bluuebunny/crossref_metadata_2025 huggingface dataset:
Oxidized Cell-Free DNA Role in the Antioxidant Defense Mechanisms under Stress
Authors: Filev A. D. , Shmarina G. V. , Ershova E. S. , Veiko N. N. , Martynov A. V. , Borzikova M. A. , Poletkina A. A. , Dolgikh O. A. , Veiko V. P. , Bekker A. A. , Chirkov A. V. , Volynshchikov Z. N. , Deviataikina A. S. , Shashin D. M. , Puretskiy V. K. , Tabakov V. J. , Izhevskaya V. L. , Kutsev S. I. , Kostyuk S. V. , Umriukhin P. E.
Published: July 2019

The present study focuses on the investigation of the oxidized cell-free DNA (cfDNA) properties in several experimental models, including cultured cerebellum cells, peripheral blood lymphocytes (PBL), plasma, and hippocampus under an acute and chronic unpredictable stress model in rats. Firstly, our study shows that Spectrum Green fluorescence-labeled oxidized cfDNA fragments were transferred into the cytoplasm of 80% of the cerebellum culture cells; meanwhile, the nonoxidized cfDNA fragments do not pass into the cells. Oxidized cfDNA stimulates the antioxidant mechanisms and induction of transcription factor NRF2 expression, followed by an activation of NRF2 signaling pathway genes—rise of Nrf2 and Hmox1 gene expression and consequently NRF2 protein synthesis. Secondly, we showed that stress increases plasma cfDNA concentration in rats corresponding with the duration of the stress exposure. At the same time, our study did not reveal any significant changes of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) level in PBL of rats under acute or chronic stress, probably due to the significantly increased Nrf2 expression, that we found in such conditions. 8-oxodG is one of the most reliable markers of DNA oxidation. We also found an increased level of 8-oxodG in the hippocampal homogenates and hippocampal dentate gyrus in rats subjected to acute and chronic stress. Taken together, our data shows that oxidized cfDNA may play a significant role in systemic and neuronal physiological mechanisms of stress and adaptation.
Advanced Lipid Technologies® (ALT®): A Proven Formulation Platform to Enhance the Bioavailability of Lipophilic Compounds
Authors: Lopez-Toledano Miguel A. , Saxena Vaibhav , Legassie Jason D. , Liu Haiyang , Ghanta Ajay , Riseman Stephen , Cocilova Courtney , Daak Ahmed , Thorsteinsson Thorsteinn , Rabinowicz Adrian L. , Sancilio Frederick D.
Published: July 2019

Despite recent advances, the drug development process continues to face significant challenges to efficiently improve the poor solubility of active pharmaceutical ingredients (API) in aqueous media or to improve the bioavailability of lipid-based formulations. The inherent high intra- and interindividual variability of absorption of oral lipophilic drug leads to inconsistent and unpredictable bioavailability and magnitude of the therapeutic effect. For this reason, the development of lipid-based drugs remains a challenging endeavour with a high risk of failure. Therefore, effective strategies to assure a predictable, consistent, and reproducible bioavailability and therapeutic effect for lipid-based medications are needed. Different solutions to address this problem have been broadly studied, including the approaches of particle size reduction, prodrugs, salt forms, cocrystals, solid amorphous forms, cyclodextrin clathrates, and lipid-based drug delivery systems such as self-emulsifying systems and liposomes. Here, we provide a brief description of the current strategies commonly employed to increase the bioavailability of lipophilic drugs and present Advanced Lipid Technologies® (ALT®), a combination of different surfactants that has been demonstrated to improve the absorption of omega-3 fatty acids under various physiological and pathological states.
Relationship between Crystalline Lens Thickness and Shape and the Identification of Anterior Ocular Segment Parameters for Predicting the Intraocular Lens Position after Cataract Surgery
Authors: Satou Tsukasa , Shimizu Kimiya , Tsunehiro Shuntaro , Igarashi Akihito , Kato Sayaka , Koshimizu Manabu , Niida Takahiro
Published: July 2019

Purpose. This study was performed to investigate the relationships among crystalline lens shape, actual intraocular lens (IOL) position, and crystalline lens thickness (LT), as measured by anterior segment optical coherence tomography (AS-OCT), and to determine anterior ocular segment parameters that predict postoperative IOL position. Methods. Seventy-nine eyes of 79 patients who underwent uneventful cataract surgery were enrolled. For crystalline lens preoperative anterior segment data, the LT, and anterior, equatorial, and posterior surface depths (ASD, ESD, and PSD, respectively) of crystalline lenses were quantitatively determined. For postoperative anterior segment data, the actual IOL position was quantified. Moreover, the following correlations were analyzed: LT with the ASD, ESD, PSD, and IOL position; IOL position with the ASD, ESD, and PSD; and refractive prediction error with the difference between the predicted postoperative anterior chamber depth (ACD) of the SRK/T formula and the IOL position, ASD, ESD, and PSD (each depth minus the predicted postoperative ACD of the SRK/T formula). Results. The LT was significantly correlated with the ASD (r = -0.65) and PSD (r = 0.41), whereas it was not correlated with the ESD or IOL position. The IOL position was significantly correlated with the ASD (r = 0.67), ESD (r = 0.72), and PSD (r = 0.74). The refractive prediction error was significantly correlated with the difference between the predicted postoperative ACD of the SRK/T formula and the IOL position (r = 0.65), ASD (r = 0.46), ESD (r = 0.54), and PSD (r = 0.58). Conclusions. The ESD and PSD obtained using AS-OCT were highly correlated with the IOL position and significantly correlated with the refractive prediction error. These findings suggest that the ESD and PSD may enhance the accuracy of actual IOL position prediction.
Clinical Aspects of HyFoSy as Tubal Patency Test in Subfertility Workup
Authors: Exalto Niek , Emanuel Mark Hans
Published: July 2019

Background. Tubal patency testing is an essential part of female subfertility evaluation. Traditionally, hysterosalpingography (HSG) was the first step to evaluate tubal patency. However, during the past decade Hysterosalpingo-Contrast Sonography (HyCoSy) was introduced in order to avoid radiation exposure and Hysterosalpingo-Foam Sonography (HyFoSy) has been developed as a safe and less painful alternative. Objectives and Rationale. The aim of this narrative review is to provide an overview of the currently available HyFoSy literature and related clinical aspects. Search Methods. A literature search was conducted using PubMed and Embase from the introduction of HyFoSy to March 2019. Unfortunately, a meta-analysis was not possible due to a too small number of studies, being mutually incomparable for the various subjects of clinical aspects, even for the reliability as a test for tubal patency. Outcomes. Nine small studies concluded that the accuracy and effectiveness as a test for tubal patency of 2D- and 3D-HyFoSy are comparable or even better than HSG or HyCoSy. With or without using Doppler techniques, 3D-HyFoSy does not seem to offer benefits above real-time 2D-HyFoSy. Five studies reported on pain and discomfort during HyFoSy, concluding that HyFoSy is a well-tolerated, less painful procedure compared to HSG, without a need for the use of analgesics. There are suggestions about an increased pregnancy rate in the first three cycles after the procedure but in no studies pregnancy outcome after HyFoSy was compared with other or no intervention. Wider Implications. HyFoSy is a promising and safe alternative for HSG with regard to accuracy and effectiveness. HyFoSy lacks radiation and iodine exposure and is a well-tolerated and less painful procedure than HSG, without the need for analgesics. However more research is needed to make clear statements regarding a therapeutic effect of HyFoSy.
Assessing Biophysical and Physiological Profiles of Scalp Seborrheic Dermatitis in the Thai Population
Authors: Suchonwanit Poonkiat , Triyangkulsri Korn , Ploydaeng Monthanat , Leerunyakul Kanchana
Published: July 2019

Background. Scalp seborrheic dermatitis (SD) is a common and chronic inflammatory skin disease which tends to recur over time. By measuring biophysical properties of the stratum corneum, many studies report abnormal biophysical profiles and their association in various dermatologic diseases. The aim of the study is to analyze the biophysical properties and skin barrier defects of scalp SD compared to healthy controls.Materials and Methods. This study is a cross-sectional study assessing the correlation of various biophysical and physiological profiles in scalp SD. Forty-two Thai participants with scalp SD were enrolled in the study and 40 healthy participants were also enrolled as the control group. Both SD and control group were subjected to a one-time biophysical and physiological properties’ measurement of transepidermal water loss (TEWL), stratum corneum hydration (SCH), skin surface pH, skin surface lipid, and skin roughness.Results. The mean TEWL of lesional skin of SD cases were significantly higher than those of control group (P<0.05). Relating to high mean TEWL, the mean SCH was found to be significantly lower in SD cases (P<0.05). Skin surface lipid was also found to be significantly higher in SD group (P<0.05). However, there were no differences in skin surface pH (P=0.104) and roughness (P=0.308) between the two groups. Pairwise comparison of each subgroup found that moderate and severe SD demonstrated significantly higher mean skin surface lipid than that of control group (P<0.05).Conclusion. Scalp SD may be associated with seborrhea in Thai population. Monitoring of SCH, TEWL, and skin surface lipid could be helpful in assessing severity and evaluating the treatment outcome in patients with scalp SD.
Causes and Clinical Profiles of Ascites at University of Gondar Hospital, Northwest Ethiopia: Institution-Based Cross-Sectional Study
Authors: Muhie Oumer Abdu
Published: July 2019

Background. Ascites is a common clinical condition encountered by physicians in day-to-day practice. It is caused by various underlying diseases. Knowing the etiologies is vital because further investigations and definitive treatment largely rely on the specific disease entity considered. Objective. The aim of this study was to determine the epidemiology of causes of ascites and complications among patients with ascites from the medical department at the University of Gondar Hospital. Methods. Data on sociodemography, major symptoms, and signs, risk factors, past medical illnesses, and results of important investigations were collected using pretested questionnaires among all patients with ascites in the University of Gondar Hospital in a sample size of 52. Data were collected by well-trained physicians and analyzed by using SPSS 16. Results were depicted descriptively with measures of central tendency, dispersion, and using tables and graphs. Results. A total of 52 patients were included in this study from November 1, 2018 to March 30, 2019. Thirty (57.7%) of them were males and the majority (77%) of the participants were fifty years old or younger. The mean age was 43.8 (± 14). The majority (86.5%) of the participants were from a rural area. Thirty-eight (73%) patients take alcohol occasionally while 11(21.2%) patients take alcohol frequently or massively. Eight (15.4%) patients reported a history of multiple sexual partners. Herbal medicine use was reported by 28 patients (53.8%). Only 5 (9.6%) patients were overweight. Chronic liver disease (CLD) was the major cause of ascites in this study in 24 (46.2%) patients. The other main causes of ascites were heart failure from various causes (19.2%), tuberculosis and hepatosplenic schistosomiasis contributing to 11.5% each and chronic kidney disease (5.8%). Five (20.8%) CLD patients had spontaneous bacterial peritonitis as a complication. Five (20.8%) and 4 (16.7%) CLD patients had hepatocellular carcinoma and hepatic encephalopathy as complications, respectively. Nine (17.3%) patients had variceal bleeding; six of the patients were diagnosed to have CLD while the remaining patients were having hepatosplenic schistosomiasis. Conclusion. In conclusion, liver cirrhosis is the major cause of ascites in Gondar, Ethiopia, while chronic viral hepatitis infections (hepatitis B (HBV) and C (HCV) viruses) are the main causes of liver cirrhosis. The other major causes included heart failure, tuberculosis, and hepatosplenic schistosomiasis. It is wise to consider and give priority to these diseases whenever one is evaluating a patient with ascites.
Azithromycin-Induced Thrombocytopenia: A Rare Etiology of Drug-Induced Immune Thrombocytopenia
Authors: Butt Muhammad Umer , Jabri Ahmad , Elayi Samy Claude
Published: July 2019

Drug-induced thrombocytopenia requires a high suspicion for diagnosis and a broad investigation to exclude other etiologies of low platelets. Cessation of the offending agent often results in recovery of platelet counts. Many medications are known to cause a degree of thrombocytopenia. We present a rare case of severe thrombocytopenia associated with administration of azithromycin.
PCDHGB7 Increases Chemosensitivity to Carboplatin by Inhibiting HSPA9 via Inducing Apoptosis in Breast Cancer
Authors: Hou Siqi , Shan Ming , Gao Chunyang , Feng Xinxin , Yang Yongheng , Zhang Ruo , He Yan , Zhang Guoqiang , Zhang Lei
Published: July 2019

Breast cancer is one of the most serious cancers worldwide, and chemotherapy resistance frequently drives cancer progression. Triple-negative breast cancer (TNBC) has a high recurrence rate and poor prognosis given its resistance to chemotherapy. In our previous study, we found a remarkable abnormal methylation modification of the PCDHGB7 gene in breast cancer. However, the roles of PCDHGB7 in the progression and treatment of breast cancer are unclear. In this study, we examined the effects of PCDHGB7 on the sensitivity of TNBC cells to carboplatin and investigated the underlying mechanism. By knocking down and overexpressing PCDHGB7 in HS578T and BT549 cells, we confirmed that PCDHGB7 increases TNBC cell chemosensitivity to carboplatin. Mechanistically, we found that PCDHGB7 negatively regulates the expression of HSPA9, uplifting its inhibition on P53 translocation and caspase-3 activation. Thus, we demonstrated that PCDHGB7 increases chemosensitivity of TNBC cells to carboplatin by inhibiting HSPA9 via inducing apoptosis. PCDHGB7 and HSPA9 represent potential therapeutic targets for chemosensitivity in breast cancer.
Importance of Both Internal and External Iliac Artery Interrogation in Pelvic Trauma as Evidenced by Hemorrhage from Bilateral Corona Mortis with Unilateral Aberrant Origin off the External Iliac Artery
Authors: Herskowitz Michael , Walsh James , Lilly Meghan , McFarland Kimberly
Published: July 2019

Transcatheter angiography and embolization has long been recognized as the gold standard for patients with hemodynamic instability secondary to blunt pelvic trauma. While often the bleeding source can be readily localized based on the distribution of extravasation on preprocedural Computed Tomographic Angiography, one should be cautious in assessment for aberrant anatomy. A variant obturator artery originating from the inferior epigastric branch of the external iliac artery is commonly referred to as the corona mortis. We present a case of blunt pelvic trauma in which a patient demonstrated extravasation in the anterior distributions of both internal iliac arteries. Following embolization of bilateral internal iliac arteries, identification and embolization of bilateral corona mortis branches was crucial to achieving hemodynamic stability in this patient.
Modulation of Conflict Processing by Theta-Range tACS over the Dorsolateral Prefrontal Cortex
Authors: Lehr Albert , Henneberg Niklas , Nigam Tarana , Paulus Walter , Antal Andrea
Published: July 2019

Behavioral response conflict arises in the color-word Stroop task and triggers the cognitive control network. Midfrontal theta-band oscillations correlate with adaptive control mechanisms during and after conflict resolution. In order to prove causality, in two experiments, we applied transcranial alternating current stimulation (tACS) at 6 Hz to the dorsolateral prefrontal cortex (DLPFC) during Stroop task performance. Sham stimulation served as a control in both experiments; 9.7 Hz tACS served as a nonharmonic alpha band control in the second experiment. We employed generalized linear mixed models for analysis of behavioral data. Accuracy remained unchanged by any type of active stimulation. Over both experiments, the Stroop effect (response time difference between congruent and incongruent trials) was reduced by 6 Hz stimulation as compared to sham, mainly in trials without prior conflict adaptation. Alpha tACS did not modify the Stroop effect. Theta tACS can both reduce the Stroop effect and modulate adaptive mechanisms of the cognitive control network, suggesting midfrontal theta oscillations as causally involved in cognitive control.
Sensing Coverage Algorithm of Sparse Mobile Sensor Node with Trade-Off between Packet Loss Rate and Transmission Delay
Authors: Zhao Kehua , Chen Yourong , Lu Siyi , Liu Banteng , Ren Tiaojuan , Wang Zhangquan
Published: July 2019

To solve the problem of sensing coverage of sparse wireless sensor networks, the movement of sensor nodes is considered and a sensing coverage algorithm of sparse mobile sensor node with trade-off between packet loss rate and transmission delay (SCA_SM) is proposed. Firstly, SCA_SM divides the monitoring area into several grids of same size and establishes a path planning model of multisensor nodes’ movement. Secondly, the social foraging behavior of Escherichia coli in bacterial foraging is used. A fitness function formula of sensor nodes’ moving paths is proposed. The optimal moving paths of all mobile sensor nodes which can cover the entire monitoring area are obtained through the operations of chemotaxis, replication, and migration. The simulation results show that SCA_SM can fully cover the monitoring area and reduce the packet loss rate and data transmission delay in the process of data transmission. Under certain conditions, SCA_SM is better than RAND_D, HILBERT, and TCM.
Utilisation of Electronic Health Records for Public Health in Asia: A Review of Success Factors and Potential Challenges
Authors: Dornan Lesley , Pinyopornpanish Kanokporn , Jiraporncharoen Wichuda , Hashmi Ahmar , Dejkriengkraikul Nisachol , Angkurawaranon Chaisiri
Published: July 2019

Introduction. Electronic health records offer a valuable resource to improve health surveillance and evaluation as well as informing clinical decision making. They have been introduced in many different settings, including low- and middle-income countries, yet little is known of the progress and effectiveness of similar information systems within Asia. This study examines the implementation of EHR systems for use at a population health level in Asia and to identify their current role within public health, key success factors, and potential barriers in implementation.Material and Methods. A systematic search process was implemented. Five databases were searched with MeSH key terms and Boolean phrases. Articles selected for this review were based on hospital provider electronic records with a component of implementation, utilisation, or evaluation for health systems or at least beyond direct patient care. A proposed analytic framework considered three interactive components: the content, the process, and the context.Results. Thirty-two articles were included in the review. Evidence suggests that benefits are significant but identifying and addressing potential challenges are critical for success. A comprehensive preparation process is necessary to implement an effective and flexible system.Discussion. Electronic health records implemented for public health can allow the identification of disease patterns, seasonality, and global trends as well as risks to vulnerable populations. Addressing implementation challenges will facilitate the development and efficacy of public health initiatives in Asia to identify current health needs and mitigate future risks.
Optimizing the Management and Outcomes of Failed Back Surgery Syndrome: A Proposal of a Standardized Multidisciplinary Team Care Pathway
Authors: Gatzinsky Kliment , Eldabe Sam , Deneuville Jean-Philippe , Duyvendak Wim , Naiditch Nicolas , Van Buyten Jean-Pierre , Rigoard Philippe
Published: July 2019

Failed back surgery syndrome (FBSS) is a major, worldwide health problem that generates considerable expense for healthcare systems. A number of controversial issues concerning the management of FBSS are regularly debated, but no clear consensus has been reached. This pitfall is the result of lack of a standardized care pathway due to insufficient characterization of underlying pathophysiological mechanisms, which are essential to identify in order to offer appropriate treatment, and the paucity of evidence of treatment outcomes. In an attempt to address the challenges and barriers in the clinical management of FBSS, an international panel of physicians with a special interest in FBSS established the Chronic Back and Leg Pain (CBLP) Network with the primary intention to provide recommendations through consensus on how to optimize outcomes. In the first of a series of two papers, a definition of FBSS was delineated with specification of criteria for patient assessment and identification of appropriate evaluation tools in order to choose the right treatment options. In this second paper, we present a proposal of a standardized care pathway aiming to guide clinicians in their decision-making on how to optimize their management of FBSS patients. The utilization of a multidisciplinary approach is emphasized to ensure that care is provided in a uniform manner to reduce variation in practice and improve patient outcomes.
Cytotoxicity of Crude Extract and Isolated Constituents of theDichrostachys cinereaBark towards Multifactorial Drug-Resistant Cancer Cells
Authors: Mbaveng Armelle T. , Damen Francois , Simo Mpetga James D. , Awouafack Maurice D. , Tane Pierre , Kuete Victor , Efferth Thomas
Published: July 2019

The effectiveness of anticancer chemotherapy is greatly impeded by the resistance of malignant cells to cytotoxic drugs. In this study, the cytotoxicity of the crude extract (DCB) and compounds isolated from the bark ofDichrostachys cinerea,namely, betulinic acid (1), glyceryl-1-hexacosanoate (2), 7-hydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one (3), and 6-hydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one (4), was investigated. The study was extended to the assessment of the mode of induction of apoptosis by DCB and compound1. The resazurin reduction assay was used for cytotoxicity studies. Assessments of cell cycle distribution, apoptosis, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) were performed by flow cytometry. Constituents of DCB were isolated by column chromatography. Triterpenoid1and flavone4had cytotoxic effects towards the 9 tested cancer cell lines with IC50values below 50μM. The recorded IC50values varied from 7.65μM (towards multidrug-resistant CEM-ADR5000 leukemia cells) to 44.17μM (against HepG2 hepatocarcinoma cells) for1, 18.90μM (CCRF-CEM leukemia cells) to 88.86μM (against HCT116p53+/+colon adenocarcinoma cells) for4,and 0.02μM (against CCRF-CEM cells) to 122.96μM (against CEM/ADR5000 cells) for doxorubicin. DCB induced apoptosis in CCRF-CEM cells mostly mediated by MMP alteration and enhanced ROS production; compound1induced apoptosis through caspases activation and MMP alteration and increased ROS production.Dichrostachys cinereais an interesting cytotoxic plant and deserves more studies leading to new antineoplastic agents to fight cancer and mostly leukemia.
Acylated Ghrelin Renders Chemosensitive Ovarian Cancer Cells Resistant to Cisplatin Chemotherapy via Activation of the PI3K/Akt/mTOR Survival Pathway
Authors: El-kott Attalla Farag , Shati Ali A. , Al-kahtani Mohammed Ali , Alqahtani Sultan
Published: July 2019

This study investigated the effect of acylated synthetic ghrelin (AG) on the survival and proliferation of human chemosensitive ovarian cancer cells (A2780) and explored some mechanisms of action with a focus on the p53 apoptotic pathway and PI3K/Akt and NF-κB survival pathways. Human A2780 ovarian cancer cells were cultured with or without AG treatment in the presence or absence of cisplatin. In some cases, cisplatin+AG-treated cells were pre-incubated either with [D-Lys3]-GHRP-6, a ghrelin receptor antagonist, or with LY294002, a PI3K inhibitor. mRNA of ghrelin receptors(GHS-R1a and GHS-R1b), as well as, protein levels of GHS-R1a, were expressed abundantly in A2780 cells. AG treatment did not affect the mRNA and protein levels of GHS-R1a and GHS-R1b in both control and Cis-treated cells. However, while AG treatment had no effect on control cell viability, it significantly increased cell viability and proliferation and inhibited cell death in Cis-treated cells. In both control and Cis-treated cells, AG treatment significantly increased PI3K/Akt/mTOR signaling and enhanced the nuclear accumulation of NF-κB. Concomitantly, in both control and Cis-treated cells, AG significantly lowered the protein levels of p53, p-p53 (Ser16), PUMA, cytochrome C, and cleaved caspase-3. Interestingly, pre-incubating the cells with either [D-Lys3]-GHRP-6 or LY294002 completely abolished the above-mentioned effect of AG in both control and Cis-treated cells. In conclusion, the findings of this study show that AG promotes cell survival of the OC cells and renders them resistat to Cis therapy, an effect that is mediated by the activation of PI3K/Akt/mTOR and activation of NF-κB, and requires GHS-R1a.
Altered Nuclear Export Signal Recognition as a Driver of Oncogenesis
Authors: Taylor Justin , Sendino Maria , Gorelick Alexander N. , Pastore Alessandro , Chang Matthew T. , Penson Alexander V. , Gavrila Elena I. , Stewart Connor , Melnik Ella M. , Herrejon Chavez Florisela , Bitner Lillian , Yoshimi Akihide , Lee Stanley Chun-Wei , Inoue Daichi , Liu Bo , Zhang Xiao J. , Mato Anthony R. , Dogan Ahmet , Kharas Michael G. , Chen Yuhong , Wang Demin , Soni Rajesh K. , Hendrickson Ronald C. , Prieto Gorka , Rodriguez Jose A. , Taylor Barry S. , Abdel-Wahab Omar
Published: July 2019

Altered expression of XPO1, the main nuclear export receptor in eukaryotic cells, has been observed in cancer, and XPO1 has been a focus of anticancer drug development. However, mechanistic evidence for cancer-specific alterations in XPO1 function is lacking. Here, genomic analysis of 42,793 cancers identified recurrent and previously unrecognized mutational hotspots in XPO1. XPO1 mutations exhibited striking lineage specificity, with enrichment in a variety of B-cell malignancies, and introduction of single amino acid substitutions in XPO1 initiated clonal, B-cell malignancy in vivo. Proteomic characterization identified that mutant XPO1 altered the nucleocytoplasmic distribution of hundreds of proteins in a sequence-specific manner that promoted oncogenesis. XPO1 mutations preferentially sensitized cells to inhibitors of nuclear export, providing a biomarker of response to this family of drugs. These data reveal a new class of oncogenic alteration based on change-of-function mutations in nuclear export signal recognition and identify therapeutic targets based on altered nucleocytoplasmic trafficking.

Significance:

Here, we identify that heterozygous mutations in the main nuclear exporter in eukaryotic cells, XPO1, are positively selected in cancer and promote the initiation of clonal B-cell malignancies. XPO1 mutations alter nuclear export signal recognition in a sequence-specific manner and sensitize cells to compounds in clinical development inhibiting XPO1 function.

This article is highlighted in the In This Issue feature, p. 1325
Extrakorporale Photopherese: Studie zum Langzeiteffekt bei chronischer Graft-versus-Host-Reaktion
Authors: Lehmann Percy
Published: July 2019

Background: Extracorporeal photopheresis (ECP) is a second-line therapy for steroid-refractory chronic graft-versus-host disease (cGVHD). Objective: We describe the long-term efficacy and tolerability of ECP according to the cutaneous phenotype of cGVHD and report on the reduced need for immunosuppressant drugs in this setting. Patients and Methods: Fourteen patients (8 females) with cutaneous and/or mucosal cGVHD, treated with ECP between October 2010 and May 2016 within a single center, were included. Final analyses included patients who had received ECP for at least 12 months. We prospectively evaluated the efficacy of ECP using lesion-specific clinical scores and by recording changed doses of systemic immunosuppressants. Results: Of the 14 patients, sclerotic skin lesions were present in 10 (71%). The mRODNAN score decreased in all patients from month 9 onwards, with 40 and 77% reductions at 12 and 36 months, respectively. Six patients (43%) presented with cutaneous lichenoid lesions: this score was reduced in all patients by month 3, reaching a 93% reduction by month 12. Five patients (36%) experienced oral mucosal lichenoid lesions: these scores were decreased by 55% at month 12 and by 100% by month 33. The use of systemic immunosuppressants was reduced in all patients; 4 patients could stop all immunosuppressant drugs after 2 years. ECP was stopped in 3 patients after a complete response. No major ECP-associated adverse effects were observed. Discussion and Conclusion: ECP was an effective long-term therapy for oral and cutaneous cGVHD: consequently, dose levels of therapeutic immunosuppression could be reduced.
Innovative Behandlungskonzepte mit Modulation der Mikroumgebung beim kutanen T-Zell-Lymphom
Authors: Leuchte Katharina , Schlaak Max , Stadler Rudolf , Theurich Sebastian , von Bergwelt-Baildon Michael
Published: July 2019

Kutane T-Zell-Lymphome (CTCL) sinde seltene und biologisch heterogene maligne Erkrankungen; die häufigsten Unterarten sind die Mycosis fungoides und das Sézary-Syndrom. Nach den derzeitigen Therapien ist der Verlauf durch hohe Rezidivraten geprägt, das Überleben ist jedoch in niedrigen Tumorstadien in der Regel nicht signifikant verkürzt. Anders ist dies in höheren Tumorstadien bzw. aggressiveren Subtypen des CTCL; hier ist die Überlebenszeit signifikant reduziert. In jüngster Zeit sind bei verschiedenen Aspekten der Tumorbiologie Fortschritte erzielt worden: Die Genomsequenzierung hat neue Strategien der NF-κB- oder JAK-Inhibition hervorgebracht, in der Translationsforschung wurden neue Zielmoleküle wie CD30 oder CCR4 identifiziert, und nicht zuletzt hat die Forschung zur Beeinträchtigung der Immunüberwachung an Bedeutung gewonnen. Auf der Grundlage der zunehmenden Kenntnis der funktionellen Rollen der Tumormikroumgebung und nichtmaligner infiltrierender Zellen zielt die Forschung gegenwärtig darauf ab, neuartige Behandlungsstrategien bei CTCL zu entwickeln. Im Mittelpunkt dieser Übersichtsarbeit steht die wachsende Evidenz für ein wirksames Targeting tumorinfiltrierender Immunzellen und die dadurch erreichte Modulation der Tumormikroumgebung und Wiederherstellung der Immunüberwachung.
Präventionskonzepte für Nahrungsmittelallergien im Wandel
Authors: Mahler Vera
Published: July 2019

In view of the dramatic rise in the prevalence of food allergy globally, effective prevention strategies have become a public health priority. Several models have emerged around the etiology of food allergy, including the hygiene hypothesis, dual allergen exposure hypothesis, and vitamin D hypothesis. These form the basis for current and potential prevention strategies. Breastfeeding remains a key pillar of primary allergy prevention. Other nutritional interventions, including the use of whey-based, partially hydrolyzed formula in non-breastfed infants, also play an important role. In recent years, there has been a shift away from prolonged food allergen avoidance to the proactive allergen introduction from 4 months of age. This approach is supported by 2 pivotal randomized clinical trials showing that the early introduction of peanut and other food allergens significantly reduces the risk of food allergy. However, the implementation of this strategy at the population level still raises significant logistic problems, including patient selection and development of suitable food formats for young infants. Other prevention strategies, including vitamin D supplementation, are currently under evaluation. Maternal elimination diets during pregnancy and lactation are not recommended for allergy prevention. The treatment of food allergies has also seen major transformations. While strict allergen avoidance is still the key treatment principle, there is a greater focus on desensitization and tolerance induction by oral and epicutaneous immunotherapy. In addition, specialized hypoallergenic infant formulas for the treatment of infants with cow's milk allergy have undergone reformulation, including the addition of lactose and probiotics in order to modulate the gut microbiome and early immune responses. Further research is needed to inform the most effective food allergy prevention strategies at the population level. In addition, the wider application of food allergen immunotherapy may provide better health outcomes and improved quality of life for families affected by food allergies.
Einfluss von Verlaufsfeedback auf die Behandlungseffektivität ambulanter Psychotherapien
Authors: Schöttke Henning , Unrath Michael , Uhlmann Christina
Published: July 2019

Hintergrund: Obwohl die Wirksamkeit ambulanter Psychotherapie bei psychischen Erkrankungen hinreichend belegt wurde, zeigen 5–10% der Patienten eine Verschlechterung im Therapieverlauf. Patienten und Methoden: In dieser randomisierten kontrollierten Studie wurde untersucht, welchen Effekt eine formalisierte therapiebegleitende Rückmeldung an den Therapeuten über Veränderungen der psychischen Belastung, Beeinträchtigung und Therapiemotivation des Patienten auf den Therapieverlauf hat. In einer poliklinischen Psychotherapieambulanz wurden 230 Patienten auf drei Studiengruppen randomisiert verteilt: Verlaufsmessung mit Feedback (EG), Verlaufsmessung ohne Feedback (KG1), keine Verlaufsmessung (KG2). Während der anschließenden verhaltenstherapeutischen Behandlung wurden die Verlaufsmessungen zur Erhebung des Therapie­fortschritts regelmäßig mithilfe des Fragebogens zur Evaluation von Psychotherapieverläufen (FEP-2), des Outcome Questionnaires (OQ-30) und des Assessment for Signal Cases (ASC) durchgeführt. In der EG wurden die Ergebnisse der Verlaufsmessungen den Therapeuten zurückgemeldet. Mittels Varianzanalysen mit Messwiederholungen wurde der Einfluss des Feedbacks auf die Wirksamkeit der Therapien überprüft. Ergebnisse: Die Patienten der drei Studiengruppen unterschieden sich nicht signifikant hinsichtlich sozio­demografischer und erkrankungsrelevanter Variablen. Die psychische Beeinträchtigung aller Gruppen ging im Therapieverlauf zurück. Zwischen den Gruppen zeigten sich keine signifikanten Unterschiede. Bei Therapien, die bis zur ersten Verlaufsmessung keine Verbesserung aufwiesen (n = 49), zeigte sich ebenfalls kein differentieller Effekt des Feedbacks. Diskussion und Schlussfolgerung: Feedback brachte in diesem Studienkollektiv einer Ausbildungsambulanz weder einen globalen noch einen differentiellen Vorteil auf den Therapieverlauf. Um einen potentiellen Feedbackeffekt besser nachweisen zu können, sollten zukünftige Studien eine höhere Frequenz des Feedbacks anstreben, die Einstellung der Therapeuten gegenüber derartigen Feedbacksystemen erheben sowie “Clinical Support Tools” einsetzen.
Topische Therapie bei Psoriasis vulgaris - ein Behandlungspfad
Authors: Philipp Sandra
Published: July 2019

Die topische Therapie besitzt auch im Zeitalter der Biologika und small molecules einen hohen Stellenwert in der Psoriasistherapie, sei es zur Behandlung milder Formen der Psoriasis oder unterstützend bei mittelschweren bis schweren Formen. Neben der Wahl geeigneter Wirkstoffe ist auch die Galenik von Bedeutung, um die Therapie zu optimieren. Der hier vorgestellte Behandlungspfad wurde im Rahmen der PsoNet-Sprecherkonferenz entwickelt und von den Teilnehmern der nationalen Versorgungskonferenz Psoriasis bestätigt. Er beinhaltet die aktuellen Therapieoptionen und stellt diese in einer Grafik dar. Als Goldstandard wird in der Initialtherapie der Plaque-Psoriasis die Fixkombination aus Calcipotriol 50 µg/g und Betamethason-Diproprionat 0,5 mg/g 1 mal täglich über 4 - 8 Wochen empfohlen. Am effektivsten ist der Schaum, jedoch sollte bei der Wahl der Grundlage auch die Patientenpräferenz einbezogen werden. Zur Erhaltungstherapie wird eine 1 - 2 mal wöchentliche (proaktive) Anwendung empfohlen. In zweiter Linie können Vitamin D Analoga und topische Steroide auch als Monotherapien zum Einsatz kommen. Zusätzlich werden spezifische Empfehlungen für besondere Therapiesituationen (Psoriasis inversa, Kopfpsoriasis, palmoplantare Psoriasis) gegeben. Auf die Festlegung von Therapiezielen wird spezieller Wert gelegt. Eine begleitende Basistherapie wird als selbstverständlich vorausgesetzt. Neue topische Wirkstoffe sind in der Pipeline.
Hippocampal Neurogenesis in Conditions of Chronic Stress Induced by Sciatic Nerve Injury in the Rat
Authors: Egorova Evgeniia , Starinets Anna , Tyrtyshnaia Anna , Ponomarenko Arina , Manzhulo Igor
Published: July 2019

The dentate gyrus of the hippocampus is the primary location of adult neurogenesis, which is affected by a variety of external and internal factors, including activity of surrounding glial cells. This study concerns alterations in hippocampal neurogenesis and changes in activity of both proinflammatory and neuroprotective microglia/macrophages after sciatic nerve injury in the rat. Here, we demonstrated that the chronic pain induced by a peripheral nerve injury manifests in the hippocampus by a decrease in proliferation (PCNA+) and neurogenesis (DCX+), an increase in proinflammatory cytokines (CD86+), and a reduction in neuroprotective (CD163+) microglia/macrophages. We suggest that a pathological increase microglia/macrophage activity is the cause of neurogenesis suppression observed in chronic neuropathic pain.
Atypisches Ansprechen mit Pseudoprogression im Knochen unter Nivolumab bei einem Patienten mit fortgeschrittenem kutanem Plattenepithelkarzinom
Authors: Oliveira Leandro J.C. , Gongora Aline B.L. , Barbosa Felipe G. , dos Anjos Carlos , Munhoz Rodrigo R.
Published: July 2019

Derzeit existiert keine etablierte Standardtherapie für Patienten mit metastasiertem cSCC. Wegen der Pathomechanismen, die bei der Karzinogenese des kutanen Plattenepithelkarzinoms eine Rolle spielen, wurde postuliert, dass diese Tumoren möglicherweise durch eine PD-1/PD-L1-Blockade beeinflussbar sind. Der vorliegende Bericht beschreibt den Fall eines Patienten, der wegen eines kutanen Plattenepithelkarzinoms mit Lymphknotenbeteiligung und Lungenmetastasen, das gegenüber 2 Therapielinien mit platinbasierten Schemata und Salvage-Operation refraktär war, eine Behandlung mit Nivolumab erhielt. Der klinische Verlauf war durch ein atypisches Ansprechmuster mit initialem Rückgang der Weichteilläsionen/viszeralen Läsionen bei gleichzeitig neu auftretenden Knochenläsionen gekennzeichnet. In den anschließenden bildgebenden Untersuchungen zeigten sich insgesamt eine Verbesserung und eine anhaltende Krankheitskontrolle unter Fortführung der Therapie. Im vorliegenden Fall erhielt der Patient mit metastasiertem therapierefraktärem cSCC eine Immuntherapie und entwickelte ein atypisches Ansprechmuster.
Novel Human Full-Thickness Three-Dimensional Nonkeratinized Mucous Membrane Model for Pharmacological Studies in Wound Healing
Authors: Schmitt Laurenz , Marquardt Yvonne , Heise Ruth , von Felbert Verena , Amann Philipp M. , Huth Laura , Steiner Timm , Hölzle Frank , Huth Sebastian , Baron Jens Malte
Published: July 2019

Introduction: Efforts are increasingly aiming to develop in vitro models that can provide effective alternatives to in vivo experiments. The main aim of this study was the establishment of an in vitro model of the nonkeratinized mucous membrane that can be used as a standardized tool to evaluate biological and therapeutic effects of pharmaceuticals for mucosal wound healing. Methods: We established a full-thickness in vitro model of the nonkeratinized mucous membrane. While histological examination was performed to assess morphological characteristics, we utilized gene expression profiling using microarray and qRT-PCR analyses to identify molecular effects of treatment with a dexpanthenol-containing ointment after laser wounding. Results: Performing histological and immunofluorescence analyses we proved that our model mimics the two distinctive layers of the mucous membrane – the stratified squamous epithelium and the lamina propria. We used this model to investigate molecular effects of a dexpanthenol-containing ointment that is commonly used for the wound treatment of mucous membranes. For that purpose, our model exhibits a unique feature in that dexpanthenol and proliferation-enhancing additives that may interfere with our studies are not required for the maintenance of the model culture. After setting standardized lesions with a nonsequential fractional ultrapulsed CO2 laser, topical treatment with the dexpanthenol-containing ointment enhanced wound closure in the model compared to placebo and untreated controls. Furthermore, microarray analysis revealed that the treatment of the laser-wounded model with the dexpanthenol-containing ointment evoked an upregulated expression of various genes related to accelerated wound healing. Conclusion: Overall, we verified that this novel mucous membrane model can be utilized in future to monitor ex vivo effects of various topical therapies on mucosa morphology, physiology, and gene expression. Our findings confirm the potential of the model as an in vitro tool for the replacement of pharmacological in vivo studies regarding mucosal wound healing.
Food habits of Rhinella proboscidea (Anura: Bufonidae) in terra firme forests of central Amazonia
Authors: Borges Alice Cristina Rodrigues , Santos Talitha Ferreira dos , Frazão Luciana , Marques-Souza Sergio , Menin Marcelo
Published: July 2019

Food habits of Rhinella proboscidea (Anura: Bufonidae) in terra frme forests of central Amazonia. Anuran species are considered generalist and opportunist feeders. However, some species have dietary specializations. Here we describe the diet composition of Rhinella proboscidea based on the stomach content of 29 individuals captured in terra frme forests in Manaus and São Sebastião do Uatumã, state of Amazonas, Brazil. Each prey item was measured and identifed to Order, Suborder or Family; ants were identifed to Genus. We determined and tested for differences in the trophic niche breadth and the relationships between the frog size and the volume of the largest prey item. We recorded 1614 prey items of 44 taxa. Hymenoptera was the most abundant Order followed by Isoptera, Acari, Coleoptera, Orthoptera, Araneae, Hemiptera, Dermaptera, Diptera, and Collembola. Formicidae comprised 46.56% of the all stomach items and was represented by six subfamilies and 22 genera. Additionally, we found 80 nematodes in a total of 18 frogs. There was a signifcant difference in the trophic niche breadths of the study areas, and a positive relationship between the toad size and volume of the largest prey item consumed. Rhinella proboscidea feeds on a variety of invertebrates, with ants, termites, and mites being the most abundant; this suggests that the toad is an active forager. The most common subfamily was Myrmicinae primarily represented by Crematogaster and Atta. Differences in trophic niche breadths of the study areas may be related to seasonal differences in the diet composition or local factors.
Analysis of diet composition and morphological characters of the Peruvian lizard Microlophus stolzmanni (Squamata: Tropiduridae)
Authors: Beuttner Antonia , Koch Claudia
Published: July 2019

Analysis of diet composition and morphological characters of the Peruvian lizard Microlophus stolzmanni (Squamata: Tropiduridae). Microlophus stolzmanni is a diurnal lizard that is endemic to the dry forest of northern Peru. Little is known about the ecology of the species and the composition of its diet never has been studied. The stomach contents and morphological features related to feeding behavior are analyzed herein. Microlophus stolzmanni is a semi-herbivorous food generalist that also consumes animal items. All age groups prefer sedentary prey for which M. stolzmanni forages actively. As the lizard matures, plant material becomes a more important part of the diet.
Retinal Microvasculature in Relation to Central Hemodynamics in a Flemish Population
Authors: Wei Fang-Fei , Thijs Lutgarde , Yu Cai-Guo , Melgarejo Jesus D. , Zhang Zhen-Yu , Maestre Gladys E. , Struijker-Boudier Harry A.J. , Verhamme Peter , Staessen Jan A.
Published: July 2019

Arterial stiffness and wave reflection predict cardiovascular mortality and morbidity and are associated with renal microvascular disease. We hypothesized that the retinal microvascular traits might be associated with central hemodynamic properties. In 735 randomly recruited Flemish (mean age, 50.3 years; 47.1% women), we derived central pulse pressure and carotid-femoral pulse wave velocity by applanation tonometry and calculated forward (Pf) and backward (Pb) pulse waves, using an automated pressure-based wave separation algorithm. We measured central retinal arteriolar (CRAE) and venular equivalent and their ratio, using IVAN software (Vasculomatic ala Nicola, version 1.1). Mean values for pulse wave velocity (n=554), Pf and Pb were 7.50 m/s, 32.0 mm Hg, and 21.5 mm Hg, respectively. In multivariable-adjusted analyses, CRAE was 4.62 µm and 1.26 µm smaller (
P
≤0.034) for a 1-SD increment in central mean arterial pressure (+11.3 mm Hg) and central pulse pressure (+15.2 mm Hg); a 1-SD increment in the augmentation ratio (+7.0%), aortic pulse wave velocity (+1.66 m/s), Pf (+10.0 mm Hg), and Pb (+8.5 mm Hg), was associated with smaller CRAE; the association sizes were −1.91 µm, −1.59 µm, −1.45 µm, and −2.38 µm (
P
≤0.014), respectively. Associations of arteriole-to-venule diameter ratio with the central hemodynamic traits mirrored those of CRAE. None of the multivariable-adjusted associations of central retinal venular diameter with the central hemodynamic traits reached significance with the exception of central diastolic blood pressure (−1.62 µm;
P
=0.030). In conclusion, in the general population, higher central pulse pressure, pulse wave velocity, Pf, and Pb were associated with smaller CRAE.