bluuebunny/crossref_metadata_2025 huggingface dataset:
Emerin Deregulation Links Nuclear Shape Instability to Metastatic Potential
Authors: Reis-Sobreiro Mariana , Chen Jie-Fu , Novitskaya Tatiana , You Sungyong , Morley Samantha , Steadman Kenneth , Gill Navjot Kaur , Eskaros Adel , Rotinen Mirja , Chu Chia-Yi , Chung Leland W.K. , Tanaka Hisashi , Yang Wei , Knudsen Beatrice S. , Tseng Hsian-Rong , Rowat Amy C. , Posadas Edwin M. , Zijlstra Andries , Di Vizio Dolores , Freeman Michael R.
Published: August 2018

Abnormalities in nuclear shape are a well-known feature of cancer, but their contribution to malignant progression remains poorly understood. Here, we show that depletion of the cytoskeletal regulator, Diaphanous-related formin 3 (DIAPH3), or the nuclear membrane–associated proteins, lamin A/C, in prostate and breast cancer cells, induces nuclear shape instability, with a corresponding gain in malignant properties, including secretion of extracellular vesicles that contain genomic material. This transformation is characterized by a reduction and/or mislocalization of the inner nuclear membrane protein, emerin. Consistent with this, depletion of emerin evokes nuclear shape instability and promotes metastasis. By visualizing emerin localization, evidence for nuclear shape instability was observed in cultured tumor cells, in experimental models of prostate cancer, in human prostate cancer tissues, and in circulating tumor cells from patients with metastatic disease. Quantitation of emerin mislocalization discriminated cancer from benign tissue and correlated with disease progression in a prostate cancer cohort. Taken together, these results identify emerin as a mediator of nuclear shape stability in cancer and show that destabilization of emerin can promote metastasis.

Significance: This study identifies a novel mechanism integrating the control of nuclear structure with the metastatic phenotype, and our inclusion of two types of human specimens (cancer tissues and circulating tumor cells) demonstrates direct relevance to human cancer.

Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/21/6086/F1.large.jpg. Cancer Res; 78(21); 6086–97. ©2018 AACR.
Inverse Correlation of STAT3 and MEK Signaling Mediates Resistance to RAS Pathway Inhibition in Pancreatic Cancer
Authors: Nagathihalli Nagaraj S. , Castellanos Jason A. , Lamichhane Purushottam , Messaggio Fanuel , Shi Chanjuan , Dai Xizi , Rai Priyamvada , Chen Xi , VanSaun Michael N. , Merchant Nipun B.
Published: August 2018

Major contributors to therapeutic resistance in pancreatic ductal adenocarcinoma (PDAC) include Kras mutations, a dense desmoplastic stroma that prevents drug delivery to the tumor, and activation of redundant signaling pathways. We have previously identified a mechanistic rationale for targeting STAT3 signaling to overcome therapeutic resistance in PDAC. In this study, we investigate the molecular mechanisms underlying the heterogeneous response to STAT3 and RAS pathway inhibition in PDAC. Effects of JAK/STAT3 inhibition (STAT3i) or MEK inhibition (MEKi) were established in Ptf1acre/+; LSL-KrasG12D/+; and Tgfbr2flox/flox (PKT) mice and patient-derived xenografts (PDX). Amphiregulin (AREG) levels were determined in serum from human patients with PDAC, LSL-KrasG12D/+;Trp53R172H/+;Pdx1Cre/+ (KPC), and PKT mice. MEKi/STAT3i–treated tumors were analyzed for integrity of the pancreas and the presence of cancer stem cells (CSC). We observed an inverse correlation between ERK and STAT3 phosphorylation. MEKi resulted in an immediate activation of STAT3, whereas STAT3i resulted in TACE-induced, AREG-dependent activation of EGFR and ERK. Combined MEKi/STAT3i sustained blockade of ERK, EGFR, and STAT3 signaling, overcoming resistance to individual MEKi or STAT3i. This combined inhibition attenuated tumor growth in PDX and increased survival of PKT mice while reducing serum AREG levels. Furthermore, MEKi/STAT3i altered the PDAC tumor microenvironment by depleting tumor fibrosis, maintaining pancreatic integrity, and downregulating CD44+ and CD133+ CSCs. These results demonstrate that resistance to MEKi is mediated through activation of STAT3, whereas TACE-AREG-EGFR–dependent activation of RAS pathway signaling confers resistance to STAT3 inhibition. Combined MEKi/STAT3i overcomes these resistances and provides a novel therapeutic strategy to target the RAS and STAT3 pathway in PDAC.

Significance: This report describes an inverse correlation between MEK and STAT3 signaling as key mechanisms of resistance in PDAC and shows that combined inhibition of MEK and STAT3 overcomes this resistance and provides an improved therapeutic strategy to target the RAS pathway in PDAC.

Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/21/6235/F1.large.jpg. Cancer Res; 78(21); 6235–46. ©2018 AACR.
A Mutant p53-Dependent Embryonic Stem Cell Gene Signature Is Associated with Augmented Tumorigenesis of Stem Cells
Authors: Koifman Gabriela , Shetzer Yoav , Eizenberger Shay , Solomon Hilla , Rotkopf Ron , Molchadsky Alina , Lonetto Giuseppe , Goldfinger Naomi , Rotter Varda
Published: August 2018

Mutations in the tumor suppressor p53 are the most frequent alterations in human cancer. These mutations include p53-inactivating mutations as well as oncogenic gain-of-function (GOF) mutations that endow p53 with capabilities to promote tumor progression. A primary challenge in cancer therapy is targeting stemness features and cancer stem cells (CSC) that account for tumor initiation, metastasis, and cancer relapse. Here we show that in vitro cultivation of tumors derived from mutant p53 murine bone marrow mesenchymal stem cells (MSC) gives rise to aggressive tumor lines (TL). These MSC-TLs exhibited CSC features as displayed by their augmented oncogenicity and high expression of CSC markers. Comparative analyses between MSC-TL with their parental mutant p53 MSC allowed for identification of the molecular events underlying their tumorigenic properties, including an embryonic stem cell (ESC) gene signature specifically expressed in MSC-TLs. Knockout of mutant p53 led to a reduction in tumor development and tumorigenic cell frequency, which was accompanied by reduced expression of CSC markers and the ESC MSC-TL signature. In human cancer, MSC-TL ESC signature–derived genes correlated with poor patient survival and were highly expressed in human tumors harboring p53 hotspot mutations. These data indicate that the ESC gene signature–derived genes may serve as new stemness-based prognostic biomarkers as well as novel cancer therapeutic targets.

Significance: Mesenchymal cancer stem cell-like cell lines express a mutant p53-dependent embryonic stem cell gene signature, which can serve as a potential prognostic biomarker and therapeutic target in cancer. Cancer Res; 78(20); 5833–47. ©2018 AACR.
PTTG and PBF Functionally Interact with p53 and Predict Overall Survival in Head and Neck Cancer
Authors: Read Martin L. , Modasia Bhavika , Fletcher Alice , Thompson Rebecca J. , Brookes Katie , Rae Peter C. , Nieto Hannah R. , Poole Vikki L. , Roberts Sally , Campbell Moray J. , Boelaert Kristien , Turnell Andrew S. , Smith Vicki E. , Mehanna Hisham , McCabe Christopher J.
Published: August 2018

Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide and poses a significant health burden due to its rising incidence. Although the proto-oncogene pituitary tumor–transforming gene 1 (PTTG) predicts poor patient outcome, its mechanisms of action are incompletely understood. We show here that the protein PBF modulates PTTG function, is overexpressed in HNSCC tumors, and correlates with significantly reduced survival. Lentiviral shRNA attenuation of PTTG or PBF expression in HNSCC cells with either wild-type or mutant p53, and with and without HPV infection, led to dysregulated expression of p53 target genes involved in DNA repair and apoptosis. Mechanistically, PTTG and PBF affected each other's interaction with p53 and cooperated to reduce p53 protein stability in HNSCC cells independently of HPV. Depletion of either PTTG or PBF significantly repressed cellular migration and invasion and impaired colony formation in HNSCC cells, implicating both proto-oncogenes in basic mechanisms of tumorigenesis. Patients with HNSCC with high tumoral PBF and PTTG had the poorest overall survival, which reflects a marked impairment of p53-dependent signaling.

Significance: These findings reveal a complex and novel interrelationship between the expression and function of PTTG, PBF, and p53 in human HNSCC that significantly influences patient outcome. Cancer Res; 78(20); 5863–76. ©2018 AACR.
Clinical Proteomics of Breast Cancer Reveals a Novel Layer of Breast Cancer Classification
Authors: Yanovich Gali , Agmon Hadar , Harel Michal , Sonnenblick Amir , Peretz Tamar , Geiger Tamar
Published: August 2018

Breast cancer classification has been the focus of numerous worldwide efforts, analyzing the molecular basis of breast cancer subtypes and aiming to associate them with clinical outcome and to improve the current diagnostic routine. Genomic and transcriptomic profiles of breast cancer have been well established, however the proteomic contribution to these profiles has yet to be elucidated. In this work, we utilized mass spectrometry–based proteomic analysis on more than 130 clinical breast samples to demonstrate intertumor heterogeneity across three breast cancer subtypes and healthy tissue. Unsupervised analysis identified four proteomic clusters, among them, one that represents a novel luminal subtype characterized by increased PI3K signaling. This subtype was further validated using an independent protein-based dataset, but not in two independent transcriptome cohorts. These results demonstrate the importance of deep proteomic analysis, which may affect cancer treatment decision making.

Significance: These findings utilize extensive proteomics to identify a novel luminal breast cancer subtype, highlighting the added value of clinical proteomics in breast cancer to identify unique features not observable by genomic approaches. Cancer Res; 78(20); 6001–10. ©2018 AACR.
Ribonucleotide Excision Repair Is Essential to Prevent Squamous Cell Carcinoma of the Skin
Authors: Hiller Björn , Hoppe Anja , Haase Christa , Hiller Christina , Schubert Nadja , Müller Werner , Reijns Martin A.M. , Jackson Andrew P. , Kunkel Thomas A. , Wenzel Jörg , Behrendt Rayk , Roers Axel
Published: August 2018

Because of imperfect discrimination against ribonucleoside triphosphates by the replicative DNA polymerases, large numbers of ribonucleotides are incorporated into the eukaryotic nuclear genome during S-phase. Ribonucleotides, by far the most common DNA lesion in replicating cells, destabilize the DNA, and an evolutionarily conserved DNA repair machinery, ribonucleotide excision repair (RER), ensures ribonucleotide removal. Whereas complete lack of RER is embryonically lethal, partial loss-of-function mutations in the genes encoding subunits of RNase H2, the enzyme essential for initiation of RER, cause the SLE-related type I interferonopathy Aicardi-Goutières syndrome. Here, we demonstrate that selective inactivation of RER in mouse epidermis results in spontaneous DNA damage and epidermal hyperproliferation associated with loss of hair follicle stem cells and hair follicle function. The animals developed keratinocyte intraepithelial neoplasia and invasive squamous cell carcinoma with complete penetrance, despite potent type I interferon production and skin inflammation. These results suggest that compromises to RER-mediated genome maintenance might represent an important tumor-promoting principle in human cancer.

Significance: Selective inactivation of ribonucleotide excision repair by loss of RNase H2 in the murine epidermis results in spontaneous DNA damage, type I interferon response, skin inflammation, and development of squamous cell carcinoma. Cancer Res; 78(20); 5917–26. ©2018 AACR.
Intensive Surveillance with Biannual Dynamic Contrast-Enhanced Magnetic Resonance Imaging Downstages Breast Cancer in BRCA1 Mutation Carriers
Authors: Guindalini Rodrigo Santa Cruz , Zheng Yonglan , Abe Hiroyuki , Whitaker Kristen , Yoshimatsu Toshio F. , Walsh Tom , Schacht David , Kulkarni Kirti , Sheth Deepa , Verp Marion S. , Bradbury Angela R. , Churpek Jane , Obeid Elias , Mueller Jeffrey , Khramtsova Galina , Liu Fang , Raoul Akila , Cao Hongyuan , Romero Iris L. , Hong Susan , Livingston Robert , Jaskowiak Nora , Wang Xiaoming , Debiasi Marcio , Pritchard Colin C. , King Mary-Claire , Karczmar Gregory , Newstead Gillian M. , Huo Dezheng , Olopade Olufunmilayo I.
Published: August 2018

Purpose:

To establish a cohort of high-risk women undergoing intensive surveillance for breast cancer.

Experimental Design: We performed dynamic contrast-enhanced MRI every 6 months in conjunction with annual mammography (MG). Eligible participants had a cumulative lifetime breast cancer risk ≥20% and/or tested positive for a pathogenic mutation in a known breast cancer susceptibility gene.

Results:

Between 2004 and 2016, we prospectively enrolled 295 women, including 157 mutation carriers (75 BRCA1, 61 BRCA2); participants' mean age at entry was 43.3 years. Seventeen cancers were later diagnosed: 4 ductal carcinoma in situ (DCIS) and 13 early-stage invasive breast cancers. Fifteen cancers occurred in mutation carriers (11 BRCA1, 3 BRCA2, 1 CDH1). Median size of the invasive cancers was 0.61 cm. No patients had lymph node metastasis at time of diagnosis, and no interval invasive cancers occurred. The sensitivity of biannual MRI alone was 88.2% and annual MG plus biannual MRI was 94.1%. The cancer detection rate of biannual MRI alone was 0.7% per 100 screening episodes, which is similar to the cancer detection rate of 0.7% per 100 screening episodes for annual MG plus biannual MRI. The number of recalls and biopsies needed to detect one cancer by biannual MRI were 2.8 and 1.7 in BRCA1 carriers, 12.0 and 8.0 in BRCA2 carriers, and 11.7 and 5.0 in non-BRCA1/2 carriers, respectively.

Conclusions:

Biannual MRI performed well for early detection of invasive breast cancer in genomically stratified high-risk women. No benefit was associated with annual MG screening plus biannual MRI screening.

See related commentary by Kuhl and Schrading, p. 1693
Exome Analysis Reveals Genomic Markers Associated with Better Efficacy of Nivolumab in Lung Cancer Patients
Authors: Richard Corentin , Fumet Jean-David , Chevrier Sandy , Derangère Valentin , Ledys Fanny , Lagrange Aurélie , Favier Laure , Coudert Bruno , Arnould Laurent , Truntzer Caroline , Boidot Romain , Ghiringhelli François
Published: August 2018

Purpose:

Immune checkpoint inhibitors revolutionized the treatment of non-small cell lung cancer (NSCLC). However, only one-quarter of patients benefit from these new therapies. PD-L1 assessment and tumor mutational burden (TMB) are available tools to optimize use of checkpoint inhibitors but novel tools are needed. Exome sequencing could generate many variables but their role in identifying predictors of response is unknown.

Experimental Design:

We performed somatic and constitutional exome analyses for 77 patients with NSCLC treated with nivolumab. We studied: one-tumor-related characteristics: aneuploidy, CNA clonality, mutational signatures, TMB, mutations in WNT, AKT, MAPK, and DNA repair pathways, and two-immunologic characteristics: number of intratumoral TCR clones, HLA types, and number of neoantigens; and six clinical parameters.

Results:

A high TMB per Mb, a high number of neoantigens, mutational signatures 1A and 1B, mutations in DNA repair pathways, and a low number of TCR clones are associated with greater PFS. Using a LASSO method, we established an exome-based model with nine exome parameters that could discriminate patients with good or poor PFS (P < 0.0001) and overall survival (P = 0.002). This model shows better ability to predict outcomes compared with a PD-L1 clinical model with or without TMB. It was externally validated on two cohorts of patients with NSCLC treated with pembrolizumab or with nivolumab and ipilimumab as well as in urothelial tumors treated with atezolizumab.

Conclusions:

Altogether, these data provide a validated biomarker that predicts the efficacy of nivolumab or pembrolizumab in patients with NSCLC. Our biomarker seems to be superior to PD-L1 labeling and TMB models.
SD-101 in Combination with Pembrolizumab in Advanced Melanoma: Results of a Phase Ib, Multicenter Study
Authors: Ribas Antoni , Medina Theresa , Kummar Shivaani , Amin Asim , Kalbasi Anusha , Drabick Joseph J. , Barve Minal , Daniels Gregory A. , Wong Deborah J. , Schmidt Emmett V. , Candia Albert F. , Coffman Robert L. , Leung Abraham C.F. , Janssen Robert S.
Published: August 2018

PD-1 inhibitors are approved for treating advanced melanoma, but resistance has been observed. This phase Ib trial evaluated intratumoral SD-101, a synthetic CpG oligonucleotide that stimulates Toll-like receptor 9 (TLR9), in combination with pembrolizumab in patients with unresectable or metastatic malignant melanoma. The most common adverse events related to SD-101 were injection-site reactions and transient, mild-to-moderate “flu-like” symptoms. Among the 9 patients naïve to anti–PD-1 therapy, the overall response rate (ORR) was 78%. The estimated 12-month progression-free survival rate was 88%, and the overall survival rate was 89%. Among 13 patients having prior anti–PD-1 therapy, the ORR was 15%. RNA profiling of tumor biopsies demonstrated increased CD8+ T cells, natural killer cells, cytotoxic cells, dendritic cells, and B cells. The combination of intratumoral SD-101 and pembrolizumab was well tolerated and induced broad immune activation in the tumor microenvironment with durable tumor responses in both peripheral and visceral lesions.

Significance: These early data demonstrate that the combination of pembrolizumab with intratumoral SD-101 is well tolerated and can induce immune activation at the tumor site. Combining an intratumoral TLR9 innate immune stimulant with PD-1 blockade can potentially increase clinical efficacy with minimal additional toxicity relative to PD-1 blockade alone. Cancer Discov; 8(10); 1250–7. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 1195
In Situ Vaccination with a TLR9 Agonist and Local Low-Dose Radiation Induces Systemic Responses in Untreated Indolent Lymphoma
Authors: Frank Matthew J. , Reagan Patrick M. , Bartlett Nancy L. , Gordon Leo I. , Friedberg Jonathan W. , Czerwinski Debra K. , Long Steven R. , Hoppe Richard T. , Janssen Robert , Candia Albert F. , Coffman Robert L. , Levy Ronald
Published: August 2018

This multicenter phase I/II clinical trial evaluated intratumoral SD-101, a TLR9 agonist, and low-dose radiation in patients with untreated indolent lymphoma. Twenty-nine enrolled patients received 4 Gy of radiation followed by 5 weekly intratumoral injections of SD-101 at a single tumor site. No treatment-related grade 4 or serious adverse events occurred. Nearly all patients had tumor reduction at their treated site. More importantly, 24 patients had tumor reduction at their nontreated sites, with 5 patients achieving a partial response and one achieving a complete response. Treatment-related increases of CD8+ and CD4+ effector T cells and decreases of T follicular helper and T regulatory cells (Treg) were observed in the tumor microenvironment. Low pretreatment levels of CD4+ Tregs, proliferating CD8+ T cells, and Granzyme B+ CD8+ T cells were associated with favorable outcomes. Intratumoral SD-101 in combination with low-dose radiation is well tolerated and results in regression of both treated and untreated sites of disease.

Significance: In situ vaccination with the TLR9 agonist SD-101, along with low-dose radiation, was safe and induced systemic responses in patients with indolent lymphoma. Low levels of CD4+ Tregs, proliferating CD8+ T cells, and Granzyme B+ CD8+ T cells in the tumor microenvironment predicted favorable response to treatment. Cancer Discov; 8(10); 1258–69. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 1195
GITR Agonism Enhances Cellular Metabolism to Support CD8+ T-cell Proliferation and Effector Cytokine Production in a Mouse Tumor Model
Authors: Sabharwal Simran S. , Rosen David B. , Grein Jeff , Tedesco Dana , Joyce-Shaikh Barbara , Ueda Roanna , Semana Marie , Bauer Michele , Bang Kathy , Stevenson Christopher , Cua Daniel J. , Zúñiga Luis A.
Published: August 2018

GITR is a costimulatory receptor currently undergoing phase I clinical trials. Efficacy of anti-GITR therapy in syngeneic mouse models requires regulatory T-cell depletion and CD8+ T-cell costimulation. It is increasingly appreciated that immune cell proliferation and function are dependent on cellular metabolism. Enhancement of diverse metabolic pathways leads to different immune cell fates. Little is known about the metabolic effects of GITR agonism; thus, we investigated whether costimulation via GITR altered CD8+ T-cell metabolism. We found activated, GITR-treated CD8+ T cells upregulated nutrient uptake, lipid stores, glycolysis, and oxygen consumption rate (OCR) in vitro. Using MEK, PI3Kδ, and metabolic inhibitors, we show increased metabolism is required, but not sufficient, for GITR antibody (DTA-1)-induced cellular proliferation and IFNγ production. In an in vitro model of PD-L1–induced CD8+ T-cell suppression, GITR agonism alone rescued cellular metabolism and proliferation, but not IFNγ production; however, DTA-1 in combination with anti–PD-1 treatment increased IFNγ production. In the MC38 mouse tumor model, GITR agonism significantly increased OCR and IFNγ and granzyme gene expression in both tumor and draining lymph node (DLN) CD8+ T cells ex vivo, as well as basal glycolysis in DLN and spare glycolytic capacity in tumor CD8+ T cells. DLN in GITR-treated mice showed significant upregulation of proliferative gene expression compared with controls. These data show that GITR agonism increases metabolism to support CD8+ T-cell proliferation and effector function in vivo, and that understanding the mechanism of action of agonistic GITR antibodies is crucial to devising effective combination therapies. Cancer Immunol Res; 6(10); 1199–211. ©2018 AACR.
Neun-Jahres-Ergebnisse zur Ranibizumab-Monotherapie der choroidalen Neovaskularisation infolge pathologischer Myopie
Authors: Pastore Marco , Capuano Vittorio , Bruyère Elsa , Miere Alexandra , Corbelli Eleonora , Querques Lea , Tognetto Daniele , Bandello Francesco , Querques Giuseppe , Souied Eric
Published: August 2018

Zweck: Mit der vorliegenden Studie sollten die 9-Jahres-Ergebnisse der Behandlung der myopen choroidalen Neovaskularisation (mCNV) mit Ranibizumab als Monotherapie beurteilt werden. Methoden: Es handelt sich um eine retrospektive, nicht randomisierte Multicenterstudie zur Beurteilung der Langzeitergebnisse einer mindestens 9-jährigen Behandlung der mCNV mit Ranibizumab als Monotherapie gemäß einem streng bedarfsbasierten Therapieschema. Ergebnisse: In die Studie wurden 17 Augen von 17 Patienten (12 Frauen; Durchschnittsalter 57,9 ± 7,7 Jahre) eingeschlossen. Die mittlere Nachbeobachtungsdauer betrug 112,4 ± 3,9 Monate (Spanne: 108-120). Die mittlere Differenz in der bestkorrigierten Sehschärfe (BCVA) zwischen dem Ausgangswert und der letzten Nachuntersuchung lag bei +1,2 ± 15,6 ETDRS (Early Treatment for Diabetic Retinopathy Study)-Buchstaben (p = 0,004, Ausgangswert vs. 12 und 24 Monate). Die mittlere Gesamtzahl intravitrealer Injektionen bei jedem Patienten betrug 1,24 ± 1,70 pro Jahr (Spanne: 2-25). Während der 9-jährigen Nachbeobachtung wurden keine systemischen Nebenwirkungen im Zusammenhang mit der Arzneimitteltherapie beobachtet. Schlussfolgerungen: Die Langzeit-Monotherapie mit Ranibizumab bewirkt nach 9-jähriger Behandlung bei fast allen Augen eine gegenüber Studienbeginn unveränderte oder verbesserte BCVA. Übersetzung aus Ophthalmologica 2018;239:133-142 (DOI: 10.1159/000485112)
Recanalization for Tight Bile Duct-Jejunum Anastomosis Stricture Using Peroral Transliminal Cholangioscopy (with Video)
Authors: Ogura Takeshi , Miyano Akira , Nishioka Nobu , Higuchi Kazuhide
Published: August 2018

Recently, due to improvement of imaging modality, malignant tumor such as pancreatic or bile duct cancer can be detected at earlier stage. Therefore, the frequency of surgical treatment may be increasing. According to this background, benign biliary stricture in anastomosis site may also be increasing. This complication can lead to repeated cholangitis, obstructive jaundice, or liver abscess. Traditionally, interventional radiology such as percutaneous transhepatic biliary drainage (PTCD) or surgical re-anastomosis may be the first choice of treatment for benign biliary stricture in anastomosis site. Recently, double balloon enteroscopy-assisted endoscopic retrograde cholangiopancreatography (DB-ERCP) has emerged. This relatively novel procedure has less invasiveness compared with PTCD or surgical re-anastomosis. However, DB-ERCP has also several disadvantages such as long procedure time or low technical success rate if DB-ERCP is performed by non-expert hands. On the other hand, endoscopic ultrasound-guided biliary drainage has been developed as alternative biliary drainage technique. More recently, novel transluminal approach for biliary tract through endoscopic ultrasound-guided transluminal drainage route has been reported using digital single-operator cholangioscope. We herein report technical tips for peroral transluminal cholangioscopy using digital single-operator cholangioscope, and successfully performed recanalization for tight stricture of bile duct-jejunum anastomosis.
Low-Volume Leukapheresis in Non-Cytokine-Stimulated Donors for the Collection of Mononuclear Cells
Authors: Anyanwu Adamma , Sitzmann Nicole , Hetjens Svetlana , Klüter Harald , Wuchter Patrick
Published: August 2018

Background: There is an increasing demand for products containing mononuclear cells (MNCs) for cellular immune therapy. Hence, leukapheresis is increasingly performed in healthy volunteer donors. Methods: We evaluated 147 low-volume leukapheresis procedures from 77 healthy non-cytokine-stimulated donors. Complete blood counts (CBCs) of the donors were measured before and directly after the procedures as well as from the MNC products. Follow-up CBCs were collected from donors within 21 days. Results: The product hematocrit within a range from 1.2 to 6.0% did not correlate with the collection efficiency of any cell population or the granulocyte and platelet yield. There was a strong correlation between the CBC values before leukapheresis and the cell yield of lymphocytes and monocytes as well as a perfect negative correlation between cell recruitment and cell loss in all cell populations. Furthermore, we observed a significant decrease in the CBC values in all cell populations directly after leukapheresis, which recovered within a mean of 16.1 days (SD ± 2.1 days) and even showed a significant increase in granulocytes and platelets. Conclusion: Low-volume leukapheresis is feasible for the collection of MNCs in which the product hematocrit is negligible for the collection efficiency, cell yield, or contamination of residual cells under operational settings recommended by the manufacturer. Our data suggests that cell recruitment is regulated by the number of cells removed, which may also be the stimulus to induce granulo- and thrombopoiesis within the first days after leukapheresis.
Nichtansprechen auf Therapie bei Strahlenmakulopathie - frühzeitiger Therapiewechsel verbessert Ergebnisse
Authors: Seibel Ira
Published: August 2018

Background/Aims: To investigate the efficacy of intravitreal aflibercept as rescue therapy for post-radiation cystoid macular edema (CME) resistant to prior treatment with intravitreal bevacizumab (IVB). Methods: Retrospective, interventional, case-controlled series. Eyes with persistent post-radiation CME were treated with intravitreal aflibercept (2 mg/0.05 mL). Central macular thickness (CMT) and visual acuity were compared to a matched control group treated with only IVB at 1 year. Results: Ten eyes of 10 patients were included, with 5 eyes in the intervention and 5 in the control group. The eyes in the intervention group had previously been treated with IVB (mean 11.6 injections, range 6-22) but failed to show resolution of CME. Following rescue treatment with a mean of 9 injections of aflibercept, the mean CMT was reduced from 463 ± 138 to 267 ± 80 μm (p = 0.02) and the mean Snellen visual acuity was improved from 20/67 to 20/42 (p = 0.03). At 1 year, the eyes in the intervention group had lower CMT (267 ± 80 vs. 361 ± 71 μm, p = 0.09) and significantly better Snellen visual acuity (20/48 vs. 20/76, p = 0.02) compared to the control group. Conclusions: Aflibercept may be an effective rescue therapy for persistent post-radiation CME in eyes with incomplete response to IVB, with reduction in CMT and improvement in visual acuity.
Association of Menopausal Symptoms with Different Constitutions in Climacteric Women
Authors: Wu Hsien-Chang , Chen Kuo-Hu , Hwang Jing-Shiang
Published: August 2018

Objective: The aim of this study was to assess the correlation between the body constitution and menopausal symptoms in climacteric women. Methods: This cross-sectional study recruited 427 women aged 40-60 years from the hospital and nearby community. In addition to filling out a questionnaire on menopause rating scale - Traditional Chinese version, the participants completed the body constitution questionnaire. This classifies a person to 1 or more of 3 imbalanced constitutional types, which are yin-xu, yang-xu and stasis-stagnation. We constructed logistic regression models to estimate probabilities of the menopausal symptoms among climacteric women presenting with various menopausal status and differing body constitutions. Results: The frequency and scores of the yin-xu, yang-xu, and stasis-stagnation constitutions were significantly higher in perimenopausal and postmenopausal than premenopausal women. Compared to the non-constitution women, the odds ratio of having hot flushes, sleeping disorders, sexual problems, irritability, and anxiety were significantly higher with the yin-xu constitution. The women with a yang-xu constitution had significantly higher odds ratios for having bladder problems, muscle and joint problems, depressive mood, and heart discomfort. Symptoms of heart discomfort, physical and mental exhaustion, and sleeping disorders were correlated to the stasis-stagnation constitution. Conclusion: With the additional key symptoms related to the 3 constitutional types, physicians performing traditional Chinese medicine (TCM) are able to diagnose the menopausal syndrome more accurately. Integrating menopausal symptoms with TCM constitutional theory will contribute to a more rapid diagnosis and treatment of menopausal syndrome.
MACUSTAR: Development and Clinical Validation of Functional, Structural, and Patient-Reported Endpoints in Intermediate Age-Related Macular Degeneration
Authors: Finger Robert P. , Schmitz-Valckenberg Steffen , Schmid Matthias , Rubin Gary S. , Dunbar Hannah , Tufail Adnan , Crabb David P. , Binns Alison , Sánchez Clara I. , Margaron Philippe , Normand Guillaume , Durbin Mary K. , Luhmann Ulrich F.O. , Zamiri Parisa , Cunha-Vaz José , Asmus Friedrich , Holz Frank G. ,   on behalf of the MACUSTAR consortium
Published: August 2018

Purpose: Currently, no outcome measures are clinically validated and accepted as clinical endpoints by regulatory agencies for drug development in intermediate age-related macular degeneration (iAMD). The MACUSTAR Consortium, a public-private research group funded by the European Innovative Medicines Initiative intends to close this gap. Procedures: Development of study protocol and statistical analysis plan including predictive modelling of multimodal endpoints based on a review of the literature and expert consensus. Results: This observational study consists of a cross-sectional and a longitudinal part. Functional outcome measures assessed under low contrast and low luminance have the potential to detect progression of visual deficit within iAMD and to late AMD. Structural outcome measures will be multimodal and investigate topographical relationships with function. Current patient-reported outcome measures (PROMs) are not acceptable to regulators and may not capture the functional deficit specific to iAMD with needed precision, justifying development of novel PROMs for iAMD. The total sample size will be n = 750, consisting mainly of subjects with iAMD (n = 600). Conclusions: As clinical endpoints currently accepted by regulators cannot detect functional loss or patient-relevant impact in iAMD, we will clinically validate novel candidate endpoints for iAMD.
Safe Stereotactic Biopsy for Basal Ganglia Lesions: Avoiding Injury to the Basal Perforating Arteries
Authors: Sato Sumito , Dan Mitsuru , Hata Hirofumi , Miyasaka Kazuhiro , Hanihara Mitsuto , Shibahara Ichiyo , Inoue Yusuke , Kumabe Toshihiro
Published: August 2018

Background: One of the most serious complications of stereotactic biopsy is postoperative symptomatic hemorrhage due to injury to the basal perforating arteries such as the lenticulostriate arteries neighboring the basal ganglia lesions. Objectives: A new target-planning method was proposed to reduce hemorrhagic complications by avoiding injury to the perforating arteries. Methods: Three-dimensional 3-T time-of-flight (3D 3-T TOF) imaging was applied to delineate the basal perforating arteries such as the lenticulostriate arteries. The incidence of postoperative hemorrhage in basal ganglia cases was compared between a new method using 3D 3-T TOF and a conventional target-planning method based on contrast-enhanced T1-weighted magnetic resonance images obtained by 1.5-T scanning. Results: 3D 3-T TOF imaging could delineate the basal perforating arteries sufficiently in target planning. No postoperative hemorrhage occurred with the new method (n = 10), while 6 postoperative hemorrhages occurred with the conventional method (n = 14). The new method significantly reduced the occurrence of postoperative hemorrhages (p = 0.017). Conclusions: 3D 3-T TOF MR imaging with contrast medium administration provides useful information about the perforating arteries and allows safe stereotactic biopsy of basal ganglia lesions.
Extracranial Metastases of a Cerebral Glioblastoma: A Case Report and Review of the Literature
Authors: Rosen Jurij , Blau Tobias , Grau Stefan J. , Barbe Michael T. , Fink Gereon R. , Galldiks Norbert
Published: August 2018

The glioblastoma, a malignant human brain tumor, is known for its devastating intracranial progress and its dismal prognosis. Whereas treatment and research are most prominently focused on the primary tumor lesion, in recent years evidence has accumulated that points to the rare occurrence of extracranial glioblastoma metastases. We here present a case of a female patient with a known glioblastoma who was detected to harbor multiple metastases in the bones, lung, pleura, liver, mesentery, and the subcutaneous soft tissue. Pathogenetically, these metastatic lesions developed most probably after a local progression of the left temporal glioblastoma through the skull base, thus getting access to the systemic lymphatics. Similar cases of extensive glioblastoma metastization, their putative underlying mechanisms, and implications for clinical care are discussed.
Comprehensive Examination of Therapies for Pain in Parkinson’s Disease: A Systematic Review and Meta-Analysis
Authors: Qureshi Abdul Rehman , Rana Abdul Qayyum , Malik Suleiman H. , Rizvi Syed Fayyaz H. , Akhter Shakib , Vannabouathong Christopher , Sarfraz Zainab , Rana Ruqqiyah
Published: August 2018

Pain in Parkinson’s disease (PD) is a debilitating symptom with a prevalence of 68%, yet is untreated 50% of the time. What is unclear, however, is which treatment is optimal for minimizing pain severity in PD. Thus, the objective of this systematic review and meta-analysis was to investigate the efficacy of a variety of novel, complimentary, and conventional treatments for pain in PD and elucidate which therapy is the most effective. A systematic search was performed using MEDLINE, PsycINFO, Embase, CINAHL, and CENTRAL databases. To identify additional articles, manual searches of reference lists of included trials were also searched. Major neurology conference proceedings occurring between January 2014 and February 2018 were also searched to identify unpublished studies that may be potentially eligible. Twenty-five randomized controlled trials that encompassed medical, surgical, and complementary therapies met our inclusion criteria and exhibited moderate quality evidence. Two reviewers conducted assessments for study eligibility, risk of bias, data extraction, and quality of evidence rating. A conservative random-effects model was used to pool effect estimates of pain severity. The greatest reductions in pain were found with safinamide (Standardized mean difference = –4.83, 95% CI [–5.07 to –4.59], p < 0.0001), followed by cannabinoids and opioids, multidisciplinary team care, catechol-O-methyltransferase inhibitors, and electrical and Chinese therapies. Moderate effects in reducing pain were in pardoprunox and surgery, while the weakest effects were in dopaminergic agonists and miscellaneous therapies. Safinamide is an important adjunct to standard parkinsonian medication for alleviating pain in PD.
Assessing Renal Recovery after Acute Kidney Injury: Can Biomarkers Help?
Authors: Endre Zoltán H.
Published: August 2018

While there are no clear definitions of recovery, it is clear that the goals of recovery depend on the severity of acute kidney injury and the clinical context. The degree of renal recovery affects both renal and clinical prognosis. There are presently few guidelines on recovery targets, which range in extent from dialysis independence via normalization of serum creatinine to recovery of renal functional reserve. However, while there are no validated biomarkers for predicting recovery, evidence suggests that both functional and damage biomarkers can aid the assessment of recovery.
Synergism between Female Gender and High Levels of Daily Stress Associated with Migraine Headaches in Ontario, Canada
Authors: Slatculescu Andreea M. , Chen Yue
Published: August 2018

Background: Migraines affect women more than men and originate from interactions of genetic and environmental factors. This study assessed the prevalence of migraines in Ontario, Canada and the effect of gender and stress on migraines. Methods: Our analysis was based on data from 42,282 persons 12 years or older who participated in the 2013–2014 Canadian Community Health Survey. Multivariate log-binomial model was used to calculate adjusted prevalence ratios for migraines associated with individual and joint exposures of female gender and stress. We used relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (S index) to measure additive interaction. Results: The prevalence of migraines was 10.7%. The adjusted prevalence ratios were 2.37 (95% CI 2.13–2.63) for female versus male, 1.63 (95% CI 1.39–1.90) for persons with high versus low levels of stress, and 3.38 (95% CI 3.00–3.80) for women with high stress versus men with low stress. The RERI estimate was 0.38 (95% CI 0.04–0.73), the AP estimate was 0.11 (95% CI 0.02–0.21), and the S index was 1.19 (95% CI 1.01–1.41). Conclusion: We report 10.7% prevalence of migraines and synergism between female gender and stress on risk of migraine, suggesting health interventions targeting women under stress may be beneficial.
BrightOcular® Cosmetic Iris Implant: A Spectrum from Tolerability to Severe Morbidity
Authors: Koaik Mona K. , Mansour Ahmad M. , Saad Alain , Farah Samir G.
Published: August 2018

Purpose: The BrightOcular® implants are the newest model of cosmetic iris devices that are currently advertised as safe. The previous generation known as NewColorIris® have had severe ocular side effects and were subsequently withdrawn from the market. There is little literature on the safety profile of BrightOcular® implants. Case Report: Herein we describe two cases with varying degrees of ocular tolerability. The first case had a normal ocular exam 1 year after implantation, whereas the second case had unilateral severe corneal edema requiring explantation of the iris device and Descemet membrane endothelial keratoplasty 9 months after bilateral implantation. Conclusions: These two cases attest to the unpredictability of the results of these cosmetic surgeries. Patients should be counseled about the vision-threatening complications of iris implants.
Evald Ilyenkov’s ‘Creative Marxism’
Authors: Maidansky Andrey , Pavlov Evgeni V.
Published: August 2018

The latest book by Russian philosopher Sergey Mareev consists of two parts: recollections of his teacher Evald Ilyenkov, and reflections on some of the key themes of Ilyenkov’s philosophical heritage. The author traces several polemical lines related to the problem of the ideal (Ilyenkov versus Losev and Lifschitz), dialectics of the abstract and the concrete, the principle of historicism, as well as Ilyenkov’s interpretation of Spinoza and Hegel.
Social Class in China Today
Authors: Westra Richard
Published: August 2018

This article looks anew at questions of social class in China. It does this through the prism of three recent books on China dealing with class. Key problems regarding social class in China treated in the article are those of the constitution of the working class given the fact that China’s workforce is largely composed of a ‘floating population’ of migrants, and of the position of the peasantry which had emerged as the revolutionary agent of the Mao years.
Going and Coming Home in Diasporan Pilgrimage: The Case of Philo’s Ἱεροποµποί and Diaspora-Homeland Relations in Alexandrian Jewish Perspective
Authors: Trotter Jonathan
Published: August 2018

This article focuses on how community-sanctioned pilgrimage to Jerusalem could be employed to establish both the homeland and the diaspora as places of belonging. As a case study, I will analyze Philo’s portrayal of the ἱεροποµποί—a term unique to Philo used to describe those chosen to carry offerings, especially the annual half-shekels—from the diaspora to the Jerusalem temple. I will argue that, according to Philo, the ἱεροποµποί (1) were elected community leaders who functioned as representatives of their communities, (2) enabled those who did not travel to Jerusalem to participate vicariously in sacrifice and pilgrimage, and (3) established both the homeland and the diaspora as places of belonging for their community through providing a context for participating in and perpetuating the collective memory of the Jewish nation, in general, and the Alexandrian Jewish community, in particular.
Nestling begging calls increase predation risk by corvids
Authors: Husby Magne
Published: August 2018

Despite nest predation being the most common cause of breeding failure in open-nesting birds, we have little insight into the cues used by nest predators when they search for nests. So far we have assumed that nest-predating birds are visually oriented while mammal predators to a large extent use scent and auditory cues like nestling begging calls. To evaluate how important nestling begging calls are for corvid nest predators searching for nests, I used artificial nests, which made it possible to find the real costs of the begging without mitigation by parental and nestling behavior. I used paired artificial nests, one with and one without nestling begging call playback. Within 10 days, 62.9% of the nests were predated. The analyses showed that nests with begging calls suffered a significantly higher predation rate than nests without begging calls, especially when the nests were placed close to corvid nests. Moreover, nests with begging calls were predated significantly earlier than nests without begging calls. In artificial nest pairs with both nests predated but on different days, nests with begging calls were predated first. In nest pairs with only one predated nest, nests with begging calls were predated most often. This experiment shows that nestling begging calls imply a cost in terms of increased and earlier nest predation, and that corvids use nestling begging calls as a cue to find and depredate bird nests, challenging earlier expectations.
Benthodytes marianensis, a new species of abyssal elasipodid sea cucumbers (Elasipodida: Psychropotidae) from the Mariana Trench area
Authors: LI YA-NAN , XIAO NING , ZHANG LV-PING , ZHANG HAIBIN
Published: August 2018

Benthodytes marianensis sp. nov., is described from the Mariana Trench at the depth of 5567 m. This is the thirteenth species in Benthodytes Théel, 1882. The new species has a broad brim around the body, dark violet skin, 9 pairs of large dorsal papillae with other papillae of equal or smaller size situated elsewhere, forming two zigzag rows, and some minute papillae scattered around the anterior region. Body wall ossicles are rods, crosses with three or four arms and central apophyses, and crosses of an unusual type. Crosses with four arms and central bipartite, tripartite and tetrapartite apophyses and peculiar cross-shaped ossicles with high apophyses ending in two horizontal arms are present in the dorsum. Large rod-shaped ossicles with bipartite apophyses and crosses with three or four arms and rudimentary apophyses are present on the ventrum. B. marianensis is morphologically most similar to B. incerta, but it is distinguished from B. incerta by the number and arrangement of dorsal large papillae, the broad brim and details of ossicle morphology. The phylogenetic analyses based on (16S, COI) and nuclear genes (H3) all confirm the morphological identification.
The discovery of Euryrhynchidae (Crustacea: Decapoda) in India, with the description of a new genus and species
Authors: GRAVE SAMMY DE , ARJUN CHARAMBILLY PURUSHOTHAMAN , RAGHAVAN RAJEEV
Published: August 2018

A new genus and species of Euryrhynchidae is described from Kerala, India. This freshwater shrimp family was previously only known from northern South America and West Africa. Although the inclusion of the genus in Euryrhynchidae is unequivocal (e.g. shape of the accessory ramus of the antennular flagellum, frontal margin of the carapace, telson ornamentation), the presence of a number of unique characters makes the relative placement of the genus within the family unclear, but likely basal to the other genera. The new genus can be easily distinguished from all others within the family by these characters, e.g. the upper antennular flagellum and its accessory ramus being joined over three divisions, the presence of a reduced carpo-propodal brush and a well-developed branchiostegal groove.
Two new troglobitic species of Oxarthrius Reitter (Coleoptera, Staphylinidae, Pselaphinae) from Brazil
Authors: ASENJO ANGÉLICO , ZAMPAULO ROBSON DE ALMEIDA , FERREIRA RODRIGO LOPES
Published: August 2018

Two new species, Oxarthrius inexpectatus and Oxarthrius aurora, are described from caves in Minas Gerais and Tocantins states in Brazil, respectively. The major diagnostic features are illustrated and a key to the known species from Brazil is given.
Morphology of the immature stages and notes on the natural history of the little-known plume moth Stenoptilodes juanfernandicus Gielis (Lepidoptera: Pterophoridae)
Authors: ESPINOZA-DONOSO SEBASTIÁN , PARRA LUIS E. , GONZÁLEZ-ESPINOZA CRISTÓBAL , VARGAS-ORTIZ MARCELO , VARGAS HÉCTOR A.
Published: August 2018

Stenoptilodes juanfernandicus Gielis, 1991 (Lepidoptera: Pterophoridae) was described from the Juan Fernandez Islands, Chile; it was subsequently recorded from the Galápagos Islands and mainland Ecuador. Its larva and pupa are described and illustrated for the first time with the aid of light and scanning electron microscopy. Descriptions are based on specimens collected as larvae displaying cryptic coloration feeding on inflorescences of Verbena hispida Ruiz & Pav. (Verbenaceae) in the Andes of northern Chile. Several differences were found with the larva and pupa of congeneric representatives, suggesting that immature morphology should be further explored to assess its value in the taxonomy and systematics of Stenoptilodes Zimmerman, 1958. Verbena hispida is the first host plant recorded for S. juanfernandicus, a finding that will be helpful to further explore different Neotropical environments to better characterize the geographic range of this plume moth.