiltrating populations, whereas the same cells exhibit chemoresistance. Conversely, drug-resistant sublines with enhanced invasive potential were generated to compare differential treatment response in identical ECM conditions, monitored by particle tracking microrheology measurements of matrix remodeling. In both scenarios, ECM-infiltrating cell populations exhibit increased sensitivity to PDT, whether invasion is consequent to selection of chemoresistance, or whether chemoresistance is correlated with acquisition of invasive behavior. However, while ECM-invading, chemoresistant cells exhibit mesenchymal phenotype, induction of EMT in monolayers without ECM was not sufficient to enhance PDT sensitivity, yet does impart chemoresistance as expected. In addition to containing platform development with broader applicability to inform microenvironment-dependent therapeutics, these results reveal the efficacy of PDT for targeting the most aggressive, chemoresistant, invasive pancreatic ductal adenocarcinoma associated with dismal outcomes for this disease.

Implications: ECM-infiltrating and chemoresistant pancreatic tumor populations exhibit increased sensitivity to PDT. Mol Cancer Res; 15(1); 15–25. ©2016 AACR.
Molecular Triage of Premalignant Lesions in Liquid-Based Cervical Cytology and Circulating Cell-Free DNA from Urine, Using a Panel of Methylated Human Papilloma Virus and Host Genes
Authors: Guerrero-Preston Rafael , Valle Blanca L. , Jedlicka Anne , Turaga Nitesh , Folawiyo Oluwasina , Pirini Francesca , Lawson Fahcina , Vergura Angelo , Noordhuis Maartje , Dziedzic Amanda , Pérez Gabriela , Renehan Marisa , Guerrero-Diaz Carolina , De Jesus Rodríguez Edgar , Diaz-Montes Teresa , Rodríguez Orengo José , Méndez Keimari , Romaguera Josefina , Trock Bruce J. , Florea Liliana , Sidransky David
Published: September 2016

Clinically useful molecular tools to triage women for a biopsy upon referral to colposcopy are not available. We aimed to develop a molecular panel to detect cervical intraepithelial neoplasia (CIN) grade 2 or higher lesions (CIN2+) in women with abnormal cervical cytology and high-risk HPV (HPV+). We tested a biomarker panel in cervical epithelium DNA obtained from 211 women evaluated in a cervical cancer clinic in Chile from 2006 to 2008. Results were verified in a prospective cohort of 107 women evaluated in a high-risk clinic in Puerto Rico from 2013 to 2015. Promoter methylation of ZNF516, FKBP6, and INTS1 discriminated cervical brush samples with CIN2+ lesions from samples with no intraepithelial lesions or malignancy (NILM) with 90% sensitivity, 88.9% specificity, 0.94 area under the curve (AUC), 93.1% positive predictive value (PPV), and 84.2% negative predictive value (NPV). The panel results were verified in liquid-based cervical cytology samples from an independent cohort with 90.9% sensitivity, 60.9% specificity, 0.90 AUC, 52.6% PPV, and 93.3% NPV, after adding HPV16-L1 methylation to the panel. Next-generation sequencing results in HPV+ cultured cells, and urine circulating cell-free DNA (ccfDNA) were used to design assays that show clinical feasibility in a subset (n = 40) of paired plasma (AUC = 0.81) and urine (AUC = 0.86) ccfDNA samples obtained from the prospective cohort. Viral and host DNA methylation panels can be tested in liquid cytology and urine ccfDNA from women referred to colposcopy, to triage CIN2+ lesions for biopsy and inform personalized screening algorithms. Cancer Prev Res; 9(12); 915–24. ©2016 AACR.
Targeted Next Generation Sequencing Identifies Markers of Response to PD-1 Blockade
Authors: Johnson Douglas B. , Frampton Garrett M. , Rioth Matthew J. , Yusko Erik , Xu Yaomin , Guo Xingyi , Ennis Riley C. , Fabrizio David , Chalmers Zachary R. , Greenbowe Joel , Ali Siraj M. , Balasubramanian Sohail , Sun James X. , He Yuting , Frederick Dennie T. , Puzanov Igor , Balko Justin M. , Cates Justin M. , Ross Jeffrey S. , Sanders Catherine , Robins Harlan , Shyr Yu , Miller Vincent A. , Stephens Philip J. , Sullivan Ryan J. , Sosman Jeffrey A. , Lovly Christine M.
Published: September 2016

Therapeutic antibodies blocking programmed death-1 and its ligand (PD-1/PD-L1) induce durable responses in a substantial fraction of melanoma patients. We sought to determine whether the number and/or type of mutations identified using a next-generation sequencing (NGS) panel available in the clinic was correlated with response to anti–PD-1 in melanoma. Using archival melanoma samples from anti–PD-1/PD-L1-treated patients, we performed hybrid capture–based NGS on 236–315 genes and T-cell receptor (TCR) sequencing on initial and validation cohorts from two centers. Patients who responded to anti–PD-1/PD-L1 had higher mutational loads in an initial cohort (median, 45.6 vs. 3.9 mutations/MB; P = 0.003) and a validation cohort (37.1 vs. 12.8 mutations/MB; P = 0.002) compared with nonresponders. Response rate, progression-free survival, and overall survival were superior in the high, compared with intermediate and low, mutation load groups. Melanomas with NF1 mutations harbored high mutational loads (median, 62.7 mutations/MB) and high response rates (74%), whereas BRAF/NRAS/NF1 wild-type melanomas had a lower mutational load. In these archival samples, TCR clonality did not predict response. Mutation numbers in the 315 genes in the NGS platform strongly correlated with those detected by whole-exome sequencing in The Cancer Genome Atlas samples, but was not associated with survival. In conclusion, mutational load, as determined by an NGS platform available in the clinic, effectively stratified patients by likelihood of response. This approach may provide a clinically feasible predictor of response to anti–PD-1/PD-L1. Cancer Immunol Res; 4(11); 959–67. ©2016 AACR.
Surgical Treatment of Facial Basal Cell Carcinoma: Patient-Based Assessment of Clinical Outcome in a Prospective Cohort Study
Authors: Ofaiche Joséphine , Lopez Raphael , Bérard Emilie , André Aymeric , Bulai-Livideanu Cristina , Méresse Thomas , Vairel Benjamin B. , Grolleau Jean-Louis , Paul Carle , Meyer Nicolas
Published: September 2016

Background: There are limited data on the esthetic, functional, and morphological outcomes of surgical treatment of facial basal cell carcinoma (BCC). Objective: The aim of our study was to assess the determinants of the evaluation of both the patients and the investigator of the esthetic, functional, and morphological impact of the surgical treatment of facial BCC. Methods: A prospective observational study evaluated 111 patients treated surgically for facial BCCs (n = 135 BCCs), using the Patient and Observer Scar Assessment Scale (POSAS), a validated and reliable scale designed for the evaluation of all types of scars by professionals and patients. Results: Scar assessment rated by the patients was very good. Skin aging was associated with a better surgical outcome as evaluated by POSAS (OR = 0.30, 95% CI: 0.09-0.98; p = 0.04). Conversely, histologically infiltrative or sclerosing BCC (OR = 2.33, 95% CI: 0.95-5.71; p = 0.06) was independently associated with poorer POSAS. In terms of the investigator's evaluation, aging signs (protective factor: OR = 0.17, 95% CI: 0.04-0.73; p = 0.01), location on the H-zone of the face (risk factor: OR = 2.95, 95% CI: 1.07-8.15; p = 0.03), and histologically infiltrative or sclerosing BCC (risk factor: OR = 2.89, 95% CI: 1.01-8.29; p = 0.04) were independently associated with POSAS. Conclusion: Esthetic, functional, and morphological outcomes of facial BCC surgery provide high patient satisfaction overall. Taking wider margins requires specific measures to improve the surgical outcome.
Risk Factors and Prognosis of Cardiorenal Syndrome Type 1 in Elderly Chinese Patients: A Retrospective Observational Cohort Study
Authors: Hu Wenxue , He Wenna , Liu Wei , Fang Xiaowu , Wu Yanhua , Yu Feng , Hao Wenke
Published: September 2016

Background/Aims: Cardiorenal syndrome type 1 (CRS1) is a syndrome characterized by a rapid worsening of cardiac function leading to acute kidney injury (AKI). The aims of this study were to investigate the risk factors and the prognosis of CRS1 in elderly patients. Methods: A total of 312 elderly patients (≥60 years old) with acute heart failure (AHF) were studied. They were assigned as CRS1 (suffered from in-hospital AKI) or NCRS1 (without AKI) group. Clinical and laboratory data were recorded. Univariate and multivariate analysis were performed to clarify the risk factors for occurrence and mortality of CRS1 in this cohort. Results: Incidence of CRS1 was 52.56%. Basic estimated glomerular filtration (eGFR <60 ml/(min.1.73m2) and use of diuretics were associated with the higher risk of CRS1 in elderly patients (OR=2.239, P=0.025; OR=2.555, P=0.001; respectively). Whereas higher concentration of serum albumin was protective factor for them (OR=0.907, P=0.007). The in-hospital mortality of CRS1 was 23.2%. Dialysis, use of beta blockers or diuretics were associated with all-cause death of CRS1 patients (OR=10.407, P<0.001; OR=0.312, P=0.011; OR=0.345, P=0.040; respectively). The in-hospital mortality of AHF patients was 13.1%. Higher Charlson comorbidity index, occurrence of CRS1 and dialysis were risk factors for in-hospital mortality of AHF patients (OR=4.723, P=0.041; OR=6.096, P=0.008; OR=18.743, P<0.001; respectively). Conclusions: Incidence of CRS1 in elderly patients is relatively high and associated with poor outcome. Reduced basic eGFR, lower serum albumin and use of diuretics are risk factors for the occurrence of CRS1 in elderly patients, while use of diuretics, beta blockers and dialysis during hospitalization are predictors of in-hospital mortality in patients with CRS1. These results above suggest that more suitable treatments for the elderly with CRS1 might be needed.
Early Predictors of Acute Kidney Injury: A Narrative Review
Authors: Liu Xiaoqin , Guan Yi , Xu Sheng , Li Qingzhao , Sun Yuanbo , Han Ruijie , Jiang Chunyang
Published: September 2016

Accompanied with the broad application of interventional therapy, the incidence of acute kidney injury (AKI) has been recently increasing in clinical renal medicine. The pathogenesis of AKI is diverse and complex. In the context of the requirements for the diagnosis and treatment of a renal disorder, a large number of studies have explored biological markers and their usefulness to the early diagnosis and treatment of AKI, including glomerular injury, renal tubular injury, and others. These biomarkers provide an important basis for early monitoring of AKI, but are still not quite sufficient. More ideal biomarkers are needed to be identified. Therefore, future studies are necessary to explore more effective biomarkers for AKI clinical practice, which would play an important role in the early diagnosis and intervention treatment of AKI. This review summarizes the important biomarkers identified by previous studies and aims to highlight the advancements that might provide new methods for early clinical diagnosis and effective therapeutic options, along with prediction of response to treatment for AKI.
Genotype-Phenotype Relationship in Patients and Relatives with SHOX Region Anomalies in the French Population
Authors: Auger Julie , Baptiste Amandine , Benabbad Imane , Thierry Gaëlle , Costa Jean-Marc , Amouyal Mélanie , Kottler Marie-Laure , Leheup Bruno , Touraine Renaud , Schmitt Sébastien , Lebrun Marine , Cormier Daire Valérie , Bonnefont Jean-Paul , de Roux Nicolas , Elie Caroline , Rosilio Myriam
Published: September 2016

Background: The aim of our study was to describe a large population with anomalies involving the SHOX region, responsible for idiopathic short stature and Léri-Weill dyschondrosteosis (LWD), and to identify a possible genotype/phenotype correlation. Methods: We performed a retrospective multicenter study on French subjects with a SHOX region anomaly diagnosed by multiplex ligation-dependent probe amplification or Sanger sequencing. Phenotypes were collected in each of the 7 genetic laboratories practicing this technique for SHOX analysis. Results: Among 205 index cases and 100 related cases, 91.3% had LWD. For index cases, median age at evaluation was 11.7 (9.0; 15.9) years and mean height standard deviation score was -2.3 ± 1.1. A deletion of either SHOX or PAR1 or both was found in 74% of patients. Duplications and point mutations/indels affected 8 and 18% of the population, respectively. Genotype-phenotype correlation showed that deletions were more frequently associated with Madelung deformity and mesomelic shortening in girls, as well as with presence of radiologic anomalies, than duplications. Conclusions: Our results highlight genotype-phenotype relationships in the French population with a SHOX defect and provide new information showing that clinical expression is milder in cases of duplication compared to deletions.
Inhibitory Effect of β-Elemene on Human Airway Granulation Tissue in vivo and in vitro
Authors: Hong Lingling , Zeng Yiming , Yang Dongyong
Published: September 2016

Background: Recurrent airway granulation hyperplasia and scar formation make airway stenosis a clinical challenge. Therefore, a new approach for the treatment of airway stenosis is necessary. Objective: To explore the inhibitory effect of β-elemene on the proliferation of fibroblasts and airway granulation. Methods: In vivo: (1) study of the effect of local β-elemene injection by bronchoscopy. (2) During bronchoscopy, granulation tissues both before and after treatment were obtained. HE staining was performed and the result compared. In vitro: (1) human airway primary fibroblasts were purified and characterized. (2) Fibroblasts were treated with β-elemene and normal saline (NS) and then examined by optical and electron microscopy. (3) Fibroblasts treated with β-elemene or NS were assessed for viability by tetrazolium salt assay. (4) Apoptotic rates were determined by flow cytometry. Results: In vivo: (1) after local injection of β- elemene, airway granulation tissue was reduced. (2) Granulation tissue was found to have less edema, and fibroblasts turned into mature fiber cells. In vitro: (1) human airway primary fibroblasts were successfully purified and cultured. (2) Compared with the control group, fibroblasts of the experimental group became clumped, the plasma granules were increased, and some fibroblasts lost their nucleus and organelles. (3) Compared with the control group, reduction of cell viability was detected with increased concentrations of β-elemene. (4) With increased concentrations of β-elemene, apoptotic rates of the fibroblasts were raised compared with the control group. Conclusions: β-Elemene may induce apoptosis and necrosis of airway primary fibroblasts and inhibit the proliferation of fibroblasts and airway granulation. The results provide a new approach for the treatment of airway stenosis.
Hyperglycemia and Advanced Glycation End Products Regulate miR-126 Expression in Endothelial Progenitor Cells
Authors: Li Yeting , Zhou Qing , Pei ChongZhe , Liu Bo , Li MaoQuan , Fang Lu , Sun YingGang , Li YiGang , Meng Shu
Published: September 2016

Background/Aims: Dysfunction of endothelial progenitor cell (EPCs) contributes to diabetic vascular disease. We reported that downregulated miR-126 in diabetic patients causes EPC dysfunction. The study was designed to investigate how high glucose (HG) and advanced glycation end products (AGEs) regulate miR-126 expression and whether miR-126 mediates the effects of HG and AGEs on EPCs. Methods: We first tested the effects of glucose (5.5-50 mM) and AGEs at 50-200 mg/l on EPC proliferation and selected HG at 50 mM and AGEs at 50 mg/l for further experiments. EPCs were stimulated with HG and AGEs, and miR-126 expression was measured by real-time PCR. Reactive oxygen species (ROS) were measured by immunofluorescence microscopy and flow cytometry. IL-6 and TNF-α levels in EPC supernatants were determined by ELISA. The effects of miR-126 on ROS and inflammatory markers under stimulation of HG and AGEs were also assessed. Finally, the effects of inhibitors of PI3K and Akt on AGE-mediated miR-126 expression were examined. Results: HG and AGEs increased IL-6, TNF-α and ROS and decreased miR-126 expression in EPCs. miR-126 negatively regulated IL-6, TNF-α and ROS. miR-126 overexpression reduced and miR-126 inhibition further increased the inflammatory markers and ROS induced by HG and AGEs. Inhibitors of PI3K and Akt further decreased miR-126 expression in the presence of AGEs. Conclusions: In conclusion, hyperglycemia and AGEs decrease miR-126 expression in EPCs. Recovering miR-126 expression may protect EPCs against dysfunction induced by HG and AGEs.
Angiotensin-(1-7) Selectively Induces Relaxation and Modulates Endothelium-Dependent Dilation in Mesenteric Arteries of Salt-Fed Rats
Authors: Raffai Gábor , Lombard Julian H.
Published: September 2016

This study investigated the acute effects of angiotensin-(1-7) and AVE0991 on active tone and vasodilator responses to bradykinin and acetylcholine in isolated mesenteric arteries from Sprague-Dawley rats fed a high-salt (HS; 4% NaCl) versus a normal salt (NS; 0.4% NaCl) diet. Angiotensin-(1-7) and AVE0991 elicited relaxation, and angiotensin-(1-7) unmasked vasodilator responses to bradykinin in arteries from HS-fed rats. These effects of angiotensin-(1-7) and AVE0991 were inhibited by endothelium removal, A779, PD123319, HOE140 and L-NAME. Angiotensin-(1-7) also restored the acetylcholine-induced relaxation that was suppressed by the HS diet. Vasodilator responses to bradykinin and acetylcholine in the presence of angiotensin-(1-7) were mimicked by captopril and the AT2 receptor agonist CGP42112 in arteries from HS-fed rats. Thus, in contrast to salt-induced impairment of vascular relaxation in response to vasodilator stimuli, angiotensin-(1-7) induces endothelium-dependent and NO-mediated relaxation, unmasks bradykinin responses via activation of mas and AT2 receptors, and restores acetylcholine-induced vasodilation in HS-fed rats. AT2 receptor activation and angiotensin-converting enzyme (ACE) inhibition shared the ability of angiotensin-(1-7) to enhance bradykinin and acetylcholine responses in HS-fed rats. These findings suggest a therapeutic potential for mas and/or AT2 receptor activation and ACE inhibition in restoring endothelial function impaired by elevated dietary salt intake or other pathological conditions.
Correlating Prenatal Imaging Findings of Fetal Ventriculomegaly with the Need for Surgical Intervention in the First 3 Months after Birth
Authors: Gu Joshua L. , Johnson Anthony , Kerr Marcia , Moise Jr. Kenneth J. , Bebbington Michael W. , Pedroza Claudia , Sandberg David I.
Published: September 2016

Background/Aims: This study evaluates the predictive value of prenatal imaging measurements regarding the need for cerebrospinal fluid (CSF) diversion for fetal hydrocephalus in the first 3 months after birth. Methods: We retrospectively reviewed a consecutive case series of patients with fetal hydrocephalus from January 2011 to December 2014 (n = 45). Prenatal measurements included head circumference (HC), biparietal diameter (BPD), and lateral ventricle (LV) width. Patients requiring CSF diversion within 12 weeks of birth were compared to those who did not require CSF diversion using the Wilcoxon rank sum test, and receiver-operating characteristic analysis was used to evaluate threshold values. Results: CSF diversion was required within 12 weeks of birth in 30 of 45 patients. Mean LV width (mm) during the entire pregnancy was greater for the surgery group than the nonsurgery group. Neither BPD nor HC showed differences between the groups. A mean LV size ≥15 mm predicted the need for CSF diversion with a sensitivity of 67% and specificity of 73%. Conclusion: LV width is the prenatal imaging measurement that best predicts the need for postnatal CSF diversion.
A Retrospective Analysis of Toxicity and Efficacy for 2 Hypofractionated Irradiation Schedules Versus a Conventional One for Post-Mastectomy Adjuvant Radiotherapy in Breast Cancer
Authors: Kouloulias Vassilis , Mosa Eftychia , Zygogianni Anna , Kypraiou Efrosini , Georgakopoulos John , Platoni Kalliopi , Antypas Christos , Kyrgias George , Tolia Maria , Papadimitriou Christos , Psyrri Amanda , Patatoukas George , Dilvoi Maria , Armpilia Christina , Theodorou Kyriaki , Kalogeridi Maria-Aggeliki , Beli Ivelina , Kouvaris John , Kelekis Nikolaos
Published: September 2016

Introduction: The aim of this analysis was a retrospective evaluation of the efficacy and toxicity of 2 hypofractionated irradiation schedules compared to conventional therapy in post-mastectomy patients. Methods: 3 irradiation schedules were analyzed: 48.30 Gy in 21 fractions (group A, n = 60), 42.56 Gy in 16 fractions (group B, n = 27) and 50 Gy in 25 fractions (group C, n = 30) of the front chest wall. All groups were also treated with a supraclavicular field, with 39.10 Gy in 17 fractions (group A), 37.24 Gy in 14 fractions (group B) or 45 Gy in 25 fractions (group C). Results: No local recurrences were noted in any group during 36 months of follow-up. Acute skin toxicity presented in all groups, with 58.3%, 70.4% and 60% of grade I; 35%, 25.9% and 40% of grade II; 6.7%, 3.7% and 0% of grade III being seen in groups A, B and C, respectively. Late skin toxicity was noted only as grade I in 16.7%, 25.9% and 26.7% of groups A, B and C, respectively. No significant difference was noted among all groups for either acute or late skin toxicity, or for radio-pneumonitis (chi2 test, p > 0.05). Conclusion: All schedules were equally effective with equivalent toxicity. A prospective randomized study is needed to confirm our results.
Roles of HDAC2 and HDAC8 in Cardiac Remodeling in Renovascular Hypertensive Rats and the Effects of Valproic Acid Sodium
Authors: Li Rui-fang , Cao Shan-shan , Fang Wei-jin , Song Ying , Luo Xue-Ting , Wang Hong-yun , Wang Jian-gang
Published: September 2016

Recent studies indicate that histone deacetylases (HDACs) activity is associated with the development and progression of cardiac hypertrophy. In this study, we investigated the effects of a HDACs inhibitor, valproic acid sodium (VPA), on cardiac remodeling and the differential expression of HDACs in left ventricles (LVs) of renovascular hypertensive rats. Renovascular hypertension was induced in rats by the two-kidney two-clip (2K2C) method. Cardiac remodeling, heart function and the differential expression of HDACs were examined at different weeks after 2K2C operation. The effects of VPA on cardiac remodeling, the expressions of HDACs, transforming growth factor-beta 1 (TGF-β1) and connective tissue growth factor (CTGF) in LV were investigated. The expressions of atrial natriuretic factor, β-myosin heavy chain, HDAC2 and HDAC8 increased in LV of 2K2C rats at 4, 8, 12 weeks after operation. Cardiac dysfunction, cardiac hypertrophy and fibrosis were markedly attenuated by VPA treatment in 2K2C rats. Further studies revealed that VPA inhibited the expressions of HDAC2, HDAC8, TGF-β1 and CTGF in LV of 2K2C rats. In summary, these data indicate that HDAC2 and HDAC8 play a key role in cardiac remodeling in renovascular hypertensive rats and that VPA attenuates hypertension and cardiac remodeling. The effect of VPA is possibly exerted via decreasing HDAC2, HDAC8, TGF-β1 and CTGF expressions in LV of 2K2C rats.
Genus Epidemicus: Are Notions of Entanglement Relevant to the Homeopathic Understanding of Epidemic Disease?
Authors: Milgrom Lionel R.
Published: September 2016

Background: Patient-practitioner-remedy (PPR) entanglement postulates non-local triadic interaction between patient (Px), practitioner (Pr) and potentised medicine (Rx), resulting in the patient's journey to cure; the in-depth homeopathic interview is considered a major contributing factor in this process. Also, by modelling entelechy, a quantised gyroscopic analogue of the Vital Force (Vf) has been developed. Objective: To discover whether entanglement notions explain the mode of action of homeopathy during the treatment of epidemic diseases, when the individualising in-depth homeopathic interview is neither possible nor necessary. Method: The current Vf wave equation applies specifically to the in-depth patient/practitioner consultation in chronic dis-ease. A generalised form of the Vf wave equation, an earlier hypothesis based on quantum field theory (QFT) and PPR entanglement were all re-investigated. Results: The generalised Vf wave equation was found applicable in 3 main conditions: acute self-limiting, chronic and epidemic dis-ease. In the latter, a single, coherent Vf epidemic ‘wave function' covering all susceptible beings could be identified, which, after practitioner intervention, disappears. Analogies were drawn between groups of atoms in a p-doped semiconductor and a collection of susceptible beings in an epidemic. Here, genus epidemicus is likened to an ‘n-type dopant', which forms a ‘p-n junction' with the dis-ease. Using the QFT hypothesis/metaphor, genus epidemicus acts as a ‘gauge field' restoring ‘global invariance' to the symmetry-broken, symptom-expressing Vf, i.e., restoring health. Conclusion: Entanglement hypotheses/metaphors may have application in the homeopathic therapeutic process beyond the one-to-one in-depth interview, and so are relevant to describing the mode of action of homeopathy during treatment of epidemic disease.
Use of Extended-Release Calcifediol to Treat Secondary Hyperparathyroidism in Stages 3 and 4 Chronic Kidney Disease
Authors: Sprague Stuart M. , Crawford Paul W. , Melnick Joel Z. , Strugnell Stephen A. , Ali Shaukat , Mangoo-Karim Roberto , Lee Sungchun , Petkovich P. Martin , Bishop Charles W.
Published: September 2016

Background/Aims: Vitamin D insufficiency and secondary hyperparathyroidism (SHPT) are associated with increased morbidity and mortality in chronic kidney disease (CKD) and are poorly addressed by current treatments. The present clinical studies evaluated extended-release (ER) calcifediol, a novel vitamin D prohormone repletion therapy designed to gradually correct low serum total 25-hydroxyvitamin D, improve SHPT control and minimize the induction of CYP24A1 and FGF23. Methods: Two identical multicenter, randomized, double-blind, placebo-controlled studies enrolled subjects from 89 US sites. A total of 429 subjects, balanced between studies, with stage 3 or 4 CKD, SHPT and vitamin D insufficiency were randomized 2:1 to receive oral ER calcifediol (30 or 60 µg) or placebo once daily at bedtime for 26 weeks. Most subjects (354 or 83%) completed dosing, and 298 (69%) entered a subsequent open-label extension study wherein ER calcifediol was administered without interruption for another 26 weeks. Results: ER calcifediol normalized serum total 25-hydroxyvitamin D concentrations (>30 ng/ml) in >95% of per-protocol subjects and reduced plasma intact parathyroid hormone (iPTH) by at least 10% in 72%. The proportion of subjects receiving ER calcifediol who achieved iPTH reductions of ≥30% increased progressively with treatment duration, reaching 22, 40 and 50% at 12, 26 and 52 weeks, respectively. iPTH lowering with ER calcifediol was independent of CKD stage and significantly greater than with placebo. ER calcifediol had inconsequential impact on serum calcium, phosphorus, FGF23 and adverse events. Conclusion: Oral ER calcifediol is safe and effective in treating SHPT and vitamin D insufficiency in CKD.
Exosporium monanthotaxis Piroz. (Fungi: Ascomycota: Pezizomycotina) from Biligirirangan Hills, southern India
Authors: Dubey Rashmi , Sengupta Shreya
Published: September 2016

The paper reports the fungus Exosporium monanthotaxis Piroz. on an unidentified dead twig from the forest floor of Biligirirangan Hills, Karnataka, India.
Distribution records and extended range of the Sri Lanka Frogmouth Batrachostomus moniliger (Aves: Caprimulgiformes: Podargidae) in the Western Ghats: a review from 1862 to 2015
Authors: Mahabal Anil , Thakur Sanjay , Patil Rajgopal
Published: September 2016

The Sri Lanka Frogmouth (or Ceylon Frogmouth) Batrachostomus moniliger is an endemic resident bird confined to the evergreen and secondary forests of Sri Lanka and the Western Ghats of India.  The earlier distribution range of the Frogmouth was from the Uttara Kannada District of Karnataka to the southern tip of India and most of Sri Lanka.  Recently, the range has been extended further north to Goa and up to Mumbai in Maharashtra.  A number of observations summarized into 202 distributional records (published reports and records uploaded to eBird basic data set, Oriental Bird Images, and GBIF.org from the years 1862 to 2015) of the Frogmouth have been tabulated with its maps, and reviewed for their state-wise distribution records.  The need of undertaking surveys to fill up the gaps in their distribution range as well as any further northward extension till the culmination of the Western Ghats has been discussed.  It is urged that taxonomical and molecular phylogenetic studies are required to be carried out in different populations of Frogmouths across the entire range.
Sallywalkerana, a replacement name for Walkerana Dahanukar et al. 2016 (Anura: Ranixalidae)
Authors: Dahanukar Neelesh , Modak Nikhil , Krutha Keerthi , Nameer P. O. , Padhye Anand D. , Molur Sanjay
Published: September 2016

Dahanukar et al. (2016: pp. 9234) made available the genus name Walkerana (type species: Ixalus diplostictus Günther, 1876: 574, Pl. 63 fig. C) within family Ranixalidae for the monophyletic group with reduced webbing endemic to the Western Ghats of India south of Palghat gap. We were unaware that this name was preoccupied by Walkerana Otte and Perez-Gelabert in Otte 2009, in Insecta: Orthoptera: Gryllidae. As a result, a replacement name for this genus of frogs becomes necessary. Here we propose Sallywalkerana gen. nov. as the replacement name for Walkerana Dahanukar, Modak, Krutha, Nameer, Padhye & Molur, 2016.