bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alleles of Insm1 determine whether RIP1-Tag2 mice produce insulinomas or nonfunctioning pancreatic neuroendocrine tumors
Authors: Kobayashi Shinta , Contractor Tanupriya , Vosburgh Evan , Du Yi-Chieh Nancy , Tang Laura H. , Clausen Richard , Harris Chris R. 
Published: February 2019

AbstractThe two most common types of pancreatic neuroendocrine tumors (PanNETs) are insulinomas and nonfunctioning PanNETs (NF-PanNETs). Insulinomas are small, rarely metastatic tumors that secrete high amounts of insulin, and nonfunctioning PanNETs are larger tumors that are frequently metastatic but that do not secrete hormones. Insulinomas are modeled by the highly studied RIP1-Tag2 (RT2) transgenic mice when bred into a C57Bl/6 (B6) genetic background (also known as RT2 B6 mice). But there has been a need for an animal model of nonfunctioning PanNETs, which in the clinic are a more common and severe disease. Here we show that when bred into a hybrid AB6F1 genetic background, RT2 mice make nonfunctioning PanNETs. Compared to insulinomas produced by RT2 B6 mice, the tumors produced by RT2 AB6F1 mice were larger and more metastatic, and the animals did not suffer from hypoglycemia or hyperinsulinemia. Genetic crosses revealed that a locus in mouse chromosome 2qG1 was linked to liver metastasis and to lack of insulin production. This locus was tightly linked to the gene encoding Insm1, a beta cell transcription factor that was highly expressed in human insulinomas but unexpressed in other types of PanNETs due to promoter hypermethylation. Insm1-deficient human cell lines expressed stem cell markers, were more invasive in vitro, and metastasized at higher rates in vivo when compared to isogenic Insm1-expressing cell lines. These data demonstrate that expression of Insm1 can determine whether a PanNET is a localized insulinoma or a metastatic nonfunctioning tumor.
Health-related quality of life in the ENDEAVOR study: carfilzomib-dexamethasone vs bortezomib-dexamethasone in relapsed/refractory multiple myeloma
Authors: Ludwig Heinz , Moreau Philippe , Dimopoulos Meletios A. , Mateos Maria-Victoria , Kaiser Martin , Hajek Roman , Feng Shibao , Cocks Kim , Buchanan Jaqueline , Weisel Katja 
Published: February 2019

AbstractWe examined effects of carfilzomib-dexamethasone (Kd56) versus bortezomib-dexamethasone (Vd) on health-related quality of life (HR-QoL) in relapsed/refractory multiple myeloma (MM) patients from the ENDEAVOR study. HR-QoL was assessed by the European Organisation for Research and Treatment of Cancer QoL Questionnaire (QLQ-C30), MM-specific module (QLQ-MY20), and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT-GOG-Ntx) “Additional Concerns” neurotoxicity subscale. The QLQ-C30 Global Health Status (GHS)/QoL scale and seven prespecified subscales were compared between groups using mixed model for repeated measures. Of 929 randomized patients, 911 with ≥1 post-baseline assessment were included. Kd56 was associated with statistically significant improvements in GHS/QoL, fatigue, pain, side effects, and FACT/GOG-Ntx scores versus Vd, although mean differences did not meet thresholds for clinical significance. The Kd56 group had longer time to deterioration (TTD) in GHS/QoL (median 3.7 versus 2.8 months,p = 0.0046), physical function (5.6 versus 3.7 months,p = 0.0390), nausea/vomiting (17.6 versus 8.2 months,p = 0.0358), side effects (6.4 versus 3.7 monthsp < 0.0001), and FACT/GOG-Ntx (11.1 versus 5.5 months, p = 0.0004). Overall, Kd56 resulted in statistically but not clinically significant improvements in mean GHS/QoL scores versus Vd. Treatment with Kd56 versus Vd also significantly prolonged TTD in GHS/QoL, physical function, nausea/vomiting, side effects, and FACT/GOG-Ntx.
Type 3 inositol 1,4,5-trisphosphate receptor has antiapoptotic and proliferative role in cancer cells
Authors: Rezuchova Ingeborg , Hudecova Sona , Soltysova Andrea , Matuskova Miroslava , Durinikova Erika , Chovancova Barbora , Zuzcak Michal , Cihova Marina , Burikova Monika , Penesova Adela , Lencesova Lubomira , Breza Jan , Krizanova Olga 
Published: February 2019

AbstractAlthough the involvement of type 1 (IP3R1) and type 2 (IP3R2) inositol 1,4,5-trisphosphate receptors in apoptosis induction has been well documented in different cancer cells and tissues, the function of type 3 IP3R (IP3R3) is still elusive. Therefore, in this work we focused on the role of IP3R3 in tumor cells in vitro and in vivo. We determined increased expression of this receptor in clear cell renal cell carcinoma compared to matched unaffected part of the kidney from the same patient. Thus, we hypothesized about different functions of IP3R3 compared to IP3R1 and IP3R2 in tumor cells. Silencing of IP3R1 prevented apoptosis induction in colorectal cancer DLD1 cells, ovarian cancer A2780 cells, and clear cell renal cell carcinoma RCC4 cells, compared to apoptosis in cells treated with scrambled siRNA. As expected, silencing of IP3R3 and subsequent apoptosis induction resulted in increased levels of apoptosis in all these cells. Further, we prepared a DLD1/IP3R3_del cell line using CRISPR/Cas9 gene editing method. These cells were injected into nude mice and tumor's volume was compared with tumors induced by DLD1 cells. Lower volume of tumors originated from DLD1/IP3R3_del cells was observed after 12 days, compared to wild type DLD1 cells. Also, the migration of these cells was lesser compared to wild type DLD1 cells. Apoptosis under hypoxic conditions was more pronounced in DLD1/IP3R3_del cells than in DLD1 cells. These results clearly show that IP3R3 has proliferative and anti-apoptotic effect in tumor cells, on contrary to the pro-apoptotic effect of IP3R1.
Ocean precursors to the extreme Atlantic 2017 hurricane season
Authors: Hallam Samantha , Marsh Robert , Josey Simon A. , Hyder Pat , Moat Ben , Hirschi Joël J.-M. 
Published: February 2019

AbstractActive Atlantic hurricane seasons are favoured by positive precursor sea surface temperature anomalies (SSTA) in the main development region (MDR, 10–20°N, 20–80°W). Here, we identify a different driving mechanism for these anomalies in 2017 (most costly season on record) compared to the recent active 2005 and 2010 seasons. In 2005 and 2010, a weakened Atlantic Meridional Overturning Circulation is the primary driver of positive SSTA. However, in 2017, reduced wind-driven cold water upwelling and weaker surface net heat loss in the north-eastern MDR were the main drivers. Our results are the first to show that air-sea heat flux and wind stress related processes are important in generating precursor positive SSTAs and that these processes were active pre-determinants of the 2017 season severity. In contrast to other strong seasons, positive SSTA developed later in 2017 (between April and July rather than March) compounding the challenge of predicting Atlantic hurricane season severity.
Characterized cis-FeV(O)(OH) intermediate mimics enzymatic oxidations in the gas phase
Authors: Borrell Margarida , Andris Erik , Navrátil Rafael , Roithová Jana , Costas Miquel 
Published: February 2019

AbstractFeV(O)(OH) species have long been proposed to play a key role in a wide range of biomimetic and enzymatic oxidations, including as intermediates in arene dihydroxylation catalyzed by Rieske oxygenases. However, the inability to accumulate these intermediates in solution has thus far prevented their spectroscopic and chemical characterization. Thus, we use gas-phase ion spectroscopy and reactivity analysis to characterize the highly reactive [FeV(O)(OH)(5tips3tpa)]2+ (32+) complex. The results show that 32+ hydroxylates C–H bonds via a rebound mechanism involving two different ligands at the Fe center and dihydroxylates olefins and arenes. Hence, this study provides a direct evidence of FeV(O)(OH) species in non-heme iron catalysis. Furthermore, the reactivity of 32+ accounts for the unique behavior of Rieske oxygenases. The use of gas-phase ion characterization allows us to address issues related to highly reactive intermediates that other methods are unable to solve in the context of catalysis and enzymology.
The human gut Firmicute Roseburia intestinalis is a primary degrader of dietary β-mannans
Authors: La Rosa Sabina Leanti , Leth Maria Louise , Michalak Leszek , Hansen Morten Ejby , Pudlo Nicholas A. , Glowacki Robert , Pereira Gabriel , Workman Christopher T. , Arntzen Magnus Ø. , Pope Phillip B. , Martens Eric C. , Hachem Maher Abou , Westereng Bjørge 
Published: February 2019

Abstractβ-Mannans are plant cell wall polysaccharides that are commonly found in human diets. However, a mechanistic understanding into the key populations that degrade this glycan is absent, especially for the dominant Firmicutes phylum. Here, we show that the prominent butyrate-producing Firmicute Roseburia intestinalis expresses two loci conferring metabolism of β-mannans. We combine multi-“omic” analyses and detailed biochemical studies to comprehensively characterize loci-encoded proteins that are involved in β-mannan capturing, importation, de-branching and degradation into monosaccharides. In mixed cultures, R. intestinalis shares the available β-mannan with Bacteroides ovatus, demonstrating that the apparatus allows coexistence in a competitive environment. In murine experiments, β-mannan selectively promotes beneficial gut bacteria, exemplified by increased R. intestinalis, and reduction of mucus-degraders. Our findings highlight that R. intestinalis is a primary degrader of this dietary fiber and that this metabolic capacity could be exploited to selectively promote key members of the healthy microbiota using β-mannan-based therapeutic interventions.
Inducing cancer indolence by targeting mitochondrial Complex I is potentiated by blocking macrophage-mediated adaptive responses
Authors: Kurelac Ivana , Iommarini Luisa , Vatrinet Renaud , Amato Laura Benedetta , De Luise Monica , Leone Giulia , Girolimetti Giulia , Umesh Ganesh Nikkitha , Bridgeman Victoria Louise , Ombrato Luigi , Columbaro Marta , Ragazzi Moira , Gibellini Lara , Sollazzo Manuela , Feichtinger Rene Gunther , Vidali Silvia , Baldassarre Maurizio , Foriel Sarah , Vidone Michele , Cossarizza Andrea , Grifoni Daniela , Kofler Barbara , Malanchi Ilaria , Porcelli Anna Maria , Gasparre Giuseppe 
Published: February 2019

AbstractConverting carcinomas in benign oncocytomas has been suggested as a potential anti-cancer strategy. One of the oncocytoma hallmarks is the lack of respiratory complex I (CI). Here we use genetic ablation of this enzyme to induce indolence in two cancer types, and show this is reversed by allowing the stabilization of Hypoxia Inducible Factor-1 alpha (HIF-1α). We further show that on the long run CI-deficient tumors re-adapt to their inability to respond to hypoxia, concordantly with the persistence of human oncocytomas. We demonstrate that CI-deficient tumors survive and carry out angiogenesis, despite their inability to stabilize HIF-1α. Such adaptive response is mediated by tumor associated macrophages, whose blockage improves the effect of CI ablation. Additionally, the simultaneous pharmacological inhibition of CI function through metformin and macrophage infiltration through PLX-3397 impairs tumor growth in vivo in a synergistic manner, setting the basis for an efficient combinatorial adjuvant therapy in clinical trials.
Prototype of running clinical trials in an untrustworthy environment using blockchain
Authors: Wong Daniel R. , Bhattacharya Sanchita , Butte Atul J. 
Published: February 2019

AbstractMonitoring and ensuring the integrity of data within the clinical trial process is currently not always feasible with the current research system. We propose a blockchain-based system to make data collected in the clinical trial process immutable, traceable, and potentially more trustworthy. We use raw data from a real completed clinical trial, simulate the trial onto a proof of concept web portal service, and test its resilience to data tampering. We also assess its prospects to provide a traceable and useful audit trail of trial data for regulators, and a flexible service for all members within the clinical trials network. We also improve the way adverse events are currently reported. In conclusion, we advocate that this service could offer an improvement in clinical trial data management, and could bolster trust in the clinical research process and the ease at which regulators can oversee trials.
Halogen bonding as a supramolecular dynamics catalyst
Authors: Szell Patrick M. J. , Zablotny Scott , Bryce David L. 
Published: February 2019

AbstractDynamic processes have many implications in functional molecules, including catalysts, enzymes, host-guest complexes, and molecular machines. Here, we demonstrate via deuterium NMR relaxation experiments how halogen bonding directly impacts the dynamics in solid 2,3,5,6-tetramethylpyrazine cocrystals, catalyzing the methyl group rotation. On average, we observe a reduction of 56% in the rotational activation energy of the methyl groups in the halogen bonded cocrystals, contrasting the reduction of 36% in the hydrogen bonded cocrystals, with respect to pure 2,3,5,6-tetramethylpyrazine. Density functional theory calculations attribute this superior catalytic ability of the halogen bond to the simultaneous destabilization of the staggered conformation and stabilization of the gauche conformation, overall reducing the rotational energy barrier. Furthermore, the calculations suggest that the catalytic ability of the halogen bond may be tuneable, with stronger halogen bond donors acting as superior dynamics catalysts. Thus, halogen bonding may play a role in both assembly and promoting dynamical processes.
Overexpression of Claspin and Timeless protects cancer cells from replication stress in a checkpoint-independent manner
Authors: Bianco Julien N. , Bergoglio Valérie , Lin Yea-Lih , Pillaire Marie-Jeanne , Schmitz Anne-Lyne , Gilhodes Julia , Lusque Amelie , Mazières Julien , Lacroix-Triki Magali , Roumeliotis Theodoros I. , Choudhary Jyoti , Moreaux Jérôme , Hoffmann Jean-Sébastien , Tourrière Hélène , Pasero Philippe 
Published: February 2019

AbstractOncogene-induced replication stress (RS) promotes cancer development but also impedes tumor growth by activating anti-cancer barriers. To determine how cancer cells adapt to RS, we have monitored the expression of different components of the ATR-CHK1 pathway in primary tumor samples. We show that unlike upstream components of the pathway, the checkpoint mediators Claspin and Timeless are overexpressed in a coordinated manner. Remarkably, reducing the levels of Claspin and Timeless in HCT116 cells to pretumoral levels impeded fork progression without affecting checkpoint signaling. These data indicate that high level of Claspin and Timeless increase RS tolerance by protecting replication forks in cancer cells. Moreover, we report that primary fibroblasts adapt to oncogene-induced RS by spontaneously overexpressing Claspin and Timeless, independently of ATR signaling. Altogether, these data indicate that enhanced levels of Claspin and Timeless represent a gain of function that protects cancer cells from of oncogene-induced RS in a checkpoint-independent manner.
Bacterial release from pipe biofilm in a full-scale drinking water distribution system
Authors: Chan Sandy , Pullerits Kristjan , Keucken Alexander , Persson Kenneth M. , Paul Catherine J. , Rådström Peter 
Published: February 2019

AbstractSafe drinking water is delivered to the consumer through kilometres of pipes. These pipes are lined with biofilm, which is thought to affect water quality by releasing bacteria into the drinking water. This study describes the number of cells released from this biofilm, their cellular characteristics, and their identity as they shaped a drinking water microbiome. Installation of ultrafiltration (UF) at full scale in Varberg, Sweden reduced the total cell count to 1.5 × 103 ± 0.5 × 103 cells mL−1 in water leaving the treatment plant. This removed a limitation of both flow cytometry and 16S rRNA amplicon sequencing, which have difficulties in resolving small changes against a high background cell count. Following installation, 58% of the bacteria in the distributed water originated from the pipe biofilm, in contrast to before, when 99.5% of the cells originated from the treatment plant, showing that UF shifts the origin of the drinking water microbiome. The number of bacteria released from the biofilm into the distributed water was 2.1 × 103 ± 1.3 × 103 cells mL−1 and the percentage of HNA (high nucleic acid) content bacteria and intact cells increased as it moved through the distribution system. DESeq2 analysis of 16S rRNA amplicon reads showed increases in 29 operational taxonomic units (OTUs), including genera identified as Sphingomonas, Nitrospira, Mycobacterium, and Hyphomicrobium. This study demonstrated that, due to the installation of UF, the bacteria entering a drinking water microbiome from a pipe biofilm could be both quantitated and described.
ESR1 mutations in metastatic lobular breast cancer patients
Authors: Desmedt Christine , Pingitore Julien , Rothé Françoise , Marchio Caterina , Clatot Florian , Rouas Ghizlane , Richard François , Bertucci François , Mariani Odette , Galant Christine , Fribbens Charlotte , O’Leary Ben , van den Eynden Gert , Salgado Roberto , Turner Nicholas C. , Piccart Martine , Vincent-Salomon Anne , Pruneri Giancarlo , Larsimont Denis , Sotiriou Christos 
Published: February 2019

AbstractInvasive lobular breast cancer (ILC) represents the second most common histology of breast cancer after invasive ductal breast cancer (IDC), accounts for up to 15% of all invasive cases and generally express the estrogen receptor (ER, coded by the ESR1 gene). ESR1 mutations have been associated with resistance to endocrine therapy, however these have not been specifically evaluated in ILC. We assessed the frequency of ESR1 mutations by droplet digital PCR in a retrospective multi-centric series of matched primary tumor and recurrence samples (n = 279) from 80 metastatic ER-positive ILC patients. We further compared ESR1 mutations between IDC and ILC patients in metastatic samples from MSKCC-IMPACT (n = 595 IDC and 116 ILC) and in ctDNA from the SoFEA and PALOMA-3 trials (n = 416 IDC and 76 ILC). In the retrospective series, the metastases from seven patients (9%) harbored ESR1 mutations, which were absent from the interrogated primary samples. Five patients (6%) had a mutation in the primary tumor or axillary metastasis, which could not be detected in the matched distant metastasis. In the MSKCC-IMPACT cohort, as well as in the SoFEA and PALOMA-3 trials, there were no differences in prevalence and distribution of the mutations between IDC and ILC, with D538G being the most frequent mutation in both histological subtypes. To conclude, no patient had an identical ESR1 mutation in the early and metastatic disease in the retrospective ILC series. In the external series, there was no difference in terms of prevalence and type of ESR1 mutations between ILC and IDC.
Mutations in the palm domain disrupt modulation of acid-sensing ion channel 1a currents by neuropeptides
Authors: Bargeton Benoîte , Iwaszkiewicz Justyna , Bonifacio Gaetano , Roy Sophie , Zoete Vincent , Kellenberger Stephan 
Published: February 2019

AbstractModulation by neuropeptides enhances several functions of acid-sensing ion channels (ASICs), such as pain sensation and acid-induced neuronal injury. The acid-induced opening of ASICs is transient, because of a rapid desensitization. Neuropeptides containing an Arg-Phe-amide motif affect ASIC desensitization and allow continuous activity of ASICs. In spite of the importance of the sustained ASIC activity during prolonged acidification, the molecular mechanisms of ASIC modulation by neuropeptides is only poorly understood. To identify the FRRFa (Phe-Arg-Arg-Phe-amide) binding site on ASIC1a, we carried out anin silicodocking analysis and verified functionally the docking predictions. The docking experiments indicated three possible binding pockets, located (1) in the acidic pocket between the thumb, finger, β-ball and palm domains, (2) in a pocket at the bottom of the thumb domain, and (3) in the central vestibule along with the connected side cavities. Functional measurements of mutant ASIC1a confirmed the importance of residues of the lower palm, which encloses the central vestibule and its side cavities, for the FRRFa effects. The combined docking and functional experiments strongly suggest that FRRFa binds to the central vestibule and its side cavities to change ASIC desensitization.
A method to identify respiratory virus infections in clinical samples using next-generation sequencing
Authors: Kustin Talia , Ling Guy , Sharabi Sivan , Ram Daniela , Friedman Nehemya , Zuckerman Neta , Bucris Efrat Dahan , Glatman-Freedman Aharona , Stern Adi , Mandelboim Michal 
Published: February 2019

AbstractRespiratory virus infections are very common. Such infections impose an enormous economic burden and occasionally lead to death. Furthermore, every few decades, respiratory virus pandemics emerge, putting the entire world population at risk. Thus, there is an urgent need to quickly and precisely identify the infecting agent in a clinical setting. However, in many patients with influenza-like symptoms (ILS) the identity of the underlying pathogen remains unknown. In addition, it takes time and effort to individually identify the virus responsible for the ILS. Here, we present a new next-generation sequencing (NGS)-based method that enables rapid and robust identification of pathogens in a pool of clinical samples without the need for specific primers. The method is aimed at rapidly uncovering a potentially common pathogen affecting many samples with an unidentified source of disease.
Maternal Supplementation of Low Dose Fluoride Alleviates Adverse Perinatal Outcomes Following Exposure to Intrauterine Inflammation
Authors: Jia Bei , Zong Lu , Lee Ji Yeon , Lei Jun , Zhu Yan , Xie Han , Clemens Julia L. , Feller Mia C. , Na Quan , Dong Jie , McLane Michael W. , Jones-Beatty Kimberly , Burd Irina 
Published: February 2019

AbstractMaternal periodontal disease has been linked to adverse pregnancy sequelae, including preterm birth (PTB); yet, root planing and scaling in pregnancy has not been associated with improved perinatal outcomes. Fluoride, a cariostatic agent, has been added to drinking water and dental products to prevent caries and improve dental health. The objective of this study was to explore the effects of fluoride supplementation using a mouse model of preterm birth and perinatal sequalae. Pregnant mice were fed low dose fluoride (LF−) or high dose fluoride (HF−) and given intrauterine injections of lipopolysaccharide (LPS) or phosphate-buffered saline (PBS). We found that LPS + LF− significantly increased livebirths, pup survival, and litter size compared to LPS alone. Moreover, offspring from the LPS + LF− group exhibited significantly improved neuromotor performance and more neurons compared to those from the LPS group. Additionally, LF− treatment on human umbilical vein endothelial cells (HUVECs) increased cell viability and decreased oxidative stress after treatment with LPS. Collectively, our data demonstrates that maternal LF− supplementation during pregnancy postpones the onset of PTB, acts to increase the liveborn rate and survival time of newborns, and reduces perinatal brain injury in cases of intrauterine inflammation.