bluuebunny/crossref_metadata_2025 huggingface dataset:
MFF Regulation of Mitochondrial Cell Death Is a Therapeutic Target in Cancer
Authors: Seo Jae Ho , Chae Young Chan , Kossenkov Andrew V. , Lee Yu Geon , Tang Hsin-Yao , Agarwal Ekta , Gabrilovich Dmitry I. , Languino Lucia R. , Speicher David W. , Shastrula Prashanth K. , Storaci Alessandra Maria , Ferrero Stefano , Gaudioso Gabriella , Caroli Manuela , Tosi Davide , Giroda Massimo , Vaira Valentina , Rebecca Vito W. , Herlyn Meenhard , Xiao Min , Fingerman Dylan , Martorella Alessandra , Skordalakes Emmanuel , Altieri Dario C.
Published: October 2019

The regulators of mitochondrial cell death in cancer have remained elusive, hampering the development of new therapies. Here, we showed that protein isoforms of mitochondrial fission factor (MFF1 and MFF2), a molecule that controls mitochondrial size and shape, that is, mitochondrial dynamics, were overexpressed in patients with non–small cell lung cancer and formed homo- and heterodimeric complexes with the voltage-dependent anion channel-1 (VDAC1), a key regulator of mitochondrial outer membrane permeability. MFF inserted into the interior hole of the VDAC1 ring using Arg225, Arg236, and Gln241 as key contact sites. A cell-permeable MFF Ser223-Leu243 d-enantiomeric peptidomimetic disrupted the MFF–VDAC1 complex, acutely depolarized mitochondria, and triggered cell death in heterogeneous tumor types, including drug-resistant melanoma, but had no effect on normal cells. In preclinical models, treatment with the MFF peptidomimetic was well-tolerated and demonstrated anticancer activity in patient-derived xenografts, primary breast and lung adenocarcinoma 3D organoids, and glioblastoma neurospheres. These data identify the MFF–VDAC1 complex as a novel regulator of mitochondrial cell death and an actionable therapeutic target in cancer.

Significance:

These findings describe mitochondrial fission regulation using a peptidomimetic agent that disturbs the MFF–VDAC complex and displays anticancer activity in multiple tumor models.

See related commentary by Rao, p. 6074
HER2-Overexpressing/Amplified Breast Cancer as a Testing Ground for Antibody–Drug Conjugate Drug Development in Solid Tumors
Authors: Pegram Mark D. , Miles David , Tsui C. Kimberly , Zong Yu
Published: October 2019

Efficacy data from the KATHERINE clinical trial, comparing the HER2-directed antibody-drug conjugate (ADC) ado-trastuzumab emtansine (T-DM1) to trastuzumab in patients with early-stage HER2-amplified/overexpressing breast cancer with residual disease after neoadjuvant therapy, demonstrates superiority of T-DM1 (HR for invasive disease or death, 0.50; P < 0.001). This establishes foundational precedent for ADCs as effective therapy for treatment of subclinical micrometastasis in an adjuvant (or post-neoadjuvant) early-stage solid tumor setting. Despite this achievement, general principles from proposed systems pharmacokinetic modeling for intracellular processing of ADCs indicate potential shortcomings of T-DM1: (i) Cmax limited by toxicities; (ii) slow internalization rate; (iii) resistance mechanisms due to defects in intracellular trafficking [loss of lysosomal transporter solute carrier family 46 member 3, (SLC46A3)], and increased expression of drug transporters MDR1 and MRP1; and (iv) lack of payload bystander effects limiting utility in tumors with heterogeneous HER2 expression. These handicaps may explain the inferiority of T-DM1–based therapy in the neoadjuvant and first-line metastatic HER2+ breast cancer settings, and lack of superiority to chemotherapy in HER2+ advanced gastric cancer. In this review, we discuss how each of these limitations is being addressed by manipulating internalization and trafficking using HER2:HER2 bispecific or biparatopic antibody backbones, using site-specific, fixed DAR conjugation chemistry, and payload swapping to exploit alternative intracellular targets and to promote bystander effects. Newer HER2-directed ADCs have impressive clinical activity even against tumors with lower levels of HER2 receptor expression. Finally, we highlight ongoing clinical efforts to combine HER2 ADCs with other treatment modalities, including chemotherapy, molecularly targeted therapies, and immunotherapy.
The Outcome of TGFβ Antagonism in Metastatic Breast Cancer Models In Vivo Reflects a Complex Balance between Tumor-Suppressive and Proprogression Activities of TGFβ
Authors: Yang Yuan , Yang Howard H. , Tang Binwu , Wu Alex Man Lai , Flanders Kathleen C. , Moshkovich Nellie , Weinberg Douglas S. , Welsh Michael A. , Weng Jia , Ochoa Humberto J. , Hu Tiffany Y. , Herrmann Michelle A. , Chen Jinqiu , Edmondson Elijah F. , Simpson R. Mark , Liu Fang , Liu Huaitian , Lee Maxwell P. , Wakefield Lalage M.
Published: October 2019

Purpose:

TGFβs are overexpressed in many advanced cancers and promote cancer progression through mechanisms that include suppression of immunosurveillance. Multiple strategies to antagonize the TGFβ pathway are in early-phase oncology trials. However, TGFβs also have tumor-suppressive activities early in tumorigenesis, and the extent to which these might be retained in advanced disease has not been fully explored.

Experimental Design:

A panel of 12 immunocompetent mouse allograft models of metastatic breast cancer was tested for the effect of neutralizing anti-TGFβ antibodies on lung metastatic burden. Extensive correlative biology analyses were performed to assess potential predictive biomarkers and probe underlying mechanisms.

Results:

Heterogeneous responses to anti-TGFβ treatment were observed, with 5 of 12 models (42%) showing suppression of metastasis, 4 of 12 (33%) showing no response, and 3 of 12 (25%) showing an undesirable stimulation (up to 9-fold) of metastasis. Inhibition of metastasis was immune-dependent, whereas stimulation of metastasis was immune-independent and targeted the tumor cell compartment, potentially affecting the cancer stem cell. Thus, the integrated outcome of TGFβ antagonism depends on a complex balance between enhancing effective antitumor immunity and disrupting persistent tumor-suppressive effects of TGFβ on the tumor cell. Applying transcriptomic signatures derived from treatment-naïve mouse primary tumors to human breast cancer datasets suggested that patients with breast cancer with high-grade, estrogen receptor–negative disease are most likely to benefit from anti-TGFβ therapy.

Conclusions:

Contrary to dogma, tumor-suppressive responses to TGFβ are retained in some advanced metastatic tumors. Safe deployment of TGFβ antagonists in the clinic will require good predictive biomarkers.
ctDNA in Gastric and Gastroesophageal Cancer: Prognostic, Predictive, or Preliminary?
Authors: Frankell Alexander M. , Smyth Elizabeth C.
Published: October 2019

In gastric and gastroesophageal adenocarcinoma, circulating tumor DNA identifies molecular drivers missed using routine tumor biopsy, can refine patient selection for targeted therapy, and may be prognostic following surgical resection. However, lack of standardization could impede adoption of this technology as a clinically useful tool; prospective validation in clinical trials is required.

See related article by Maron et al., p. 7098
Dual Inhibition of Angiopoietin-TIE2 and MET Alters the Tumor Microenvironment and Prolongs Survival in a Metastatic Model of Renal Cell Carcinoma
Authors: Elbanna May , Orillion Ashley R. , Damayanti Nur P. , Adelaiye-Ogala Remi , Shen Li , Miles Kiersten Marie , Chintala Sreenivasulu , Ciamporcero Eric , Ramakrishnan Swathi , Ku Sheng-yu , Rex Karen , Caenepeel Sean , Coxon Angela , Pili Roberto
Published: October 2019

Receptor tyrosine kinase inhibitors have shown clinical benefit in clear cell renal cell carcinoma (ccRCC), but novel therapeutic strategies are needed. The angiopoietin/Tie2 and MET pathways have been implicated in tumor angiogenesis, metastases, and macrophage infiltration. In our study, we used trebananib, an angiopoietin 1/2 inhibitor, and a novel small-molecule MET kinase inhibitor in patient-derived xenograft (PDX) models of ccRCC. Our goal was to assess the ability of these compounds to alter the status of tumor-infiltrating macrophages, inhibit tumor growth and metastases, and prolong survival. Seven-week-old SCID mice were implanted subcutaneously or orthotopically with human ccRCC models. One month postimplantation, mice were treated with angiopoietin 1/2 inhibitor trebananib (AMG 386), MET kinase inhibitor, or combination. In our metastatic ccRCC PDX model, RP-R-02LM, trebananib alone, and in combination with a MET kinase inhibitor, significantly reduced lung metastases and M2 macrophage infiltration (P = 0.0075 and P = 0.0205, respectively). Survival studies revealed that treatment of the orthotopically implanted RP-R-02LM tumors yielded a significant increase in survival in both trebananib and combination groups. In addition, resection of the subcutaneously implanted primary tumor allowed for a significant survival advantage to the combination group compared with vehicle and both single-agent groups. Our results show that the combination of trebananib with a MET kinase inhibitor significantly inhibits the spread of metastases, reduces infiltrating M2-type macrophages, and prolongs survival in our highly metastatic ccRCC PDX model, suggesting a potential use for this combination therapy in treating patients with ccRCC.
A Multifunctional Therapy Approach for Cancer: Targeting Raf1- Mediated Inhibition of Cell Motility, Growth, and Interaction with the Microenvironment
Authors: Zhang Limin , Pattanayak Abhinandan , Li Wenqi , Ko Hyun-Kyung , Fowler Graham , Gordon Ryan , Bergan Raymond
Published: October 2019

Prostate cancer cells move from their primary site of origin, interact with a distant microenvironment, grow, and thereby cause death. It had heretofore not been possible to selectively inhibit cancer cell motility. Our group has recently shown that inhibition of intracellular activation of Raf1 with the small-molecule therapeutic KBU2046 permits, for the first time, selective inhibition of cell motility. We hypothesized that simultaneous disruption of multiple distinct functions that drive progression of prostate cancer to induce death would result in advanced disease control. Using a murine orthotopic implantation model of human prostate cancer metastasis, we demonstrate that combined treatment with KBU2046 and docetaxel retains docetaxel's antitumor action, but provides improved inhibition of metastasis, compared with monotherapy. KBU2046 does not interfere with hormone therapy, inclusive of enzalutamide-mediated inhibition of androgen receptor (AR) function and cell growth inhibition, and inclusive of the ability of castration to inhibit LNCaP-AR cell outgrowth in mice. Cell movement is necessary for osteoclast-mediated bone degradation. KBU2046 inhibits Raf1 and its downstream activation of MEK1/2 and ERK1/2 in osteoclasts, inhibiting cytoskeleton rearrangement, resorptive cavity formation, and bone destruction in vitro, with improved effects observed when the bone microenvironment is chemically modified by pretreatment with zoledronic acid. Using a murine cardiac injection model of human prostate cancer bone destruction quantified by CT, KBU2046 plus zoledronic exhibit improved inhibitory efficacy, compared with monotherapy. The combined disruption of pathways that drive cell movement, interaction with bone, and growth constitutes a multifunctional targeting strategy that provides advanced disease control.
ID1 Mediates Escape from TGFβ Tumor Suppression in Pancreatic Cancer
Authors: Huang Yun-Han , Hu Jing , Chen Fei , Lecomte Nicolas , Basnet Harihar , David Charles J. , Witkin Matthew D. , Allen Peter J. , Leach Steven D. , Hollmann Travis J. , Iacobuzio-Donahue Christine A. , Massagué Joan
Published: October 2019

TGFβ is an important tumor suppressor in pancreatic ductal adenocarcinoma (PDA), yet inactivation of TGFβ pathway components occurs in only half of PDA cases. TGFβ cooperates with oncogenic RAS signaling to trigger epithelial-to-mesenchymal transition (EMT) in premalignant pancreatic epithelial progenitors, which is coupled to apoptosis owing to an imbalance of SOX4 and KLF5 transcription factors. We report that PDAs that develop with the TGFβ pathway intact avert this apoptotic effect via ID1. ID1 family members are expressed in PDA progenitor cells and encode components of a set of core transcriptional regulators shared by PDAs. PDA progression selects against TGFβ-mediated repression of ID1. The sustained expression of ID1 uncouples EMT from apoptosis in PDA progenitors. AKT signaling and mechanisms linked to low-frequency genetic events converge on ID1 to preserve its expression in PDA. Our results identify ID1 as a crucial node and potential therapeutic target in PDA.

Significance:

Half of PDAs escape TGFβ-induced tumor suppression without inactivating the TGFβ pathway. We report that ID1 expression is selected for in PDAs and that ID1 uncouples TGFβ-induced EMT from apoptosis. ID1 thus emerges as a crucial regulatory node and a target of interest in PDA.

This article is highlighted in the In This Issue feature, p. 1
Zungenschrittmacher zur Behandlung der obstruktiven Schlafapnoe aus klinischer und ökonomischer Sicht
Authors: Galetke Wolfgang
Published: October 2019

Background: Upper airway stimulation (UAS) is a treatment approach for patients with moderate-to-severe obstructive sleep apnea who cannot adhere to continuous positive airway pressure therapy. Objective: The objective was to evaluate added patient benefit and cost-effectiveness of UAS in the German health care system. Methods: We used a decision-analytic Markov model to project major adverse cardiovascular or cerebrovascular events (myocardial infarction [MI] or stroke), motor vehicle collision (MVC), mortality, quality-adjusted life years (QALYs), and costs. The assumed reductionin the apnea-hypopnea index with UAS compared to no treatment is based on German real-world data. Other input data were derived from the literature, public statistics, and multivariate regression. Cost-effectiveness was evaluated in Euros per QALY gained, both discounted at 3%. Results: UAS was projected to reduce event risks (10-year relative risk for stroke, MI, cardiovascular death, and MVC: 0.76, 0.64, 0.65, and 0.34, respectively), and to increase survival by 1.27 years. While the UAS strategy incurred an additional 1.02 QALYs within the patient lifetime, there were also additional costs of EUR 45,196, resulting in an incremental cost-effectiveness ratio of EUR 44,446 per QALY gained. Conclusions: In the present model-based analysis, UAS therapy provides meaningful benefit to patient-relevant endpoints and is a cost-effective therapy in the German setting.
The Outcome of Hemolytic Disease of the Fetus and Newborn Caused by Anti-Rh17 Antibody: Analysis of Three Cases and Review of the Literature
Authors: Dajak Slavica , Ipavec Nina , Cuk Mia , Golubic Cepulic Branka , Mratinovic-Mikulandra Jela , Milardovic Josipa , Stefanovic Vedran
Published: October 2019

Background: Anti-Rh17 is a rare red blood cell (RBC) antibody to high-frequency antigens that may cause severe hemolytic disease of the fetus and newborn (HDFN). Despite the rarity of HDFN caused by Anti-Rh17, this antibody was reported in many different populations. Emergency transfusions, especially exchange transfusions, present a huge problem if no compatible RBCs of phenotype D-- are available. Methods: Here we report obstetrical histories of three women and describe their pregnancies complicated by anti-Rh17 antibodies. We summarized published cases of pregnancies complicated by anti-Rh17 and reviewed transfusion treatment and outcomes. Additionally, a simplified flowchart for the management of such pregnancies is proposed. Results: Four pregnancies were affected by severe HDFN, and three of them ended with perinatal death. In the fourth case, the baby was born hydropic and icteric and the condition was rapidly deteriorating. Emergency exchange transfusion was performed with incompatible O-negative RBC units in AB-negative plasma. The baby was discharged on the 14th day in good health. In the available literature, 15 women and 22 pregnancies were reported, 20 of them developed severe HDFN. According to the data, intrauterine transfusion for treatment of HDFN was the most common form of treatment with the donation of the mother’s blood. Different options for exchange transfusion were described, including incompatible RBCs. Conclusion: In more than 90% of described pregnancies of HDFN caused by anti-Rh17 antibody, transfusion treatment was required. Therefore, RBC from D-- phenotype has to be available. According to published data, in emergent circumstances when maternal and blood from donor with phenotype D-- is not available, incompatible exchange transfusion is a better choice than delaying transfusion when it is necessary. It is of essential importance that pregnancies with high risk of HDFN due to anti-Rh17 are managed by a multidisciplinary team (transfusion medicine specialist, obstetrician, neonatologist) in a highly specialized tertiary institution.
A precarização das condições de trabalho dos jornalistas de São Paulo segmentada por faixas etárias: uma identidade profissional em risco?
Authors: Lelo Thales Vilela
Published: October 2019

Este artigo parte do contexto de reestruturações produtivas no mundo do trabalho dos jornalistas, caracterizado por sistemáticas demissões e alta rotatividade de profissionais nas redações. Por meio da aplicação de dois questionários e 15 entrevistas semiestruturadas com comunicadores que atuavam no Estado de São Paulo entre dezembro de 2015 e janeiro de 2017, busca-se inicialmente avaliar os impactos dessas reestruturações nas condições de trabalho dos jornalistas. Em seguida, os dados são segmentados por faixas etárias, revelando uma precarização ascendente dos mais experientes no setor. Argumenta-se que essa tendência pode estar debilitando a construção de uma identidade profissional entre as novas gerações de repórteres.
Costa Pinto em dois tempos: os efeitos periféricos na circulação de ideias
Authors: Maia João Marcelo E.
Published: October 2019

Este artigo propõe uma abordagem sociológica para analisar como a relação entre centro e periferia afeta a produção e a circulação de ideias. Por meio do conceito de “efeitos periféricos”, procuro examinar empiricamente como essa relação afeta a construção de textos sociológicos. O objeto empírico do artigo é o texto “Sociologia e mudança social”, do brasileiro Luiz de Aguiar Costa Pinto, publicado originalmente em 1947 e republicado em 1961. O artigo compara as duas versões e demonstra como as diferentes posições do seu autor nos circuitos periféricos explicam mudanças conceituais e textuais.
Emprego doméstico e mudança social: reprodução e heterogeneidade na base da estrutura ocupacional brasileira
Authors: Lima Márcia , Prates Ian
Published: October 2019

O objetivo do presente artigo é analisar mudanças no perfil das empregadas domésticas entre 2002 e 2012 considerando não apenas as alterações pontuais na legislação que antecedeu à pec das domésticas, mas também as transformações sociais ocorridas na base da pirâmide social brasileira. Apesar da reprodução das clivagens de raça e classe que definem o perfil geral dessas trabalhadoras, o artigo demonstra que esses marcadores operam também na diferenciação interna dessa ocupação. Além disso, os dados analisados demonstram que as mudanças na base da estrutura ocupacional e no perfil educacional da força de trabalho foram decisivas para o modo como o perfil do emprego doméstico se alterou ao longo do período.
Gabriel Cohn. Weber, Frankfurt: teoria e pensamento social
Authors: Della Torre Bruna
Published: October 2019

Resenha do livro de Gabriel Cohn, Weber, Frankfurt: teoria e pensamento social, Rio de Janeiro, Azougue, 2017.
El concepto de objetividad en Gramsci
Authors: Burgos Raúl
Published: October 2019

El trabajo discute el tratamiento de la cuestión de la objetividad realizada por Gramsci en los Cuadernos de la Cárcel, sugiriendo inicialmente la existencia de dos polos de tensiones teóricas en el interior de la tradición marxista hasta entonces: las Tesis sobre Feuerbach y su crítica al materialismo metafísico y el tipo de materialismo filosófico que desagua en el marxismo soviético. A partir de esta posición inicial, en la primera parte del artículo son discutidos los conceptos de praxis, “lado activo” del pensamiento humano, devenir y objetividad. En la segunda parte es abordado, en primer lugar, el posicionamiento sobre el concepto de materia y el materialismo filosófico, subrayando la crítica gramsciana al deterioro del marxismo por la búsqueda metafísica de una “primera filosofía” y la batalla por reintegrarlo a la perspectiva marxista de la praxis, sin por esto adoptar una posición idealista; en segundo lugar, se muestra cómo, recuperando la idea labrioliana de autosuficiencia del marxismo, Gramsci erosiona hasta tal punto las bases del materialismo histórico en la forma criticada que la propia tradición debe ser denominada ya con otro nombre: filosofía de la praxis.
Antonio Gramsci e a questão feminina
Authors: Mussi Daniela
Published: October 2019

Desde os primeiros meses de redação dos Quaderni del Carcere, Gramsci escreveu sobre a centralidade da “salvaguarda da personalidade feminina” no contexto de crise capitalista que se desdobrava a partir da Primeira Guerra Mundial. Nesse sentido, o presente artigo procura responder duas questões: (a) quais as possíveis fontes para a formulação de Gramsci nos escritos carcerários sobre o papel político da questão feminina? (b) como essa formulação se desenvolveu em seu pensamento na prisão ao longo do tempo? A pesquisa reconstrói os caminhos desse problema nos escritos gramscianos anteriores e posteriores ao cárcere, explorando em especial o tratamento não economicista do mesmo. Discute, ainda, a importância da experiência pessoal de Gramsci, prisioneiro do regime fascista, para um desenvolvimento teórico da questão feminina como condição subalterna.
Mangue Bangue, filme-limite
Authors: Duarte Theo Costa
Published: October 2019

O propósito deste artigo é apresentar uma análise do “filme-limite” Mangue Bangue (1971), de Neville d’Almeida, tendo-se em vista a sua proximidade a questões e propostas contemporâneas do parceiro do cineasta, o artista plástico Hélio Oiticica, e ressaltando a convergência de ambos os artistas na experimentação com a forma cinema em interface com distintas mídias visuais e audiovisuais. Releva-se o contexto de parcerias artísticas que persistiam clandestinamente em torno da experimentação formal, de busca de ampliação das sensibilidades, catalisada pela precariedade dos meios técnicos à disposição, por necessidade e negação às convenções do cinema narrativo-representativo-industrial e à repressão estatal no período mais duro da ditadura civil-militar brasileira.
Em estado bruto
Authors: Silva Denise Ferreira da , Otoch Janaína Nagata
Published: October 2019

Nesse texto, publicado originalmente na revista e-flux [n° 93, setembro de 2018], Denise Ferreira da Silva delineia aquilo que define como uma interpretação poética, negra e feminista do trabalho de arte Majmua, de Madiha Sikander. Recusando a tradição moderna do discurso crítico, a autora busca, em vez do paradigma da abordagem analítica e a atitude de subsumir o trabalho de arte à categoria dos conceitos, a aproximação a uma matéria, por assim dizer, em estado bruto. Com tal interpretação, a autora visa uma posição que expande a relevância da arte para além dos limites da tradição filosófica crítico-kantiana, buscando libertá-la dos pilares onto-epistemológicos que alicerçam o pensamento moderno.
Seis textos de Jannis Kounellis
Authors: Vilela Jimson
Published: October 2019

Uma seleção de seis textos de Jannis Kounellis traduzidos para a língua portuguesa e acompanhados de uma breve introdução que apresenta ao leitor sua produção escrita e artística.
Clinâmen, eidôlon e o infinitesimal
Authors: Viviani Ana Elisa Antunes
Published: October 2019

Para os filósofos Gilles Deleuze e Félix Guattari a ciência nômade é um modelo que corre às margens dos paradigmas científicos tradicionais, identificados por eles como ciência de Estado. É como ciência nômade que compreendemos a trajetória empreendida pelo pensador francês Michel Serres e sua leitura da obra de Lucrécio, seguidor da filosofia epicurista e considerado um dos pais da física. Para Serres, é por meio dos conceitos de clinâmen, que explica a formação dos turbilhões e espirais, de eidôlon, sobre o qual se delineia uma razão engendrada pela percepção, e do cálculo infinitesimal, que se esboça um outro modelo de ciência. É nos caminhos das curvas e na fluidez da água que podemos encontrar explicações para o mundo, em contraposição à ciência moderna, baseada na suposição de um mundo estático e em equilíbrio. Diante disso, é necessário perguntar: é possível conciliar essa ciência nômade com a chamada ciência de dados, o Big Data, que por meio de algoritmos pretendem tornar previsíveis e padronizáveis os comportamentos humanos, tão incertos e fluidos?
Lipoprotein(a)-Lowering by 50 mg/dL (105 nmol/L) May Be Needed to Reduce Cardiovascular Disease 20% in Secondary Prevention
Authors: Madsen Christian M. , Kamstrup Pia R. , Langsted Anne , Varbo Anette , Nordestgaard Børge G.
Published: October 2019

Objective:

High Lp(a) (lipoprotein[a]) cause cardiovascular disease (CVD) in a primary prevention setting; however, it is debated whether high Lp(a) lead to recurrent CVD events. We tested the latter hypothesis and estimated the Lp(a)-lowering needed for 5 years to reduce CVD events in a secondary prevention setting.

Approach and Results:

From the CGPS (Copenhagen General Population Study; 2003–2015) of 58 527 individuals with measurements of Lp(a), 2527 aged 20 to 79 with a history of CVD were studied. The primary end point was major adverse cardiovascular event (MACE). We also studied 1115 individuals with CVD from the CCHS (Copenhagen City Heart Study; 1991–1994) and the CIHDS (Copenhagen Ischemic Heart Disease Study; 1991–1993). During a median follow-up of 5 years (range, 0–13), 493 individuals (20%) experienced a MACE in the CGPS. MACE incidence rates per 1000 person-years were 29 (95% CI, 25–34) for individuals with Lp(a)<10 mg/dL, 35 (30–41) for 10 to 49 mg/dL, 42 (34–51) for 50 to 99 mg/dL, and 54 (42–70) for ≥100 mg/dL. Compared with individuals with Lp(a)<10 mg/dL (18 nmol/L), the multifactorially adjusted MACE incidence rate ratios were 1.28 (95% CI, 1.03–1.58) for 10 to 49 mg/dL (18–104 nmol/L), 1.44 (1.12–1.85) for 50 to 99 mg/dL (105–213 nmol/L), and 2.14 (1.57–2.92) for ≥100 mg/dL (214 nmol/L). Independent confirmation was obtained in individuals from the CCHS and CIHDS. To achieve 20% and 40% MACE risk reduction in secondary prevention, we estimated that plasma Lp(a) should be lowered by 50 mg/dL (95% CI, 27–138; 105 nmol/L [55–297]) and 99 mg/dL (95% CI, 54–273; 212 nmol/L [114–592]) for 5 years.

Conclusions:

High concentrations of Lp(a) are associated with high risk of recurrent CVD in individuals from the general population. This study suggests that Lp(a)-lowering by 50 mg/dL (105 nmol/L) short-term (ie, 5 years) may reduce CVD by 20% in a secondary prevention setting.
Anti-Inflammatory Effects of HDL (High-Density Lipoprotein) in Macrophages Predominate Over Proinflammatory Effects in Atherosclerotic Plaques
Authors: Fotakis Panagiotis , Kothari Vishal , Thomas David G. , Westerterp Marit , Molusky Matthew M. , Altin Elissa , Abramowicz Sandra , Wang Nan , He Yi , Heinecke Jay W. , Bornfeldt Karin E. , Tall Alan R.
Published: October 2019

Objective:

HDL (high-density lipoprotein) infusion reduces atherosclerosis in animal models and is being evaluated as a treatment in humans. Studies have shown either anti- or proinflammatory effects of HDL in macrophages, and there is no consensus on the underlying mechanisms. Here, we interrogate the effects of HDL on inflammatory gene expression in macrophages.

Approach and Results:

We cultured bone marrow–derived macrophages, treated them with reconstituted HDL or HDL isolated from
APOA1

Tg

;Ldlr
−/−
mice, and challenged them with lipopolysaccharide. Transcriptional profiling showed that HDL exerts a broad anti-inflammatory effect on lipopolysaccharide-induced genes and proinflammatory effect in a subset of genes enriched for chemokines. Cholesterol removal by POPC (1-palmitoyl-2-oleoyl-glycero-3-phosphocholine) liposomes or β-methylcyclodextrin mimicked both pro- and anti-inflammatory effects of HDL, whereas cholesterol loading by POPC/cholesterol-liposomes or acetylated LDL (low-density lipoprotein) before HDL attenuated these effects, indicating that these responses are mediated by cholesterol efflux. While early anti-inflammatory effects reflect reduced TLR (Toll-like receptor) 4 levels, late anti-inflammatory effects are due to reduced IFN (interferon) receptor signaling. Proinflammatory effects occur late and represent a modified endoplasmic reticulum stress response, mediated by IRE1a (inositol-requiring enzyme 1a)/ASK1 (apoptosis signal-regulating kinase 1)/p38 MAPK (p38 mitogen-activated protein kinase) signaling, that occurs under conditions of extreme cholesterol depletion. To investigate the effects of HDL on inflammatory gene expression in myeloid cells in atherosclerotic lesions, we injected reconstituted HDL into
Apoe
−/−
or
Ldlr
−/−
mice fed a Western-type diet. Reconstituted HDL infusions produced anti-inflammatory effects in lesion macrophages without any evidence of proinflammatory effects.

Conclusions:

Reconstituted HDL infusions in hypercholesterolemic atherosclerotic mice produced anti-inflammatory effects in lesion macrophages suggesting a beneficial therapeutic effect of HDL in vivo.
The First Original Copy and the Role of Blockchain in the Reproduction of Cultural Heritage
Authors: Ch'ng Eugene
Published: October 2019

The First Original Copy refers to any first true 3D facsimile of a digitally reproduced physical object. The notion of a copy being the first and original implies that it is unique and therefore the approach used for managing rights and ownership influences its value. Whilst virtual goods traded within virtual worlds are subject to rules and policies, the production of digital objects in the real world does not have a mechanism from which rarity and uniqueness can be guaranteed. Digital copies are subject to further copying and thus, the value of even an exact copy can never be perceived to be equivalent to its original. Through what means can we imbue 3D reproductions of cultural objects with value that is at least asymptotic to their originals? There may be a candidate solution. Discussed in this article is a possible approach for resolving a long-term issue related to authenticity, ownership, perpetuity, and the quantitative tracking of value associated with 3D copies. Blockchains essentially bring the systemic management of virtual objects within virtual worlds into the real world. This forum article examines the candidate solution by answering the questions above, and discusses the issues associated with the concept of the First Original Copy.
Personalizing Content Presentation on Large 3D Head-Up Displays
Authors: Häuslschmid Renate , Ren Donghao , Alt Florian , Butz Andreas , Höllerer Tobias
Published: October 2019

Drivers' urge to access content on smartphones while driving causes a high number of fatal accidents every year. We explore 3D full-windshield size head-up displays as an opportunity to present such content in a safer manner. In particular, we look into how drivers would personalize such displays and whether it can be considered safe. Firstly, by means of an online survey we identify types of content users access on their smartphones while driving and whether users are interested in the same content on a head-up display. Secondly, we let drivers design personalized 3D layouts and assess how personalization impacts on driving safety. Thirdly, we compare personalized layouts to a one-fits-all layout concept in a 3D driving simulator study regarding safety. We found that drivers' content preferences diverge largely and that most of the personalized layouts do not respect safety sufficiently. The one-fits-all layout led to a better response performance but needs to be modified to consider the drivers' preferences. We discuss the implications of the presented research on road safety and future 3D information placement on head-up displays.
Calling while Driving Using Augmented Reality: Blessing or Curse?
Authors: Kun Andrew L. , Meulen Hidde van der , Janssen Christian P.
Published: October 2019

We report on an experiment on the distracting effects of in-car conversations through augmented-reality glasses. Previous research showed that in-car phone conversations can be distracting, but that the distraction might be reduced if the remote caller receives visual information about the driving context. However, what happens if such video sharing becomes bidirectional? The recent introduction of commercial augmented-reality glasses in particular might allow drivers to engage in video-supported conversations while driving. We investigate how distracting such video-based conversations are in an experiment. Our participants operated a simulated vehicle, while also playing a conversational game (Taboo) with a remote conversant. The driver either only heard the remote conversant (speech-only condition), or was also able to see the remote person in a virtual window that was presented through augmented reality (video call condition). Results show that our participants did not spend time looking at the video of the remote conversant. We hypothesize that this was due to the fact that in our experiment participants had to turn their head to get a full view of the virtual window. Our results imply that we need further studies on the effects of augmented reality on the visual attention of the driver, before the technology is used on the road.
A Survey on Simulation Sickness in Driving Applications with Virtual Reality Head-Mounted Displays
Authors: Rangelova Stanislava , Andre Elisabeth
Published: October 2019

This article discusses factors related to simulation sickness in virtual reality driving simulations with head-mounted displays. Simulation sickness is a well-known phenomenon that has physiological effects on users, such as disorientation, headache, and nausea. There are three major theories why simulation sickness arises. Previous research on this phenomenon has mostly concentrated on driving or flying simulators with standard computer displays. It is, therefore, possible to conclude that any simulated environment could have such an effect, and virtual reality should not be considered an exception to such problems. While virtual reality has had and will continue to have a positive impact on the development and testing of new automotive interior concepts, simulation sickness is a significant drawback. Despite the advances in technology, discomfort from using head-mounted displays has yet to be resolved. A review of these displays in the context of virtual reality driving applications over the recent years will be presented. Moreover, characterization and comparison of approaches to mitigate simulation sickness will be given in the text. Concluding suggestions for future work on the correlation between simulation sickness and a virtual driving environment will be provided.
Descriptive skeletal anatomy of Blommersia transmarina (Amphibia: Anura: Mantellidae) from the Comoro Islands
Authors: Santos-Santos Javier H. , Guinovart-Castán Mireia , Vieites David R.
Published: October 2019

Mantellid frogs present an extensive adaptive radiation endemic to Madagascar and Comoros, being the subfamily Mantellinae the most morphologically and ecologically diverse. The Mantellinae present key innovative evolutionary traits linked to their unique reproductive behavior, including the presence of femoral glands and a derived vomeronasal organ. In addition, previous studies pointed to size differentiation in playing an important role in species’ dispersal capacities and shaping of their geographic ranges. Despite the high phenotypic variation observed in this clade, to date an exhaustive morphological analysis of their anatomy has still not been performed, much less in relation to internal structures. Here, we present a comprehensive skeletal description of a mantellid species, Blommersia transmarina, from the island of Mayotte in the Indian Ocean, which has potentially undergone a process of moderate gigantism compared to other Blommersia species. We describe its intraspecific skeletal variation utilizing non-destructive volume renderings from μCT-scans, and characterize the presence of sexual dimorphism and size covariation in skeletal structures. Notably, we found numerous signs of hyperossification, a novel structure for mantellids: the clavicular process, and the presence of several appendicular sesamoids. Our findings suggest that skeletal phenotypic variation in this genus may be linked to biomechanical function for reproduction and locomotion.
Biopiracy of Plant Resources and Sustainable Traditional Knowledge System in Africa
Authors: Ageh Patrick Agejoh , Lall Namrita
Published: October 2019

The relationship between plant resources and traditional communities in Africa is inseparable. For centuries, indigenous communities have been depending on their cultural innovations and practices for health and food. Plant resources are part of the traditional knowledge system of indigenous communities in Africa.

Colonialism and the scramble for Africa led to plant resources being opened to bioprospecting by western scientists and multinational pharmaceutical firms. They engage in secluded locations around Africa in order to find ‘new drugs from exotic plants’ for profit-making or patent rights. The advent of technology has witnessed a lot of illegal exploitation and commercialization of plant resources (biopiracy). The traditional knowledge system is being eroded with disregard to the welfare of the owners of the knowledge to sustainably manage it. The paper looks at the challenges, the existing legal framework to appreciate if it’s adequate to ensure the sustainability of the traditional knowledge system in Africa.
The Thought of Samuel J. Levine at the Intersection of the Talmudic and Constitutional Law
Authors: Meyers Jeffrey B.
Published: October 2019

Samuel J. Levine’s research and writing collected in the two-volume anthology, Jewish Law and American Law: A Comparative Study addresses the connection between contemporary American Law and ancient Talmudic Law through the lens of contemporary Constitutional Law and Professional Ethics. Professor Levine mines the legacy of the late Robert Cover and his theory of law and narrative in particular to draw out the similarities and differences between rabbinic interpretation of the Torah and judicial interpretation of the US Constitution. He also considers where Jewish ethics converge and diverge from professional rules of conduct in the legal profession. This article summarizes some of the key turns in Levine’s recently published collected works and reflects critically on their key themes.
Reply to Andrew Brower’s critique of the evidence for hybridization among Heliconius butterfly species in the wild
Authors: MALLET JAMES
Published: October 2019

Andrew Brower recently published a long article in this journal that seeks to dismantle evidence for hybridization between species of Heliconius butterflies. The main evidence that Brower criticizes here is given in two papers published by my colleagues and myself in 2007. In this reply, I briefly defend our evidence, and at greater length provide additional background information to help establish the credibility of the evidence even more firmly than previously.
A review of the Malagasy species of the genus Trigonochilus Brenske (Coleoptera: Scarabaeidae: Rutelinae: Adoretini) with description of a new species
Authors: MONTREUIL OLIVIER , FROLOV ANDREY V.
Published: October 2019

Africa and Madagascar have a large and diverse fauna of the chafers of the ruteline beetle tribe Adoretini (Ohaus 1912, 1918). Many nominal taxa from Madagascar are still poorly known and many new ones were described recently (Akhmetova & Montreuil 2010; Montreuil 2010, 2013; Montreuil & Frolov 2014; Frolov & Montreuil 2018). One of the poorly known Adoretini taxa is the genus Trigonochilus Brenske, 1896. Trigonochilus was proposed to accommodate the East-African species T. coriaceus Brenske, 1896, based on the enlarged and curved metatibiae and a short, spur-like process of the labrum (Brenske 1896). Arrow (1901) noted that the enlarged metatibiae of this species (described from a single male) is a secondary sexual character and added another species to this genus, T. politus Arrow, 1901, from Angola. These species were revised by Krikken (1979). Fairmaire (1903) described Adoretus oedipus from Madagascar (without any precise locality) and noted its enlarged metatibia and the shape of the labrum similar to that in Trigonostonum Burmeister, 1844. Fairmaire was apparently unaware of the Brenske’s and Arrow’s works as he did not discuss the possible affinities of A. oedipus with Trigonochilus species. Ohaus (1912) moved A. oedipus to Trigonochilus after examination of the type series but he did not discuss the characters of the species in detail as well as its distribution on the island. Therefore, the genus Trigonochilus Brenske comprised three species described so far, two from Africa and one from Madagascar.
Unexpected diversity of Microscydmus Saulcy & Croissandeau in Japan (Coleoptera: Staphylinidae: Scydmaeninae)
Authors: JAŁOSZYŃSKI PAWEŁ
Published: October 2019

The genus Microscydmus Saulcy & Croissandeau is recorded for the first time from the Japanese Archipelago. Eight species are described: Microscydmus okinawanus sp. n., M. oharaensis sp. n., M. nishimeanus sp. n., M. kochiensis sp. n., M. elytratus sp. n., M. tibialis sp. n., M. yusuharanus sp. n., and M. omogonus sp. n. All new species are placed in the nominotypical subgenus, and Japan becomes a country that houses the greatest recorded species richness of Microscydmus (s. str.). The new species are distributed on Shikoku and in the Ryukyus. A novel character was found, previously unknown in Microscydmus: a pair of long lateral setae on the posterior margin of vertex, clearly visible in some of the newly described species. These setae are not thicker than surrounding ones, but stand out because of their remarkable length. A re-examination of SEM images obtained during previous studies confirmed the presence of these setae also in M. nanus, the European type species of the genus, in which, however, these setae are obscured by surrounding vestiture. Among Glandulariini, such a pair of setae has been known only in the extinct Upper Cretaceous Scydmobisetia Jałoszyński & Yamamoto.
Four new Oriental species of the ‘Cephennomicrus group’ (Coleoptera: Staphylinidae: Scydmaeninae)
Authors: JAŁOSZYŃSKI PAWEŁ
Published: October 2019

The 'Cephennomicrus group' of Cephenniini includes nine genera distributed mostly in SE Asia (but with some species known also from other continents, except for the Americas). Four new Oriental species are described: Cephennococcus penangensis sp. n. (W Malaysia), Cephennomicrus matangensis sp. n. (E Malaysia), Cephennomicrus selangorensis sp. n. (E Malaysia), and Trurlia nova sp. n. (E Malaysia). Cephennomicrus selangorensis is unique in having the pronotum in both sexes with broad lateral impressions demarcated from the disc by a sharp ridge, a modification slightly similar to that of only one (Australian) congener.
New species, new records, and new synonymy in Hemilophini (Coleoptera, Cerambycidae, Lamiinae)
Authors: HEFFERN DANIEL , BOTERO JUAN PABLO , SANTOS-SILVA ANTONIO
Published: October 2019

A new species, Hemierana rileyi sp. nov., is described from the USA (Texas). Tyrinthia lycinella Bates, 1881 is synonymized with T. xanthe Bates, 1881. A new country record (Panama), and a new province record in Costa Rica (Limón) is given for Eranina cretaria (Galileo & Martins, 2005), and a new country record (Panama) is given for Eranina costaricensis (Galileo & Martins, 2005).
Turritellidae (Gastropoda) of the Miocene Paratethys Sea with considerations about turritellid genera
Authors: HARZHAUSER MATHIAS , LANDAU BERNARD
Published: October 2019

We present a critical evaluation of the taxonomy, stratigraphy and biogeography of the turritellid gastropods of the Miocene Paratethys Sea. 159 species-level names and 6 infrasubspecific names have been used for Paratethyan Turritellidae since 1848. Of these, only 35 species are accepted herein as valid species, with some uncertainties due to poor preservation or limited access to type material. Maximum diversities occurred during the early middle Miocene (Langhian, Badenian) coinciding with the Miocene Climatic Optimum. Whilst early Miocene turritellid assemblages are characterized by large to very large species of Peyrotia, Turritella and Allmonia, middle Miocene assemblages are predominated by medium-sized species of Archimediella, Helminthia, Oligodia and Ptychidia. The taxonomic composition of these faunas, with representatives of Archimediella, Helminthia, Mesalia and Vermicularia suggests a biogeographic affiliation with Atlantic and especially West African faunas.                Turritellinella new gen. is established as new genus for the eastern Atlantic-Mediterranean Turritella tricarinata/communis complex. Viennella is described as new genus with Turritella incisaeformis Csepreghy-Meznerics 1956 as type species. Allmonia new gen. is introduced as new genus for European Cenozoic Protominae previously placed in Protoma. For the first time, inner lirae are documented as conchological features of Turritellidae.                Six species are described as new, three within the Turritellinae: Archimediella carpathica new sp., Ptychidia erynella new sp. and Viennella ignorata new sp., and three within the Pareorinae: Mesalia sovisi new sp., Mesalia stryriaca new sp. and Mesalia bohnhavasae new sp.. Ptychidia austrorotundata new nom. is proposed as new name Turritella turris rotundata Schaffer 1912, non Turritella rotundata Grzybowski 1899. We designate lectotypes for Turritella gradata Menke in Hörnes, 1855, Haustator striatellatus Sacco, 1895, Allmonia carniolica (Stache, 1858) and Allmonia alterniplicata (Sacco, 1895). Neotypes are designated for Archimediella abundans (Handmann, 1882), Archimediella hoernesi (Rolle, 1856), Ptychidia partschi (Rolle, 1856), Ptychidia? ernesti (Handmann, 1882). Rhabdosis Townes, 1970 (Hymenoptera, Ichneumonidae) is a junior homonym of Rhabdosis Handmann 1882 (Gastropoda, Turritellidae) and will need a new name.
Katydids (Orthoptera: Tettigoniidae) of Gorongosa National Park and Central Mozambique
Authors: NASKRECKI PIOTR , GUTA RICARDO
Published: October 2019

A list of 60 species of the Tettigoniidae (Orthoptera) recorded from Gorongosa National Park and provinces Sofala and Manica in central Mozambique is provided and their natural history is discussed. Of these, 58 species are illustrated and bioacoustic data are presented for 47 species. Two new genera and 9 new species are described: Gorongosa carri gen. et sp. n., Ovonotus abreuae gen. et sp. n., Afroagraecia muagurai sp. n., Enyaliopsis iaculator sp. n., Eurycorypha parkeri sp. n., Eurycorypha stalmansi sp. n., Eulioptera carolli sp. n., Eulioptera mutembai sp. n., and Parpyrrhicia guytonae sp. n. Four species of Ruspolia are recognized as potentially new and their bioacoustic data are presented. Pseudorhynchus pungens meridionalis Ragge, 1969 is synonymized with Pseudorhynchus pungens pungens (Schaum, 1853); Angustithorax spiniger Massa, 2015 is synonymized with Oxyecous magnus Ragge, 1956; and the synonymy of Lanista africana (Walker, 1870) with Lanista annulicornis (Walker, 1869) is reversed. Two species, G. carri and O. abreuae, appear to be endemic to Mt. Gorongosa and 24 species are recorded for the first time from Mozambique.