bluuebunny/crossref_metadata_2025 huggingface dataset:
The Role of Matrix Metalloproteinases (MMP-2 and MMP-9) in Ageing and Longevity: Focus on Sicilian Long-Living Individuals (LLIs)
Authors: Cancemi Patrizia , Aiello Anna , Accardi Giulia , Caldarella Rosalia , Candore Giuseppina , Caruso Calogero , Ciaccio Marcello , Cristaldi Laura , Di Gaudio Francesca , Siino Valentina , Vasto Sonya
Published: May 2020

Extracellular matrix metalloproteinases (MMPs) are a group of proteins that activate substrates by enzymatic cleavage and, on the basis of their activities, have been demonstrated to play a role in ageing. Thus, in order to gain insight into the pathophysiology of ageing and to identify new markers of longevity, we analysed the activity levels of MMP-2 and MMP-9 in association with some relevant haematochemical parameters in a Sicilian population, including long-living individuals (LLIs, ≥95 years old). A cohort of 154 healthy subjects (72 men and 82 women) of different ages (age range 20-112) was recruited. The cohort was divided into five subgroups: the first group with subjects less than 40 years old, the second group ranging from 40 to 64 years old, the third group ranging from 65 to 89 years old, the fourth group ranging from 90 to 94 years old, and the fifth group with subjects more than 95 years old. A relationship was observed between LLIs and MMP-2, but not between LLIs and MMP-9. However, in the LLI group, MMP-2 and MMP-9 values were significantly correlated. Furthermore, in LLIs, we found a positive correlation of MMP-2 with the antioxidant catabolite uric acid and a negative correlation with the inflammatory marker C-reactive protein. Finally, in LLIs MMP-9 values correlated directly both with cholesterol and with low-density lipoproteins. On the whole, our data suggest that the observed increase of MMP-2 in LLIs might play a positive role in the attainment of longevity. This is the first study that shows that serum activity of MMP-2 is increased in LLIs as compared to younger subjects. As far as we are concerned, it is difficult to make wide-ranging conclusions/assumptions based on these observations in view of the relatively small sample size of LLIs. However, this is an important starting point. Larger-scale future studies will be required to clarify these findings including the link with other systemic inflammatory and antioxidant markers.
Circumferential Expansion Property of Composite Wrapping System for Main Cable Protection of Suspension Bridge
Authors: Cao Pengfei , Fang Hai , Liu Weiqing , Zhuang Yong , Fang Yuan , Li Chenglin
Published: May 2020

A composite wrapping system for main cable protection of suspension bridges was designed by using prepreg fiber-reinforced composites and nitrile rubber. The circumferential expansion performance of the system was tested, and the curves of circumferential bearing capacity and radial displacement of the components were obtained. Failure modes of each group of components were compared and analyzed. The results show that most of the components are vertically fractured at the lap transition. The increase of the number of prepreg layers contributed the most to the circumferential bearing capacity of components, with a growth rate of 65.31%~109.01%. The increase of rubber belt layers had the most significant effect on the radial displacement of the components, with a growth rate of 7.06%~23.5%. In the initial stage of the test, the strain of each part of the component was smaller due to the compaction by the loading device, and the strain value of the component was generally linearly increased during the loading process, during which the strain of the overlap was the smallest. The calculated cross-sectional temperature deformation of the main cable is in good agreement with the experimental data. The application of the rubber belt increases the deformation of the main cable; therefore, the protection system for the main cable could have more deformation redundancy and delay the arrival of the ultimate strain of the outer prepreg wrap.
Synthesis of CoFe2O4 Nanoparticles: The Effect of Ionic Strength, Concentration, and Precursor Type on Morphology and Magnetic Properties
Authors: Malinowska Izabela , Ryżyńska Zuzanna , Mrotek Eryka , Klimczuk Tomasz , Zielińska-Jurek Anna
Published: May 2020

The present study highlights the effect of metal precursor types (SO42¯, Cl¯, and NO3¯), their concentration, and the influence of ionic strength of reaction environment on the morphology, surface, and magnetic properties of CoFe2O4 particles. The magnetic nanoparticles were obtained by chemical coprecipitation in alkaline medium at increasing metal concentration in the range of 0.0425 mol·dm-3 to 0.17 mol·dm-3 and calcination temperature from 400°C to 800°C. It was found that the chemistry of precursors can be directly correlated with magnetic properties. The CoFe2O4 particles from metal sulphate precursors showed the highest saturation magnetization and the lowest coercivity. The adjustment of ionic strength in the range of 1.25–5 M was achieved by adding an appropriate quantity of metal sulphates into aqueous solutions at a constant pH or by adding an appropriate quantity of NaClO5 under similar conditions. The average hydrodynamic size of CoFe2O4 increased from 46 nm to 54 nm with increasing metal concentration and ionic strength. An explanation of magnetic properties, caused by ionic strength and metal concentration, is given based mainly on the reduction in repulsive forces at the particle interface and compensation of the double electric layer in the presence of anions. The observed coercivity was lower for the particles obtained in solutions with the highest ionic strength, whereas the concentration of metals and calcination temperature affected the saturation magnetization and morphology of the obtained cobalt ferrite particles.
A Qualitative Transcriptional Signature for Predicting Prognosis and Response to Bevacizumab in Metastatic Colorectal Cancer
Authors: Yang Jing , Song Kai , Guo Wenbing , Zheng Hailong , Fu Yelin , You Tianyi , Wang Kai , Qi Lishuang , Zhao Wenyuan , Guo Zheng
Published: May 2020

Bevacizumab is the molecular-targeted agent used for the antiangiogenic therapy of metastatic colorectal cancer. But some patients are resistant to bevacizumab, it needs an effective biomarker to predict the prognosis and responses of metastatic colorectal cancer (mCRC) to bevacizumab therapy. In this work, we developed a qualitative transcriptional signature to individually predict the response of bevacizumab in patients with mCRC. First, using mCRC samples treated with bevacizumab, we detected differentially expressed genes between response and nonresponse groups. Then, the gene pairs, consisting of at least one differentially expressed gene, with stable relative expression orderings in the response samples but reversal stable relative expression orderings in the nonresponse samples were identified, denoted as pairs-bevacizumab. Similarly, we screened the gene pairs significantly associated with primary tumor locations, donated as pairs-LR. Among the overlapped gene pairs between the pairs-bevacizumab and pairs-LR, we adopted a feature selection process to extract gene pairs that reached the highest F-score for predicting bevacizumab response status in mCRC as the final gene pair signature (GPS), denoted as 64-GPS. In two independent datasets, the predicted response group showed significantly better overall survival than the nonresponse group (P = 6.00e−4 in GSE72970; P = 0.04 in TCGA). Genomic analyses showed that the predicted response group was characterized by frequent copy number alternations, whereas the nonresponse group was characterized by hypermutation. In conclusion, 64-GPS was an objective and robust predictive signature for patients with mCRC treated with bevacizumab, which could effectively assist in the decision of clinical therapy.
FGFR Inhibition Enhances Sensitivity to Radiation in Non–Small Cell Lung Cancer
Authors: SenthilKumar Gopika , Fisher Michael M. , Skiba Justin H. , Miller Margot C. , Brennan Sean R. , Kaushik Saakshi , Bradley Samantha T. , Longhurst Colin A. , Buehler Darya , Nickel Kwangok P. , Iyer Gopal , Kimple Randall J. , Baschnagel Andrew M.
Published: May 2020

FGFRs are commonly altered in non–small cell lung cancer (NSCLC). FGFRs activate multiple pathways including RAS/RAF/MAPK, PI3K/AKT, and STAT, which may play a role in the cellular response to radiation. We investigated the effects of combining the selective FGFR 1-3 tyrosine kinase inhibitor AZD4547 with radiation in cell line and xenograft models of NSCLC. NSCLC cell lines were assessed with proliferation, clonogenic survival, apoptosis, autophagy, cell cycle, and DNA damage signaling and repair assays. In vivo xenografts and IHC were used to confirm in vitro results. NSCLC cell lines demonstrated varying degrees of FGFR protein and mRNA expression. In vitro clonogenic survival assays showed radiosensitization with AZD4547 in two NSCLC cell lines. In these two cell lines, an increase in apoptosis and autophagy was observed with combined radiation and AZD4547. The addition of AZD4547 to radiation did not significantly affect γH2AX foci formation. Enhanced xenograft tumor growth delay was observed with the combination of radiation and AZD4547 compared with radiation or drug alone. IHC results revealed inhibition of pMAPK and pS6 and demonstrated an increase in apoptosis in the radiation plus AZD4547 group. This study demonstrates that FGFR inhibition by AZD4547 enhances the response of radiation in FGFR-expressing NSCLC in vitro and in vivo model systems. These results support further investigation of combining FGFR inhibition with radiation as a clinical therapeutic strategy.
A Novel Combination Approach Targeting an Enhanced Protein Synthesis Pathway in MYC-driven (Group 3) Medulloblastoma
Authors: Chaturvedi Nagendra K. , Kling Matthew J. , Griggs Connor N. , Kesherwani Varun , Shukla Mamta , McIntyre Erin M. , Ray Sutapa , Liu Yutong , McGuire Timothy R. , Sharp J. Graham , Band Hamid , Joshi Shantaram S. , Coulter Don W.
Published: May 2020

The MYC oncogene is frequently amplified in patients with medulloblastoma, particularly in group 3 patients, who have the worst prognosis. mTOR signaling–driven deregulated protein synthesis is very common in various cancers, including medulloblastoma, that can promote MYC stabilization. As a transcription factor, MYC itself is further known to regulate transcription of several components of protein synthesis machinery, leading to an enhanced protein synthesis rate and proliferation. Thus, inhibiting enhanced protein synthesis by targeting the MYC and mTOR pathways together may represent a highly relevant strategy for the treatment of MYC-driven medulloblastoma. Here, using siRNA and small-molecule inhibitor approaches, we evaluated the effects of combined inhibition of MYC transcription and mTOR signaling on medulloblastoma cell growth/survival and associated molecular mechanism(s) in MYC-amplified (group 3) medulloblastoma cell lines and xenografts. Combined inhibition of MYC and mTOR synergistically suppressed medulloblastoma cell growth and induced G1 cell-cycle arrest and apoptosis. Mechanistically, the combined inhibition significantly downregulated the expression levels of key target proteins of MYC and mTOR signaling. Our results with RNA-sequencing revealed that combined inhibition synergistically modulated global gene expression including MYC/mTOR components. In addition, the combination treatment significantly delayed tumor growth and prolonged survival of MYC-amplified medulloblastoma xenografted mice by downregulating expression of MYC and the key downstream components of mTOR signaling, compared with single-agent therapy. Together, our findings demonstrated that dual inhibition of MYC (transcription) and mTOR (translation) of the protein synthesis pathway can be a novel therapeutic approach against MYC-driven medulloblastoma.
A Genome-scale CRISPR Screen Identifies the ERBB and mTOR Signaling Networks as Key Determinants of Response to PI3K Inhibition in Pancreatic Cancer
Authors: Milton Charlotte K. , Self Annette J. , Clarke Paul A. , Banerji Udai , Piccioni Federica , Root David E. , Whittaker Steven R.
Published: May 2020

KRAS mutation is a key driver of pancreatic cancer and PI3K pathway activity is an additional requirement for Kras-induced tumorigenesis. Clinical trials of PI3K pathway inhibitors in pancreatic cancer have shown limited responses. Understanding the molecular basis for this lack of efficacy may direct future treatment strategies with emerging PI3K inhibitors. We sought new therapeutic approaches that synergize with PI3K inhibitors through pooled CRISPR modifier genetic screening and a drug combination screen. ERBB family receptor tyrosine kinase signaling and mTOR signaling were key modifiers of sensitivity to alpelisib and pictilisib. Inhibition of the ERBB family or mTOR was synergistic with PI3K inhibition in spheroid, stromal cocultures. Near-complete loss of ribosomal S6 phosphorylation was associated with synergy. Genetic alterations in the ERBB–PI3K signaling axis were associated with decreased survival of patients with pancreatic cancer. Suppression of the PI3K/mTOR axis is potentiated by dual PI3K and ERBB family or mTOR inhibition. Surprisingly, despite the presence of oncogenic KRAS, thought to bestow independence from receptor tyrosine kinase signaling, inhibition of the ERBB family blocks downstream pathway activation and synergizes with PI3K inhibitors. Further exploration of these therapeutic combinations is warranted for the treatment of pancreatic cancer.
Inactivation of Fbxw7 Impairs dsRNA Sensing and Confers Resistance to PD-1 Blockade
Authors: Gstalder Cécile , Liu David , Miao Diana , Lutterbach Bart , DeVine Alexander L. , Lin Chenyu , Shettigar Megha , Pancholi Priya , Buchbinder Elizabeth I. , Carter Scott L. , Manos Michael P. , Rojas-Rudilla Vanesa , Brennick Ryan , Gjini Evisa , Chen Pei-Hsuan , Lako Ana , Rodig Scott , Yoon Charles H. , Freeman Gordon J. , Barbie David A. , Hodi F. Stephen , Miles Wayne , Van Allen Eliezer M. , Haq Rizwan
Published: May 2020

The molecular mechanisms leading to resistance to PD-1 blockade are largely unknown. Here, we characterize tumor biopsies from a patient with melanoma who displayed heterogeneous responses to anti–PD-1 therapy. We observe that a resistant tumor exhibited a loss-of-function mutation in the tumor suppressor gene FBXW7, whereas a sensitive tumor from the same patient did not. Consistent with a functional role in immunotherapy response, inactivation of Fbxw7 in murine tumor cell lines caused resistance to anti–PD-1 in immunocompetent animals. Loss of Fbxw7 was associated with altered immune microenvironment, decreased tumor-intrinsic expression of the double-stranded RNA (dsRNA) sensors MDA5 and RIG-I, and diminished induction of type I IFN and MHC-I expression. In contrast, restoration of dsRNA sensing in Fbxw7-deficient cells was sufficient to sensitize them to anti–PD-1. Our results thus establish a new role for the commonly inactivated tumor suppressor FBXW7 in viral sensing and sensitivity to immunotherapy.

Significance:

Our findings establish a role of the commonly inactivated tumor suppressor FBXW7 as a genomic driver of response to anti–PD-1 therapy. Fbxw7 loss promotes resistance to anti–PD-1 through the downregulation of viral sensing pathways, suggesting that therapeutic reactivation of these pathways could improve clinical responses to checkpoint inhibitors in genomically defined cancer patient populations.

This article is highlighted in the In This Issue feature, p. 1241
Alleviation of Simvastatin-Induced Myopathy in Rats by the Standardized Extract of Ginkgo Biloba (EGb761): Insights into the Mechanisms of Action
Authors: Mahmoud Amany R. , Kamel Esam Omar , Ahmed Marwa A. , Ahmed Esraa A. , Abd-Elhamid Tarek Hamdy
Published: May 2020

Statins are the most widely prescribed cholesterol-lowering drugs to reduce the risk of cardiovascular diseases. Statin-induced myopathy is the major side effect of this class of drugs. Here, we studied whether standardized leaf extracts of ginkgo biloba (EGb761) would improve simvastatin (SIM)-induced muscle changes. Sixty Wistar rats were allotted into six groups: control group, vehicle group receiving 0.5% carboxymethyl cellulose (CMC) for 30 days, SIM group receiving 80 mg/kg/day SIM in 0.5% CMC orally for 30 days, SIM withdrawal group treated with SIM for 16 days and sacrificed 14 days later, and EGb761-100 and EGb761-200 groups posttreated with either 100 or 200 mg/kg/day EGb761 orally. Muscle performance on the rotarod, serum creatine kinase (CK), coenzyme Q10 (CoQ10), serum and muscle nitrite, muscle malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) activities were estimated. Additionally, muscle samples were processed for histopathological evaluation. We found that SIM decreased muscle performance on the rotarod, serum CoQ10, as well as muscle SOD and CAT activities while it increased serum CK, serum and muscle nitrite, as well as muscle MDA levels. SIM also induced sarcoplasmic vacuolation, splitting of myofibers, disorganization of sarcomeres, and disintegration of myofilaments. In contrast, posttreatment with EGb761 increased muscle performance, serum CoQ10, as well as muscle SOD and CAT activities while it reduced serum CK as well as serum and muscle nitrite levels in a dose-dependent manner. Additionally, EGb761 reversed SIM-induced histopathological changes with better results obtained by its higher dose. Interestingly, SIM withdrawal increased muscle performance on the rotarod, reduce serum CK and CoQ10, and reduced serum and muscle nitrite while it reversed SIM-induced histopathological changes. However, SIM withdrawal was not effective enough to restore their normal values. Additionally, SIM withdrawal did not improve SIM-induce muscle MDA, SOD, or CAT activities during the period studied. Our results suggest that EGb761 posttreatment reversed SIM-induces muscle changes possibly through its antioxidant effects, elevation of CoQ10 levels, and antagonizing mitochondrial damage.
Disease Severity Is Associated with Alexithymia in Patients with Atopic Dermatitis
Authors: Chiricozzi Andrea , Esposito Maria , Gisondi Paolo , Valenti Mario , Gori Niccolò , Giovanardi Giulia , Bellinato Francesco , De Simone Clara , Costanzo Antonio , Fargnoli Maria Concetta , Peris Ketty
Published: May 2020

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disorder that is associated with higher rates of psychological disorders, but limited evidence supported the association with alexithymia, a psychoaffective dysfunction. Objectives: This study was aimed to investigate the occurrence of alexithymia in AD patients, compared to healthy subjects. Methods: This cross-sectional study assessed AD severity by the Eczema Area and Severity Index (EASI) score, sleeplessness and itch by a numeric rating scale (NRS), and alexithymia by the 20-item Toronto Alexithymia Scale (TAS-20) score. The association between disease characteristics and alexithymia was evaluated through several logistic regression models. Results: 202 AD patients and 240 healthy subjects were included in this study. The alexithymic personality trait (TAS-20 ≥51) was more frequently observed among AD patients compared to the control group (62.4% [126/202] vs. 29.2% [70/240], p < 0.0001). In particular, alexithymia (TAS-20 score ≥61) was detected in a significantly higher number of AD patients than in the controls (27.7% [56/202] vs. 7.5% [18/240]; p < 0.0001), whereas borderline alexithymia was detected in 34.6% (70/202) of AD patients compared to 21.7% of healthy controls. Alexithymia was more common among severe AD patients (43.6%) compared to mild AD patients (15.6%) and correlated with itch intensity and sleep disturbances. Among clinical variables, ordered logistic regression analyses revealed disease severity as predictor of alexithymia. Indeed, univariate analysis showed EASI score, sleep NRS, and itch NRS being significantly associated with alexithymia, while a multivariate model identified increased EASI score values as predicting factor. Conclusion:This study described alexithymia in AD patients correlating its occurrence with clinical AD severity markers (EASI score, itch, and sleeplessness) and identifying the increase in EASI score as predicting factor.
What Will It Take to Build an Expert Group of Nutrigenomic Practitioners?
Authors: Joffe Yael , Herholdt Heléne
Published: May 2020

Background: The past two decades have seen exponential growth in the number of genetic testing companies, but only a small percentage of these tests are being sold through health care professionals (HCPs). As each new genetic testing company appears, it is becoming more difficult for the practitioner and consumer to evaluate the credibility of the claims being made and the value of the tests being offered. Summary: HCPs appear to have minimal nutrigenomics knowledge and little confidence in choosing and interpreting nutrigenetic tests. To remedy this, HCPs need access to credible education, professional support, networking, career development, mentorship, and a regulated testing environment. This will enable them to evaluate the credibility of genetic tests and testing companies, provide genetic results in context, and apply appropriate clinical translation. Key Message: In order to establish an expert group of nutrigenomic practitioners, collaboration is required between educational institutions, professional organizations, and genetic testing companies. This will provide the necessary support, skills, and knowledge to ensure that the best value is extracted from nutrigenetic tests in an ethical and responsible manner.
Update on C3 Glomerulopathy: A Complement-Mediated Disease
Authors: Caravaca-Fontán Fernando , Lucientes Laura , Cavero Teresa , Praga Manuel
Published: May 2020

C3 glomerulopathy (C3G) is a clinicopathologic entity secondary to dysregulation of the alternative complement pathway in plasma and the glomerular microenvironment. The current consensus definition of C3G relies on immunofluorescence staining criteria. However, due to its high clinical variability, these criteria may not be accurate enough in some clinical scenarios. Thus, a new pathogenic classification based on a cluster analysis of clinical, histologic, and genetic data has recently been proposed, which could also help identify patients at higher risk of progression. Several pathogenic abnormalities in complement genes have been described, and the role of autoantibodies in the disease is increasingly recognized, but still the genotype-phenotype correlations in C3G are poorly understood. C3G may be diagnosed in both children and adults. The spectrum of clinical manifestations is wide, although one of the most common clinical presentations is proteinuria with relatively preserved kidney function. In order to standardize the evaluation of kidney biopsies from these patients, a histopathologic index was recently proposed, including both parameters of activity and chronicity. However, this index has not yet been validated in independent cohorts. Currently, no targeted therapies are available in clinical settings for the treatment of C3G, although several new molecules are under investigation. Treatment with corticosteroids plus mycophenolate mofetil has been shown to be associated with improved renal outcomes, as compared to other immunosuppressive regimens. Yet, the main determinants of treatment response with this regimen and the influence of the underlying pathogenic drivers have not been extensively studied. The therapeutic response to eculizumab, an anti-C5 monoclonal antibody, has been shown to be highly heterogeneous. Thus, its current clinical indication in C3G is restricted to rapidly progressive forms of the disease. To summarize, in recent years, several important advances have taken place in the understanding of C3G, but still further studies are warranted to elucidate the best therapeutic strategies that could improve prognosis of this entity.
Deficit of Long-Term Potentiation Induction, but Not Maintenance, in the Juvenile Hippocampus after Neonatal Proinflammatory Stress
Authors: Kudryashova Irina , Stepanichev Mikhail , Manolova Anna , Gulyaeva Natalia
Published: May 2020

CA3-CA1 long-term potentiation (LTP) in the hippocampal slices from juvenile Wistar rats was studied to reveal factors potentially contributing to different sensitivity to neonatal proinflammatory stress (NPS). NPS was induced by intra­peritoneal injections of bacterial lipopolysaccharide (LPS) to neonatal rats (two injections of LPS, or saline in the control group, consecutively on postnatal days 3 and 5 [PND3 and PND5]). In females, a significant effect of NPS on hippocampus development was associated with modifications of long-term synaptic plasticity, the synapses becoming more resistant to LTP induction. LTP deficit in the slices of the NPS group was not associated with a decrease in LTP maintenance, since late LTP generally corresponded to early LTP magnitude, similar in all groups. Moreover, partial correlation revealed significantly higher residual LTP 1 h after high-frequency stimulation in the NPS groups compared to the corresponding value of early LTP in the control groups, suggesting improved consolidation. Both effects were evident in NPS females. A number of males responded to NPS similarly to females, while others were relatively resistant to NPS exposure, a significant increase in variability of LTP magnitude being revealed in NPS males compared to respective females and the control groups. We suggest that postnatal development of long-term plasticity after NPS is similar in animals of both sexes; however, additional specific factor(s) may promote a relative resistance of the male brain.
Merkmale und Risikofaktoren eines diagnostizierten und nicht diagnostizierten Trockenen Auges, identifiziert mithilfe einer Smartphone-App
Authors: Siebelmann Sebastian
Published: May 2020

Ziel der Studie war es, mithilfe der Smartphone-App DryEyeRhythm Charakteristika und Risikofaktoren bei diagnostiziertem und nicht diagnostiziertem Trockenen Auge zu identifizieren. Dazu wurden die Daten der App-User gesammelt und analysiert (vorliegende Informationen schlossen ein: Demografie, medizinische Vorgeschichte, Informationen zur Lebenweise der Nutzer, subjektive und krankheitsspezifische Symptome erhoben mithilfe des Ocular Surface Disease Index und der Zung Self-Rating Depression Scale). Insgesamt wurden die Daten von 4454 Nutzern (899 mit diagnostiziertem und 2395 mit nicht diagnostiziertem Trockenen Auge) anaysiert und folgende Risikofaktoren für ein symptomatisches Trockenes Auge identifiziert: junges Alter, weibliches Geschlecht, Heuschnupfen, Depression, psychische Erkrankungen außer Depression oder Schizophrenie, momentanes Tragen von Kontaktlinsen, lange Bildschirmarbeit und Rauchen. Risikofaktoren für ein nicht diagnostiziertes symptomatisches Trockenes Auge umfassten: junges Alter, männliches Geschlecht, kein Vorliegen einer Kollagenose, psychische Erkrankungen außer Depression oder Schizophrenie, ophthalmologische chirurgische Eingriffe außer LASIK oder Kataraktoperation und Kontaktlinsennutzung (momentan oder in der Vergangenheit). Risikofaktoren für ein nicht diagnostiziertes, nicht symptomatisches Trockenes Auge konnten nicht identifiziert werden.
Mutational Profiling of Driver Tumor Suppressor and Oncogenic Genes in Brazilian Malignant Pleural Mesotheliomas
Authors: Campanella Nathália C. , Silva Eduardo Caetano , Dix Gustavo , de Lima Vazquez Fabiana  , Escremim de Paula Flávia  , Berardinelli Gustavo N. , Balancin Marcelo , Chammas Roger , Mendoza Lopez Rossana V. , Silveira Henrique César S. , Capelozzi Vera Luiza , Reis Rui Manuel
Published: May 2020

Background: Malignant pleural mesothelioma (MPM) is a highly lethal disease comprising a heterogeneous group of tumors with challenging to predict biological behavior. The diagnosis is complex, and the histologic classification includes 2 major subtypes of MPM: epithelioid (∼60% of cases) and sarcomatous (∼20%). Its identification depends upon pathological investigation supported by clinical and radiological evidence and more recently ancillary molecular testing. Treatment options are currently limited, with no known targeted therapies available. Objectives: To elucidate the mutation profile of driver tumor suppressor and oncogenic genes in a cohort of Brazilian patients. Methods: We sequenced 16 driver genes in a series of 43 Brazilian malignant mesothelioma (MM) patients from 3 distinct Brazilian centers. Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor tissue blocks, and the TERT promoter region was amplified by PCR followed by direct capillary sequencing. The Illumina TruSight Tumor 15 was used to evaluate 250 amplicons from 15 genes associated with solid tumors (AKT1, GNA11, NRAS, BRAF, GNAQ, PDGFRA, EGFR, KIT, PIK3CA, ERBB2, KRAS, RET, FOXL2, MET,and TP53). Library preparation with the TruSight Tumor 15 was performed before sequencing at the MiSeq platform. Data analysis was performed using Sophia DDM software. Results: Out of 43 MPM patients, 38 (88.4%) were epithelioid subtype and 5 (11.6%) were sarcomatoid histotype. Asbestos exposure was present in 15 (39.5%) patients with epithelioid MPM and 3 (60%) patients with sarcomatoid MPM. We found a TERT promoter mutation in 11.6% of MM, and the c.-146C>T mutation was the most common event. The next-generation sequencing was successful in 33 cases. A total of 18 samples showed at least 1 pathogenic, with a median of 1.8 variants, ranging from 1 to 6. The most mutated genes were TP53 and ERBB2 with 7 variants each, followed by NRAS BRAF, PI3KCA, EGFR and PDGFRA with 2 variants each. KIT, AKT1, and FOXL2 genes exhibited 1 variant each. Interestingly, 2 variants observed in the PDGFRA gene are classic imatinib-sensitive therapy. Conclusions: We concluded that Brazilian MPM harbor mutation in classic tumor suppressor and oncogenic genes, which might help in the guidance of personalized treatment of MPM.
NR5A1 Gene Variants: Variable Phenotypes, New Variants, Different Outcomes
Authors: Faienza Maria F. , Chiarito Mariangela , Baldinotti Fulvia , Canale Domenico , Savino Carmela , Paradies Guglielmo , Corica Domenico , Romeo Carmelo , Tyutyusheva Nina , Caligo Maria A. , Wasniewska Malgorzata G. , Bertelloni Silvano
Published: May 2020

NR5A1 (nuclear receptor subfamily 5 group A member 1) is a transcriptional regulator of adrenal and gonadal development and function. Heterozygous and homozygous NR5A1 mutations have been described in people with 46,XY disorders of sex development (DSD). The clinical, endocrine, and genetic features of four 46,XY subjects with NR5A1 genetic variants (2 sisters, 2 boys) from 3 unrelated families are reported. All subjects presented with hypergonadotropic hypogonadism and abnormal pubertal progression. Markers of Sertoli cell function were more affected than those of Leydig cell function. Genetic investigation demonstrated the presence of different heterozygous NR5A1 genetic variants. In the boys, pathogenetic NR5A1 gene variants were found that had been previously reported. The 2 sisters carried a new genetic variant in exon 4, and in silico analysis and ACMG classification indicated its pathogenicity. The data confirmed that NR5A1 gene mutations may present with variable genital phenotypes. Anyway, reproductive function was always impaired. Any clinical or endocrine data seem to be unable to differentiate these patients from other 46,XY DSD cases, suggesting that molecular analysis must be warranted. In subjects with NR5A1 mutations, different decisions in sex assignment may permit satisfying somatic and psychological outcome, but any option requires hormonal substitutive therapy from adolescence onward.
Creatine Phosphokinase Values during Low Starting Dose Isotretinoin Therapy
Authors: Manfredini Marco , Bettoli Vincenzo , Forconi Riccardo , Pacetti Lucrezia , Farnetani Francesca , Corazza Monica , Pellacani Giovanni
Published: May 2020

Background: The value of creatine phosphokinase (CPK) monitoring during isotretinoin therapy is still a matter of debate because of the rarity of muscular and kidney damage in this setting. The aim of the study was to investigate the incidence of CPK elevation during a low starting dose isotretinoin regimen and to discuss the clinical approach to patients with increased CPK. Methods: We reviewed the records of the acne patients from 2015 to 2018 at the University of Ferrara and at the University of Modena and Reggio Emilia. Routine clinical and laboratory follow-up was analyzed. Results: The records of 328 patients were included in the study. Abnormal CPK levels were observed in 5.5% of cases. Revised Leeds acne scores and visual assessment scale (VAS) measurements decreased significantly after isotretinoin therapy. Discussion: The adoption of the low starting dose isotretinoin regimen is associated with low incidence of CPK elevation. The finding of CPK over the conventional value of 5 times above the limit was rarely observed and was never associated with kidney damage. Therefore, it should be interpreted as a relatively benign phenomenon that does not require the interruption of isotretinoin therapy and that should be managed mainly through the reassurance of the patient.
International Assessment of DSM-5 and ICD-11 Personality Disorder Traits: Toward a Common Nosology in DSM-5.1
Authors: Bach Bo , Kerber André , Aluja Anton , Bastiaens Tim , Keeley Jared W. , Claes Laurence , Fossati Andrea , Gutierrez Fernando , Oliveira Sérgio E.S. , Pires Rute , Riegel Karel D. , Rolland Jean-Pierre , Roskam Isabelle , Sellbom Martin , Somma Antonella , Spanemberg Lucas , Strus Włodzimierz , Thimm Jens C. , Wright Aidan G.C. , Zimmermann Johannes
Published: May 2020

Introduction: The DSM-5 Alternative Model of Personality Disorders (AMPD) and the ICD-11 classification of personality disorders (PD) are largely commensurate and, when combined, they delineate 6 trait domains: negative affectivity, detachment, antagonism/dissociality, disinhibition, anankastia, and psychoticism. Objective: The present study evaluated the international validity of a brief 36-item patient-report measure that portrays all 6 domains simultaneously including 18 primary subfacets. Methods: We developed and employed a modified version of the Personality Inventory for DSM-5 – Brief Form Plus (PID5BF+). A total of 16,327 individuals were included, 2,347 of whom were patients. The expected 6-factor structure of facets was initially investigated in samples from Denmark (n = 584), Germany (n = 1,271), and the USA (n = 605) and subsequently replicated in both patient- and community samples from Italy, France, Switzerland, Belgium, Norway, Portugal, Spain, Poland, Czech Republic, the USA, and Brazil. Associations with interview-rated DSM-5 PD categories were also investigated. Results: Findings generally supported the empirical soundness and international robustness of the 6 domains including meaningful associations with familiar interview-rated PD types. Conclusions: The modified PID5BF+ may be employed internationally by clinicians and researchers for brief and reliable assessment of the 6 combined DSM-5 and ICD-11 domains, including 18 primary subfacets. This 6-domain framework may inform a future nosology for DSM-5.1 that is more reasonably aligned with the authoritative ICD-11 codes than the current DSM-5 AMPD model. The 36-item modified PID5BF+ scoring key is provided in online supplementary Appendix A see www.karger.com/doi/10.1159/000507589 (for all online suppl. material).
Life‐Course Reproductive History and Cardiovascular Risk Profile in Late Mid‐Life: The CARDIA Study
Authors: Lane‐Cordova Abbi D. , Gunderson Erica P. , Greenland Philip , Catov Janet M. , Lewis Cora E. , Pettee Gabriel Kelley , Wellons Melissa F. , Carnethon Mercedes R.
Published: May 2020

Background

Reproductive events, that is, a preterm birth (
PTB
), small‐for‐gestational‐age infant (
SGA
), and vasomotor symptoms of menopause, are associated with subclinical atherosclerotic cardiovascular disease (
ASCVD
). We evaluated whether women with a past
PTB
and/or
SGA
(henceforth
PTB
/
SGA
) were more likely to have severe vasomotor symptoms of menopause and whether the estimated 10‐year
ASCVD
risk was higher in women with
PTB
/
SGA
and vasomotor exposures.

Methods and Results

We assigned 1866 women (mean age=55±1 years) in the
CARDIA
(Coronary Artery Risk Development in Young Adults) study to the following categories of reproductive exposures: none,
PTB
/
SGA
only, vasomotor symptoms only, or both
PTB
/
SGA
and vasomotor symptoms. We used Kruskal‐Wallis tests to evaluate the differences in pooled cohort equation
ASCVD
risk scores by category and linear regression to evaluate the associations of categories with
ASCVD
risk scores adjusted for study center,
body mass index
, education, current hormone replacement therapy use, parity, and hysterectomy. Women with
PTB
/
SGA
were more likely to have severe vasomotor symptoms, 36% versus 30%,
P
<0.02.
ASCVD
risk score was higher in women with both
PTB
/
SGA
and vasomotor symptoms (4.6%; 95% CI, 4.1%–5.1%) versus women with no exposures (3.3%; 95%
CI
, 2.9%–3.7%) or vasomotor symptoms only (3.8%; 95%
CI
, 3.5%–4.0%).
ASCVD
risk score was higher in women
PTB
/
SGA
(4.8%; 95%
CI
, 3.6%–5.9%) versus no exposures.
PTB
/
SGA
and vasomotor symptoms was associated with
ASCVD
risk score in white women versus no exposures (β=0.40; 95% CI, 0.02–0.78).

Conclusions

Women with prior
PTB
/
SGA
were more likely to have severe vasomotor symptoms of menopause. Reproductive exposures were associated with an estimated 10‐year
ASCVD
risk in white women.
A revision of the family Thismiaceae (Dioscoreales) in Cambodia, Laos and Vietnam

Authors: NURALIEV MAXIM S. , YUDINA SOPHIA V. , TRUONG BA VUONG , DO THI XUYEN , LUU HONG TRUONG , KUZNETSOV ANDREY N. , KUZNETSOVA SVETLANA P.
Published: May 2020

We present the first taxonomic account of the family Thismiaceae in the countries of Eastern Indochina. A single genus of Thismiaceae, Thismia, with eight species is known to inhabit this region. Six species, including four national endemics, are found in Vietnam, whereas Cambodia and Laos each has a single and endemic species of Thismia. We report new records of a number of species, which allowed us to establish for the first time their distribution areas. We show geographical distribution of all species of Thismia in Cambodia, Laos and Vietnam on a map. We recognise Hon Ba Nature Reserve and Chu Yang Sin National Park as hotspots of known Thismia diversity in Eastern Indochina. We confirm the presence of T. javanica in Vietnam, earlier known as a doubtful report, by specimen investigation. We significantly amend morphological descriptions of several Vietnamese species. We highlight a number of characters with remarkable intraspecific variation, along with the most important structural differences between morphologically similar species. We discuss remaining taxonomic problems of Indochinese Thismia, and present an identification key to species of Thismiaceae in Cambodia, Laos and Vietnam.
Phylogenetic relationships of Silene sections Lasiostemones and Sclerocalycine (Caryophyllaceae) in Iran

Authors: BAHMANI FATEMEH , ASSADI MOSTAFA , YILDIZ KEMAL , MEHREGAN IRAJ
Published: May 2020

A phylogenetic study of Silene sect. Lasiostemones and sect. Sclerocalycine in Iran is presented. A total of 72 accessions (43 of which obtained from GenBank) were analyzed using nuclear ITS and chloroplast rps16 markers. It was shown that sect. Lasiostemones is not a monophyletic group, including members which would belong to sect. Sclerocalycine (i.e. S. tenella, S. longipetala, S. lasiantha, S. marschallii, S. propinqua) and sect. Siphonomorpha (i.e. S. ghahremaninejadii, S. shahrudensis, S. saxatilis, S. ruprechtii, S. parrowiana).
Bellevalia bayburtensis (Asparagaceae): a new species from northeastern Anatolia, Turkey

Authors: YILDIRIM HASAN , SEFALI ABDURRAHMAN
Published: May 2020

Bellevalia bayburtensis (Asparagaceae) is described and illustrated as a new species from Bayburt Province in northeastern Anatolia, Turkey. Diagnostic morphological characters, a full description, detailed illustrations, and a distribution map are provided. It is morphologically similar to B. rixii and B. paradoxa, but clearly differs from these species by the leaf shape, the bud and flower colour.
Bryozoa from deep-sea habitats of the northern Gulf of Cádiz (Northeastern Atlantic)
Authors: RAMALHO LAÍS V. , LÓPEZ-FÉ CARLOS M. , MATEO-RAMÍREZ ANGEL , RUEDA JOSÉ LUIS
Published: May 2020

This study examines material collected in the northern part of the Gulf of Cádiz, in the Northeastern Atlantic Ocean, between the Iberian Peninsula and northern Africa, at 300–1200 m depth, within the Site of Community Importance “Volcanes de fango del Golfo de Cádiz” (Mud volcanoes of the Gulf of Cádiz, ESZZ-12002). Several previous studies were carried out in the Iberian Peninsula and Moroccan area (shallow and deep waters), recording ca. 300 bryozoan species from the Gulf of Cádiz. In the present study a total of 40 bryozoan taxa were identified, including two species new to science—Antropora gemarita n. sp. and Microporella funbio n. sp.—and three new records for the area.
Two new Exilisia Toulgoët, 1958 from mainland Africa (Lepidoptera, Erebidae, Arctiinae)
Authors: VOLYNKIN ANTON V.
Published: May 2020

Exilisia Toulgoët, 1958 is a genus of the tribe Lithosiini distributed in the Afrotropical Region, including 38 valid species and one subspecies (De Prins & De Prins 2019) and reaching its highest species diversity in the island of Madagascar. In the mainland Africa, the genus is represented by seven valid species to date (Kühne 2007).
Five new species of the genus Noeetomima Enderlein (Diptera: Lauxaniidae) from China, with a key to world species
Authors: LI WENLIANG , CHEN XULONG , YANG DING
Published: May 2020

Five species of Noeetomima Enderlein, 1937 from Southwest China are described as new to science: Noeetomima hongshanensis sp. nov., N. lijiangensis sp. nov., N. liui sp. nov., N. trisurstyla sp. nov. and N. zhangae sp. nov.. A key to world species of the genus Noeetomima is presented. The specimens studied are deposited in the Entomological Museum of China Agricultural University, Beijing, China (CAUC).
Review of the genus Hechinoschema Thomson, 1857 (Coleoptera: Cerambycidae: Lamiinae: Monochamini), with description of a new genus and two new species
Authors: HUANG GUI-QIANG , HUANG JIAN-BIN , LIU YI-FENG
Published: May 2020

A taxonomic review of the genus Hechinoschema is presented. A new genus, Propedicellus gen. nov., is described, and two new species Propedicellus guoliangi sp. nov. and Propedicellus qiului sp. nov. are described from China. A new combination Propedicellus vitalisi (Pic, 1925) comb. nov. is proposed. A key to species of Propedicellus is presented.
The spider wasp genus Telostholus Haupt, 1929 (Hymenoptera, Pompilidae) in Malaysia, with the description of four new species
Authors: LOKTIONOV VALERY M.
Published: May 2020

The genus Telostholus Haupt, 1929 is newly reported from Malaysia, with four species that are newly described and illustrated: T. bifasciatus Loktionov, sp. nov. (Pahang), T. clypeatus Loktionov, sp. nov. (Pahang), T. malayensis Loktionov, sp. nov. (Pahang), and T. tomentosus Loktionov, sp. nov. (Pahang). A key to the Malaysian species is given.
Rotifers from inland water bodies of continental Ecuador and Galápagos Islands: An updated checklist
Authors: LÓPEZ CARLOS , SOTO LUZ MARINA , LAFUENTE WILSON , STAMOU GEORGIA , MICHALOUDI EVANGELIA , PAPAKOSTAS SPIROS , FONTANETO DIEGO
Published: May 2020

We present an updated checklist of the rotifer fauna from inland aquatic habitats in continental Ecuador and the Galápagos islands based on published rotifer records found in the literature. The checklist summarizes the status of the current taxonomic and faunistic knowledge on rotifers in Ecuador, updates the nomenclature, and reports the regions where each species has been found in the country. A total of 287 valid species (269 monogononts and 18 bdelloids was found. The Ecuadorian region with the highest number of records was Amazonia (228) followed by the Coastal region (139) and the Andes (121), whereas in the Galápagos Archipelago only 40 species have been recorded. Studies of the rotifer fauna of the areas are scarce and quite recent, pointing to important gaps in our knowledge on taxonomy and biogeography of Ecuadorian rotifers.
Improved Infrared Optical Constants from Pressed Pellets: II. Ellipsometric n and k Values for Ammonium Sulfate with Variability Analysis
Authors: Myers Tanya L. , Blake Thomas A. , Yokosuk Michael O. , Fortin Gilles , Johnson Timothy J.
Published: May 2020

Infrared reflectance analysis is facilitated via the comparison of spectra recorded in situ to a databank of actual or synthetic infrared reflectance spectra. It has recently been shown that reference spectra corresponding to the many different morphological forms of the same chemical can be generated synthetically using the imaginary, k, and real, n, components of the complex refractive index, [Formula: see text] =  n + i k. One method to obtain the n and k vectors is infrared ellipsometry, which measures the changes in amplitude, tan Ψ, and phase, Δ, of polarized light reflected from the sample both as a function of wavenumber and angle of incidence. The method requires specularly reflected light, so best results are usually obtained with polished planar samples of large surface area. Due to the difficulties of obtaining such samples, however, we investigate the possibility of pressing powders of neat materials and obtaining the corresponding optical constants from the pellets. In this paper, variability in the sample pellet and preparation method is investigated, as is variability in the fitting procedure for the derived optical constants. The n/k vectors are derived from the measured ellipsometric parameters, tan ψ and Δ, as they are fit by an oscillator model which yield n([Formula: see text]) and k([Formula: see text]) vectors as a function of wavenumber, [Formula: see text]. Construction of the oscillator model is not automatic and depends on significant input from the analyst as well as the sample’s physical characteristics. For pellet pressing, the experimental variability was found to be minimized for size-selected powdered samples as gauged by the minimal variance in ψ and Δ for three different pellets; similarly, the analytical precision for multiple measurements of the same pellet was also quite good, suggesting that a pressed pellet is a viable sample preparation method. Experimental variabilities were comparatively small; the greatest variability came in the analytic fitting procedure with differences in the k-peak values up to 10% for only the sharpest bands arising from four different fits to the same data set. The final ellipsometric n/k data are compared to literature values obtained from crystalline ammonium sulfate ((NH4)2SO4) samples as well as single-angle reflectance measurements that also used pressed pellets. Comparison with the previous literature values shows generally good agreement, although larger k-values are observed for the independent sets of data derived from pressed pellets. These data are suggested as an improved set of optical constants for (NH4)2SO4.