bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of Peripheral Effector CD8 T-cell Proliferation by Combination of Paclitaxel, Carboplatin, and Bevacizumab in Non–small Cell Lung Cancer Patients
Authors: de Goeje Pauline L. , Poncin Myrthe , Bezemer Koen , Kaijen-Lambers Margaretha E.H. , Groen Harry J.M. , Smit Egbert F. , Dingemans Anne-Marie C. , Kunert André , Hendriks Rudi W. , Aerts Joachim G.J.V. 
Published: January 2019

Abstract

Purpose:
Chemotherapy has long been the standard treatment for advanced stage non–small cell lung cancer (NSCLC), but checkpoint inhibitors are now approved for use in several patient groups and combinations. To design optimal combination strategies, a better understanding of the immune-modulatory capacities of conventional treatments is needed. Therefore, we investigated the immune-modulatory effects of paclitaxel/carboplatin/bevacizumab (PCB), focusing on the immune populations associated with the response to checkpoint inhibitors in peripheral blood.

Experimental Design:
A total of 223 patients with stage IV NSCLC, enrolled in the NVALT12 study, received PCB, with or without nitroglycerin patch. Peripheral blood was collected at baseline and after the first and second treatment cycle, proportions of T cells, B cells, and monocytes were determined by flow cytometry. Furthermore, several subsets of T cells and the expression of Ki67 and coinhibitory receptors on these subsets were determined.

Results:
Although proliferation of CD4 T cells remained stable following treatment, proliferation of peripheral blood CD8 T cells was significantly increased, particularly in the effector memory and CD45RA+ effector subsets. The proliferating CD8 T cells more highly expressed programmed death receptor (PD)-1 and cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4) compared with nonproliferating CD8 T cells. Immunologic responders (iR; &gt;2 fold increased proliferation after treatment) did not show an improved progression-free (PFS) or overall survival (OS).

Conclusions:
Paclitaxel/carboplatin/bevacizumab induces proliferation of CD8 T cells, consisting of effector cells expressing coinhibitory checkpoint molecules. Induction of proliferation was not correlated to clinical outcome in the current clinical setting. Our findings provide a rationale for combining PCB with checkpoint inhibition in lung cancer.
The Rolipram–Perillyl Alcohol Conjugate (NEO214) Is A Mediator of Cell Death through the Death Receptor Pathway
Authors: Cho Hee-Yeon , Thein Thu Zan , Wang Weijun , Swenson Stephen D. , Fayngor Rochelle A. , Ou Mengting , Marín-Ramos Nagore I. , Schönthal Axel H. , Hofman Florence M. , Chen Thomas C. 
Published: January 2019

Abstract
Glioblastoma (GBM) is a highly aggressive primary brain tumor with a poor prognosis. Treatment with temozolomide, standard of care for gliomas, usually results in drug resistance and tumor recurrence. Therefore, there is a great need for drugs that target GBM. NEO214 was generated by covalently linking rolipram to perillyl alcohol (POH) via a carbamate bond to form the rolipram–perillyl alcohol conjugate. We show here that NEO214 is effective against both temozolomide-sensitive and temozolomide-resistant glioma cells. Furthermore, NEO214 is effective for different mechanisms of temozolomide resistance: overexpression of MGMT (O6-methylguanine methyl-transferase); deficiency in specific mismatch repair proteins; and overexpression of base excision repair (BER) proteins. NEO214-induced cytotoxicity involves apoptosis triggered by endoplasmic reticulum (ER) stress, as well as activating the Death Receptor 5 (DR5)/TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) pathway. In vitro studies show that glioma cells treated with NEO214 express DR5 and exhibit cell death in the presence of recombinant TRAIL, a growth factor constitutively produced by astrocytes. Our in vitro 3D coculture data show that induction of DR5 in glioma cells with NEO214 and TRAIL cause tumor cell death very effectively and specifically for glioma cells. In vivo studies show that NEO214 has antitumor efficacy in orthotropic syngeneic rodent tumor models. Furthermore, NEO214 has therapeutic potential especially for brain tumors because this drug can cross the blood–brain barrier (BBB), and is effective in the TRAIL-rich astrocyte microenvironment. NEO214 is a strong candidate for use in the treatment of GBMs.
Chemically Modified Antisense Oligonucleotide Against ARL4C Inhibits Primary and Metastatic Liver Tumor Growth
Authors: Harada Takeshi , Matsumoto Shinji , Hirota Suguru , Kimura Hirokazu , Fujii Shinsuke , Kasahara Yuuya , Gon Hidetoshi , Yoshida Toshihiko , Itoh Tomoo , Haraguchi Naotsugu , Mizushima Tsunekazu , Noda Takehiro , Eguchi Hidetoshi , Nojima Satoshi , Morii Eiichi , Fukumoto Takumi , Obika Satoshi , Kikuchi Akira 
Published: January 2019

Abstract
ADP-ribosylation factor-like 4c (ARL4C) is identified as a small GTP-binding protein, which is expressed by Wnt and EGF signaling and plays an important role in tubulogenesis of cultured cells and the ureters. ARL4C is little expressed in adult tissues, but it is highly expressed in lung cancer and colorectal cancer and shown to represent a molecular target for cancer therapy based on siRNA experiments. This study revealed that ARL4C is highly expressed in primary hepatocellular carcinoma (HCC) tumors and colorectal cancer liver metastases, and that ARL4C expression is associated with poor prognosis for these cancers. Chemically modified antisense oligonucleotides (ASO) against ARL4C effectively reduced ARL4C expression in both HCC and colorectal cancer cells and inhibited proliferation and migration of these cancer cells in vitro. ARL4C ASOs decreased the PIK3CD mRNA levels and inhibited the activity of AKT in HCC cells, suggesting that the downstream signaling of ARL4C in HCC cells is different from that in lung and colon cancer cells. In addition, subcutaneous injection of ARL4C ASO was effective in reducing the growth of primary HCC and metastatic colorectal cancer in the liver of immunodeficient mice. ARL4C ASO accumulated in cancer cells more efficiently than the surrounding normal cells in the liver and decreased ARL4C expression in the tumor. These results suggest that ARL4C ASO represents a novel targeted nucleic acid medicine for the treatment of primary and metastatic liver cancers.
Extracellular Fatty Acids Are the Major Contributor to Lipid Synthesis in Prostate Cancer
Authors: Balaban Seher , Nassar Zeyad D. , Zhang Alison Y. , Hosseini-Beheshti Elham , Centenera Margaret M. , Schreuder Mark , Lin Hui-Ming , Aishah Atqiya , Varney Bianca , Liu-Fu Frank , Lee Lisa S. , Nagarajan Shilpa R. , Shearer Robert F. , Hardie Rae-Anne , Raftopulos Nikki L. , Kakani Meghna S. , Saunders Darren N. , Holst Jeff , Horvath Lisa G. , Butler Lisa M. , Hoy Andrew J. 
Published: January 2019

AbstractProstate cancer cells exhibit altered cellular metabolism but, notably, not the hallmarks of Warburg metabolism. Prostate cancer cells exhibit increased de novo synthesis of fatty acids (FA); however, little is known about how extracellular FAs, such as those in the circulation, may support prostate cancer progression. Here, we show that increasing FA availability increased intracellular triacylglycerol content in cultured patient-derived tumor explants, LNCaP and C4-2B spheroids, a range of prostate cancer cells (LNCaP, C4-2B, 22Rv1, PC-3), and prostate epithelial cells (PNT1). Extracellular FAs are the major source (∼83%) of carbons to the total lipid pool in all cell lines, compared with glucose (∼13%) and glutamine (∼4%), and FA oxidation rates are greater in prostate cancer cells compared with PNT1 cells, which preferentially partitioned extracellular FAs into triacylglycerols. Because of the higher rates of FA oxidation in C4-2B cells, cells remained viable when challenged by the addition of palmitate to culture media and inhibition of mitochondrial FA oxidation sensitized C4-2B cells to palmitate-induced apoptosis. Whereas in PC-3 cells, palmitate induced apoptosis, which was prevented by pretreatment of PC-3 cells with FAs, and this protective effect required DGAT-1–mediated triacylglycerol synthesis. These outcomes highlight for the first-time heterogeneity of lipid metabolism in prostate cancer cells and the potential influence that obesity-associated dyslipidemia or host circulating has on prostate cancer progression.Implications:Extracellular-derived FAs are primary building blocks for complex lipids and heterogeneity in FA metabolism exists in prostate cancer that can influence tumor cell behavior.
Dual Targeting of EGFR and IGF1R in the TNFAIP8 Knockdown Non–Small Cell Lung Cancer Cells
Authors: Day Timothy F. , Kallakury Bhaskar V.S. , Ross Jeffrey S. , Voronel Olga , Vaidya Shantashri , Sheehan Christine E. , Kasid Usha N. 
Published: January 2019

Abstract

Aberrant regulation of EGFR is common in non–small cell lung carcinomas (NSCLC), and tumor resistance to targeted therapies has been attributed to emergence of other co-occurring oncogenic events, parallel bypass receptor tyrosine kinase pathways including IGF1R, and TNFα-driven adaptive response via NF-κB. TNFAIP8, TNFα-inducible protein 8, is an NF-κB–activated prosurvival and oncogenic molecule. TNFAIP8 expression protects NF-κB–null cells from TNFα-induced cell death by inhibiting caspase-8 activity. Here, we demonstrate that knockdown of TNFAIP8 inhibited EGF and IGF-1–stimulated migration in NSCLC cells. TNFAIP8 knockdown cells showed decreased level of EGFR and increased expression of sorting nexin 1 (SNX1), a key regulator of the EGFR trafficking through the endosomal compartments, and treatment with SNX1 siRNA partially restored EGFR expression in these cells. TNFAIP8 knockdown cells also exhibited downregulation of IGF-1–induced pIGF1R and pAKT, and increased expression of IGF-1–binding protein 3 (IGFBP3), a negative regulator of the IGF-1/IGF1R signaling. Consistently, treatment of TNFAIP8 knockdown cells with IGFBP3 siRNA restored pIGF1R and pAKT levels. TNFAIP8 knockdown cells had enhanced sensitivities to inhibitors of EGFR, PI3K, and AKT. Furthermore, IHC expression of TNFAIP8 was associated with poor prognosis in NSCLC. These findings demonstrate TNFAIP8-mediated regulation of EGFR and IGF1R via SNX1 and IGFBP3, respectively. We posit that TNFAIP8 is a viable, multipronged target downstream of the TNFα/NF-κB axis, and silencing TNFAIP8 may overcome adaptive response in NSCLC.

Implications:
TNFAIP8 and its effectors SNX1 and IGFBP3 may be exploited to improve the efficacy of molecular-targeted therapies in NSCLC and other cancers.
Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/5/1207/F1.large.jpg.
Angelos Katakouzenos (1902–1982): A Lifework of Neurology and Art
Authors: Stefanou Maria-Ioanna , Peloponnissiou-Vassilacos Sophia 
Published: January 2019

Angelos Katakouzenos, a Greek neurologist and prolific medical writer at the beginning of the 20th century, belonged to a group of artists and scholars that formed the “generation of the 30s,” a cultural movement that emerged after World War I and introduced modernism in Greek art and literature. Born in 1902, Katakouzenos studied medicine in France at the Universities of Montpellier and Paris, where he trained in neurology and ­psychiatry under Georges Guillain, Henri Claude, Jean-Athanase Sicard, Pierre Marie, Clovis Vincent and Théophile ­Alajouanine. In Paris, he attended to Freud’s patients, collaborating with the psychoanalyst Marie Bonaparte, while he was introduced to the contemporary <i>avant-garde</i> movements of this time, developing long-lasting friendships with artists and intellectuals, including Marc Chagall and Tériade. Although Professor of Neurology and Psychiatry at the University of ­Paris, <i>Commandeur of the Légion d’honneur</i> and founder of the first neuropsychiatric clinics in Greece, Katakouzenos lived far from the limelight. Despite his numerous publications, his scientific work remained largely unacknowledged. Yet, as a ­psychoanalyst he gained international fame and treated patients including William Faulkner who later would write, “To the wise scientist, the in-depth judge of the human soul, my friend Dr. Katakouzenos, who has helped me like no one else to redeem myself from the tortuous questions that troubled me for years – from the depths of my heart, many, very many thanks”. In this paper, the rediscovery of Katakouzenos’s remarkable work in the field of neuroscience aims to tell the story of a great physician whose lifework in bridging art and science may, in retrospect, reinstate him as one of the most captivating neurologists of the 20th century.
Vontade de nada e vontade de saúde nos escritos tardios de Nietzsche
Authors: Araldi Clademir Luís 
Published: January 2019

Nos escritos de 1888, Nietzsche retoma com interesse redobrado duas formas antagônicas da vontade: a vontade de saúde e a vontade de nada. Investigaremos, a partir da discussão com Scarlett Marton, se e como as atitudes sadias do próprio Nietzsche decorrem de suas condições fisiológicas e, no contexto dos dois primeiros capítulos de Ecce Homo, em que medida a configuração pulsional de Nietzsche dita a sua terapêutica e sua tarefa filosófica. Da perspectiva do Nietzsche ‘saudável’, a vontade de saúde predominaria sobre a vontade de nada. Num segundo momento, questionaremos a afirmação de Nietzsche, de que ele seria “fundamentalmente sadio”, a partir dos textos de 1885 a 1888, em que ele investiga também a vontade de nada. Enquanto doente, ele poderia ser médico de si mesmo e, com isso, médico da cultura? Admitindo sua dupla natureza, o Filósofo doente poderia investigar o trabalho secreto do instinto da decadência sem ser por ele influenciado?
Palavras-chaveVontade de Saúde; Vontade de Nada; Instinto; Niilismo; Transvaloração.
Sub specie saeculi, sub specie aeterni: tempo e eternidade no jovem Nietzsche
Authors: Nasser Eduardo 
Published: January 2019

Para o jovem Nietzsche, a modernidade marca o início do ocaso da cultura ocidental em virtude da glorificação do conhecimento. Esse aspecto é a causa para que o homem moderno fique enclausurado numa perspectiva realista, sendo incapaz de se libertar do constrangimento infligido pelo vir-a-ser. Para reverter a condenação imposta à cultura pelo socratismo, é preciso restituir os direitos da arte, pois somente a arte viabiliza a recuperação do laço com a eternidade, fornecendo meios para o homem se proteger dos efeitos do tempo. Isso ocorre especialmente no âmbito da arte musical, quer em sua vertente apolínea (ritmo), quer em sua vertente dionisíaca (harmonia), na medida em que a supremacia das aparências ante a arte é enfraquecida.
Palavras-chaveTempo; Eternidade; Linguagem; Arte; Mito.
A fisiopsicologia de Nietzsche: o diagnóstico e a elevação da cultura como tarefa do médico filosófico
Authors: Frezzatti Jr. Wilson Antonio 
Published: January 2019

As produções humanas, segundo Nietzsche, são expressões fisiológicas, ou seja, expressões de um conjunto de impulsos em luta por mais potência. Essa perspectiva ocupa papel central nas reflexões da maturidade do filósofo: sua fisiopsicologia desenvolve um diagnóstico das produções culturais e indica quais manifestações possuem um caráter saudável e quais delas são doentias. Nietzsche assume o papel de médico na medida em que se preocupa com um medicamento, isto é, com um contra-ideal, com um adversário da civilização entendida enquanto domesticação dos impulsos humanos. O médico nietzschiano antagoniza-se àquele proposto pela tradição filosófica: não é um médico de almas.
Palavras-chaveCivilização; Cultura; Fisiopsicologia; Médico filosófico; Vontade de potência.
Novel Biomarkers for the Precisive Diagnosis and Activity Classification of Takayasu Arteritis
Authors: Cui Xiao , Qin Fang , Song Lei , Wang Tian , Geng Bin , Zhang Weili , Jin Ling , Wang Wenjie , Li Shuangyue , Tian Xinping , Zhang Huimin , Cai Jun 
Published: January 2019

Background:
Establishing the diagnosis and determining disease activity of Takayasu arteritis (TA) remains challenging. Novel biomarkers might help to solve this problem.

Methods:
In the screening phase, by using large-scale protein arrays detecting samples from 90 subjects (TA active, 29; TA inactive 31; and controls, 30). In the validation phase, by using enzyme-linked immunosorbent assay (ELISA), potential biomarkers for TA diagnosis, and activity classification were measured in independent cohorts, respectively.

Results:

In the screening phase, 18 cytokines significantly differentially enriched between TA patients and controls and another 15 cytokines significantly differentially enriched between TA patient in active and inactive status were identified (adjusted
P
<0.05). In the validation phase, TIMP (tissue inhibitor of metalloproteinases)-1 was identified as a specific biomarker for TA diagnosis that a cutoff value of 221.86 μg/L could provide a specificity of 89.58% and a positive predictive value of 0.92. Meanwhile, we found it unreliable to use a single biomarker for TA activity classification. Considering this, we further built a logistic regression model based on multiple cytokines, including CA (cancer antigen) 125, FLRG (follistatin-related protein), IGFBP (insulin-like growth factor-binding protein)-2, CA15-3, GROa (growth-regulated alpha protein), LYVE (lymphatic vessel endothelial hyaluronic acid receptor)-1, ULBP (UL16-binding protein)-2, and CD (cluster of differentiation) 99, with an area under the curve reaching 0.909 for discriminating TA activity status.

Conclusions:
This study suggested TIMP-1 as a specific biomarker for TA diagnosis with a cutoff value of 221.86 μg/L. Furthermore, we provided a logistic regression model based on 8 biomarkers for the precisive activity classification of TA with an area under the curve of 0.909.
Familial Sinus Node Disease Caused by a Gain of GIRK (G-Protein Activated Inwardly Rectifying K
+
Channel) Channel Function
Authors: Kuß Johanna , Stallmeyer Birgit , Goldstein Matthias , Rinné Susanne , Pees Christiane , Zumhagen Sven , Seebohm Guiscard , Decher Niels , Pott Lutz , Kienitz Marie-Cécile , Schulze-Bahr Eric 
Published: January 2019

Background:

Inherited forms of sinus node dysfunction (SND) clinically include bradycardia, sinus arrest, and chronotropic incompetence and may serve as disease models to understand sinus node physiology and impulse generation. Recently, a gain-of-function mutation in the G-protein gene
GNB2
led to enhanced activation of the GIRK (G-protein activated inwardly rectifying K
+
channel). Thus, human cardiac GIRK channels are important for heart rate regulation and subsequently, genes encoding their subunits Kir3.1 and Kir3.4 (
KCNJ3
and
KCNJ5
) are potential candidates for inherited SND in human.

Methods:

We performed a combined approach of targeted sequencing of
KCNJ3
and
KCNJ5
in 52 patients with idiopathic SND and subsequent whole exome sequencing of additional family members in a genetically affected patient. A putative novel disease-associated gene variant was functionally analyzed by voltage-clamp experiments using various heterologous cell expression systems (Xenopus oocytes, CHO cells, and rat atrial cardiomyocytes).

Results:

In a 3-generation family with SND we identified a novel variant in
KCNJ5
which leads to an amino acid substitution (p.Trp101Cys) in the first transmembrane domain of the Kir3.4 subunit of the cardiac GIRK channel. The identified variant cosegregated with the disease in the family and was absent in the Exome Variant Server and Exome Aggregation Consortium databases. Expression of mutant Kir3.4 (±native Kir3.1) in different heterologous cell expression systems resulted in increased GIRK currents (
I
K,ACh
) and a reduced inward rectification which was not compensated by intracellular spermidine. Moreover, in silico modeling of heterotetrameric mutant GIRK channels indicates a structurally altered binding site for spermine.

Conclusions:
For the first time, an inherited gain-of-function mutation in the human GIRK3.4 causes familial human SND. The increased activity of GIRK channels is likely to lead to a sustained hyperpolarization of pacemaker cells and thereby reduces heart rate. Modulation of human GIRK channels may pave a way for further treatment of cardiac pacemaking.
Hemorrhagic Transformation After Thrombectomy for Tandem Occlusions
Authors: Zhu François , Labreuche Julien , Haussen Diogo C. , Piotin Michel , Steglich-Arnholm Henrik , Taschner Christian , Papanagiotou Panagiotis , Lapergue Bertrand , Dorn Franziska , Cognard Christophe , Killer Monika , Psychogios Marios N. , Spiotta Alejandro , Mazighi Mikael , Bracard Serge , Turjman Francis , Richard Sébastien , Gory Benjamin ,   the TITAN (Thrombectomy in Tandem Lesions) Investigators
Published: January 2019

Background and Purpose—
Carotid artery stenting in tandem large vessel occlusion strokes is usually avoided because of the intracranial hemorrhagic risks induced by antiplatelet therapy during thrombectomy interventions. This study aimed to evaluate the incidence of hemorrhagic transformation following thrombectomy in large vessel occlusion strokes patients with atherosclerotic cervical carotid occlusion, associated factors, and clinical relevance.

Methods—
The TITAN (Thrombectomy in Tandem Lesions) collaboration pooled individual data of prospectively collected multicentric thrombectomy databases for consecutive anterior circulation tandem large vessel occlusion strokes patients who underwent thrombectomy. Hemorrhagic infarction (HI) and parenchymal hematoma (PH) were assessed within 24 hours.

Results—

Among 289 patients with atherosclerotic cause, 66 (24.7%) patients developed HI and 38 (14.2%) PH. Intracranial carotid occlusion, diabetes mellitus, absence of prior intravenous thrombolysis, and complete extracranial carotid occlusion were independent predictors of HI. Similar predictors were found for PH with addition of higher baseline National Institutes of Health Stroke Scale and Alberta Stroke Program Early CT Score <7. No detrimental effect of HI on 90-day clinical outcome was found. The occurrence of PH was associated with increased mortality rates (adjusted odds ratio, 2.63; 95% CI, 1.05–6.59;
P
=0.039) and had no detrimental effect on 90-day modified Rankin Scale 0 to 2 (adjusted odds ratio, 0.52; 95% CI, 0.20–1.28;
P
=0.25).

Conclusions—
Incidence of PH after tandem large vessel occlusion strokes thrombectomy is equivalent to those reported in the literature data for isolated occlusions. Similar predictors were found for PH and HI within 24 hours, whereas acute carotid artery stenting and antiplatelet therapy were not, suggesting an aggressive endovascular treatment of tandem occlusions.
Angusticopula rowlingiana, a new melosiroid diatom (Bacillariophyta) from Ascension Island (South Atlantic Ocean)
Authors: VAN DE VIJVER BART , WILFERT SANDRA , HOUK VACLAV , JOHN DAVID M. 
Published: January 2019

During a diatom survey of some samples from Ascension Island, a remote island located in the southern Atlantic Ocean, an unknown melosiroid diatom species was studied using both light and scanning electron microscopy. It proved to be a new species described as Angusticopula rowlingiana sp. nov. and characterized by a large number of narrow copulae in the girdle, a marginal ring of small granules, very small pores covering the entire valve face and occasionally having internal valves. The new species is compared with all Angusticopula species known worldwide and with several Melosira species showing a similar combination of characters. Short notes on its ecology are included.