bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effective drug treatment identified by in vivo screening in a transplantable patient-derived xenograft model of chronic myelomonocytic leukemia
Authors: Kloos Arnold , Mintzas Konstantinos , Winckler Lina , Gabdoulline Razif , Alwie Yasmine , Jyotsana Nidhi , Kattre Nadine , Schottmann Renate , Scherr Michaela , Gupta Charu , Adams Felix F. , Schwarzer Adrian , Heckl Dirk , Schambach Axel , Imren Suzan , Humphries R. Keith , Ganser Arnold , Thol Felicitas , Heuser Michael 
Published: June 2020

AbstractTo establish novel and effective treatment combinations for chronic myelomonocytic leukemia (CMML) preclinically, we hypothesized that supplementation of CMML cells with the human oncogene Meningioma 1 (MN1) promotes expansion and serial transplantability in mice, while maintaining the functional dependencies of these cells on their original genetic profile. Using lentiviral expression of MN1 for oncogenic supplementation and transplanting transduced primary mononuclear CMML cells into immunocompromised mice, we established three serially transplantable CMML-PDX models with disease-related gene mutations that recapitulate the disease in vivo. Ectopic MN1 expression was confirmed to enhance the proliferation of CMML cells, which otherwise did not engraft upon secondary transplantation. Furthermore, MN1-supplemented CMML cells were serially transplantable into recipient mice up to 5 generations. This robust engraftment enabled an in vivo RNA interference screening targeting CMML-related mutated genes including NRAS, confirming that their functional relevance is preserved in the presence of MN1. The novel combination treatment with azacitidine and the MEK-inhibitor trametinib additively inhibited ERK-phosphorylation and thus depleted the signal from mutated NRAS. The combination treatment significantly prolonged survival of CMML mice compared to single-agent treatment. Thus, we identified the combination of azacitidine and trametinib as an effective treatment in NRAS-mutated CMML and propose its clinical development.
Genome-wide association meta-analysis identifies GP2 gene risk variants for pancreatic cancer
Authors: Lin Yingsong , Nakatochi Masahiro , Hosono Yasuyuki , Ito Hidemi , Kamatani Yoichiro , Inoko Akihito , Sakamoto Hiromi , Kinoshita Fumie , Kobayashi Yumiko , Ishii Hiroshi , Ozaka Masato , Sasaki Takashi , Matsuyama Masato , Sasahira Naoki , Morimoto Manabu , Kobayashi Satoshi , Fukushima Taito , Ueno Makoto , Ohkawa Shinichi , Egawa Naoto , Kuruma Sawako , Mori Mitsuru , Nakao Haruhisa , Adachi Yasushi , Okuda Masumi , Osaki Takako , Kamiya Shigeru , Wang Chaochen , Hara Kazuo , Shimizu Yasuhiro , Miyamoto Tatsuo , Hayashi Yuko , Ebi Hiromichi , Kohmoto Tomohiro , Imoto Issei , Kasugai Yumiko , Murakami Yoshinori , Akiyama Masato , Ishigaki Kazuyoshi , Matsuda Koichi , Hirata Makoto , Shimada Kazuaki , Okusaka Takuji , Kawaguchi Takahisa , Takahashi Meiko , Watanabe Yoshiyuki , Kuriki Kiyonori , Kadota Aya , Okada Rieko , Mikami Haruo , Takezaki Toshiro , Suzuki Sadao , Yamaji Taiki , Iwasaki Motoki , Sawada Norie , Goto Atsushi , Kinoshita Kengo , Fuse Nobuo , Katsuoka Fumiki , Shimizu Atsushi , Nishizuka Satoshi S. , Tanno Kozo , Suzuki Ken , Okada Yukinori , Horikoshi Momoko , Yamauchi Toshimasa , Kadowaki Takashi , Yu Herbert , Zhong Jun , Amundadottir Laufey T. , Doki Yuichiro , Ishii Hideshi , Eguchi Hidetoshi , Bogumil David , Haiman Christopher A. , Le Marchand Loic , Mori Masaki , Risch Harvey , Setiawan Veronica W. , Tsugane Shoichiro , Wakai Kenji , Yoshida Teruhiko , Matsuda Fumihiko , Kubo Michiaki , Kikuchi Shogo , Matsuo Keitaro 
Published: June 2020

AbstractPancreatic cancer is the fourth leading cause of cancer-related deaths in Japan. To identify risk loci, we perform a meta-analysis of three genome-wide association studies comprising 2,039 pancreatic cancer patients and 32,592 controls in the Japanese population. Here, we identify 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P < 5.0 × 10−8), of which 16p12.3 has not been reported in the Western population. The lead single nucleotide polymorphism (SNP) at 16p12.3 is rs78193826 (odds ratio = 1.46, 95% confidence interval = 1.29-1.66, P = 4.28 × 10−9), an Asian-specific, nonsynonymous glycoprotein 2 (GP2) gene variant. Associations between selected GP2 gene variants and pancreatic cancer are replicated in 10,822 additional cases and controls of East Asian origin. Functional analyses using cell lines provide supporting evidence of the effect of rs78193826 on KRAS activity. These findings suggest that GP2 gene variants are probably associated with pancreatic cancer susceptibility in populations of East Asian ancestry.
Protease-activation using anti-idiotypic masks enables tumor specificity of a folate receptor 1-T cell bispecific antibody
Authors: Geiger Martina , Stubenrauch Kay-Gunnar , Sam Johannes , Richter Wolfgang F. , Jordan Gregor , Eckmann Jan , Hage Carina , Nicolini Valeria , Freimoser-Grundschober Anne , Ritter Mirko , Lauer Matthias E. , Stahlberg Henning , Ringler Philippe , Patel Jigar , Sullivan Eric , Grau-Richards Sandra , Endres Stefan , Kobold Sebastian , Umaña Pablo , Brünker Peter , Klein Christian 
Published: June 2020

AbstractT-cell bispecific antibodies (TCBs) crosslink tumor and T-cells to induce tumor cell killing. While TCBs are very potent, on-target off-tumor toxicity remains a challenge when selecting targets. Here, we describe a protease-activated anti-folate receptor 1 TCB (Prot-FOLR1-TCB) equipped with an anti-idiotypic anti-CD3 mask connected to the anti-CD3 Fab through a tumor protease-cleavable linker. The potency of this Prot- FOLR1-TCB is recovered following protease-cleavage of the linker releasing the anti-idiotypic anti-CD3 scFv. In vivo, the Prot-FOLR1-TCB mediates antitumor efficacy comparable to the parental FOLR1-TCB whereas a noncleavable control Prot-FOLR1-TCB is inactive. In contrast, killing of bronchial epithelial and renal cortical cells with low FOLR1 expression is prevented compared to the parental FOLR1-TCB. The findings are confirmed for mesothelin as alternative tumor antigen. Thus, masking the anti-CD3 Fab fragment with an anti-idiotypic mask and cleavage of the mask by tumor-specific proteases can be applied to enhance specificity and safety of TCBs.
Durable protection against repeated penile exposures to simian-human immunodeficiency virus by broadly neutralizing antibodies
Authors: Garber David A. , Adams Debra R. , Guenthner Patricia , Mitchell James , Kelley Kristen , Schoofs Till , Gazumyan Anna , Nason Martha , Seaman Michael S. , McNicholl Janet , Nussenzweig Michel C. , Heneine Walid 
Published: June 2020

AbstractPenile acquisition of HIV accounts for most infections among men globally. Nevertheless, candidate HIV interventions for men advance to clinical trials without preclinical efficacy data, due primarily to a paucity of relevant animal models of penile HIV infection. Using our recently developed macaque model, we show that a single subcutaneous administration of broadly neutralizing antibody (bNAb) 10-1074 conferred durable protection against repeated penile exposures to simian-human immunodeficiency virus (SHIVSF162P3). Macaques co-administered bNAbs 10-1074 and 3BNC117, or 3BNC117 alone, also exhibited significant protection against repeated vaginal SHIVAD8-EO exposures. Regression modeling estimated that individual plasma bNAb concentrations of 5 μg ml−1 correlated with ≥99.9% relative reduction in SHIV infection probability via penile (10-1074) or vaginal (10-1074 or 3BNC117) challenge routes. These results demonstrate that comparably large reductions in penile and vaginal SHIV infection risk among macaques were achieved at clinically relevant plasma bNAb concentrations and inform dose selection for the development of bNAbs as long-acting pre-exposure prophylaxis candidates for use by men and women.
mTOR and S6K1 drive polycystic kidney by the control of Afadin-dependent oriented cell division
Authors: Bonucci Martina , Kuperwasser Nicolas , Barbe Serena , Koka Vonda , de Villeneuve Delphine , Zhang Chi , Srivastava Nishit , Jia Xiaoying , Stokes Matthew P. , Bienaimé Frank , Verkarre Virginie , Lopez Jean Baptiste , Jaulin Fanny , Pontoglio Marco , Terzi Fabiola , Delaval Benedicte , Piel Matthieu , Pende Mario 
Published: June 2020

AbstractmTOR activation is essential and sufficient to cause polycystic kidneys in Tuberous Sclerosis Complex (TSC) and other genetic disorders. In disease models, a sharp increase of proliferation and cyst formation correlates with a dramatic loss of oriented cell division (OCD). We find that OCD distortion is intrinsically due to S6 kinase 1 (S6K1) activation. The concomitant loss of S6K1 in Tsc1-mutant mice restores OCD but does not decrease hyperproliferation, leading to non-cystic harmonious hyper growth of kidneys. Mass spectrometry-based phosphoproteomics for S6K1 substrates revealed Afadin, a known component of cell-cell junctions required to couple intercellular adhesions and cortical cues to spindle orientation. Afadin is directly phosphorylated by S6K1 and abnormally decorates the apical surface of Tsc1-mutant cells with E-cadherin and α-catenin. Our data reveal that S6K1 hyperactivity alters centrosome positioning in mitotic cells, affecting oriented cell division and promoting kidney cysts in conditions of mTOR hyperactivity.
Phosphodiesterase-5 inhibitors use and risk for mortality and metastases among male patients with colorectal cancer
Authors: Huang Wuqing , Sundquist Jan , Sundquist Kristina , Ji Jianguang 
Published: June 2020

AbstractPhosphodiesterase-5 (PDE5) inhibitors are suggested to have anti-tumor effects and to inhibit surgery-induced immunosuppression. We aimed to explore whether post-diagnostic use of PDE5 inhibitors was associated with a better prognosis among male patients with colorectal cancer (CRC) and the role of open surgery in the association. Here we show that post-diagnostic use of PDE5 inhibitors is associated with a decreased risk of CRC-specific mortality (adjusted HR = 0.82, 95% CI 0.67-0.99) as well as a decreased risk of metastasis (adjusted HR = 0.85, 95% CI 0.74-0.98). Specifically, post-operative use of PDE5 inhibitors has a strong anti-cancer effect. The reduced risk of metastasis is mainly due to distant metastasis but not regional lymphatic metastasis. PDE5 inhibitors have the potential to be an adjuvant drug for patients with CRC to improve prognosis, especially those who have undergone open surgery.
Does entry to center-based childcare affect gut microbial colonization in young infants?
Authors: Hermes Gerben D. A. , Eckermann Henrik A. , de Vos Willem M. , de Weerth Carolina 
Published: June 2020

AbstractEntry to center-based childcare (CC) at three months of life can be an important challenge for infants as it includes major stressors such as long maternal separations and frequently changing caregivers. Stress and the new environment may in turn alter the composition of the gut microbiota with possible implications for future health outcomes. As part of an ongoing longitudinal study, we investigated whether CC, as compared to being cared for by the parents at home, alters the composition of the gut microbiota, while accounting for known covariates of the infant gut microbiota. Stool samples of infants who entered CC (n = 49) and control infants (n = 49) were obtained before and four weeks after CC entrance. Using Redundancy analysis, Random Forests and Bayesian linear models we found that infant gut microbiota was not affected in a uniform way by entry to CC. In line with the literature, breastfeeding, birth mode, age, and the presence of siblings were shown to significantly impact the microbial composition.
Texture features explain the susceptibility of grapevine cultivars to Drosophila suzukii (Diptera: Drosophilidae) infestation in ripening and drying grapes
Authors: Tonina Lorenzo , Giomi Folco , Sancassani Manuel , Ajelli Matteo , Mori Nicola , Giongo Lara 
Published: June 2020

AbstractGrapevine is a well-known host plant of the invasive pestDrosophila suzukii, but its susceptibility to pest oviposition and development greatly depends on the cultivar. To address environmental sustainability during viticultural zoning planning, new vineyard plantation and Integrated Pest Management programmes, it is essential to take pest pressure and cultivar susceptibility into account. To determine the different grapevine cultivars susceptibility toD. suzukii, we tested twelve widely spread cultivars during the ripening period. We also tested three cultivars during the drying period for raisin wine production. The infestation and emergence rates were consequently related to chemical and texture features of the berries to explain the role of skin and pulp characteristics in determining the nature of the susceptibility. Our results showed that susceptibility toD. suzukiiinfestation varies across cultivars. On ripening grapes, infestation is primarily influenced by skin and pulp firmness, elasticity and consistency. Suitability for egg development resulted mainly related to skin and pulp deformation. In a drying loft, infestation may also occur in relation to skin and pulp consistency. Lastly, we discuss the practical implication of the underestimated role of berry texture inD. suzukiioviposition and emergence success, in both ripening and drying grapes.
Combination of preoperative tumour markers and lymphovascular invasion with TNM staging as a cost and labour efficient subtyping of colorectal cancer
Authors: Yamano Tomoki , Yamauchi Shinichi , Igeta Masataka , Takenaka Yuya , Song Jihyung , Kimura Kei , Yasuhara Michiko , Babaya Akihito , Kataoka Kozo , Beppu Naohito , Ikeda Masataka , Tomita Naohiro , Sugihara Kenichi 
Published: June 2020

AbstractTumour-Node-Metastasis (TNM) staging of colorectal cancer (CRC) needs further classification for better treatment because of disease heterogeneity. Although molecular classifications which are expensive and laborious are under study, cost and labour efficient subtyping is desirable. We assessed the combinations of preoperative tumour marker (TM) elevation and tumour lymphovascular invasion (LVI) as a solution. We used the pooled data of 7151 colon cancer (CC) patients and 4620 rectal cancer (RC) patients who received curative surgery between 2004 and 2008 in Japan. The best-matched subtyping for predicting relapse-free survival (RFS) was statistically selected using the c-index and Akaike’s information criterion. This subtyping (TM-LVI), which consisted of three categories by TM elevation status and severity of LVI status, was an independent prognostic factor for RFS of CC (stage IIa, IIIb, and IIIc) and RC (stage I, IIa, IIb, IIIa, and IIIb) and also for disease specific survival of CC (stage IIa, IIb, IIIb, and IIIc) and RC (all stage except for IIc). Although TM-LVI classified CRC patients into low and high recurrence risk groups, the application of adjuvant therapy was not accordance with the TM-LVI status. TM-LVI may be a cost and labour efficient subtyping of colorectal cancer for better treatment strategy.
Safety Assessment of a Nham Starter Culture Lactobacillus plantarum BCC9546 via Whole-genome Analysis
Authors: Chokesajjawatee Nipa , Santiyanont Pannita , Chantarasakha Kanittha , Kocharin Kanokarn , Thammarongtham Chinae , Lertampaiporn Supatcha , Vorapreeda Tayvich , Srisuk Tanawut , Wongsurawat Thidathip , Jenjaroenpun Piroon , Nookaew Intawat , Visessanguan Wonnop 
Published: June 2020

AbstractThe safety of microbial cultures utilized for consumption is vital for public health and should be thoroughly assessed. Although general aspects on the safety assessment of microbial cultures have been suggested, no methodological detail nor procedural guideline have been published. Herein, we propose a detailed protocol on microbial strain safety assessment via whole-genome sequence analysis. A starter culture employed in traditional fermented pork production, nham, namely Lactobacillus plantarum BCC9546, was used as an example. The strain’s whole-genome was sequenced through several next-generation sequencing techniques. Incomplete plasmid information from the PacBio sequencing platform and shorter chromosome size from the hybrid Oxford Nanopore-Illumina platform were noted. The methods for 1) unambiguous species identification using 16S rRNA gene and average nucleotide identity, 2) determination of virulence factors and undesirable genes, 3) determination of antimicrobial resistance properties and their possibility of transfer, and 4) determination of antimicrobial drug production capability of the strain were provided in detail. Applicability of the search tools and limitations of databases were discussed. Finally, a procedural guideline for the safety assessment of microbial strains via whole-genome analysis was proposed.
Distinct abdominal and gluteal adipose tissue transcriptome signatures are altered by exercise training in African women with obesity
Authors: Nono Nankam Pamela A. , Blüher Matthias , Kehr Stephanie , Klöting Nora , Krohn Knut , Adams Kevin , Stadler Peter F. , Mendham Amy E. , Goedecke Julia H. 
Published: June 2020

AbstractThe differential associations of adipose depots with metabolic risk during obesity have been proposed to be controlled by environmental and genetic factors. We evaluated the regional differences in transcriptome signatures between abdominal (aSAT) and gluteal subcutaneous adipose tissue (gSAT) in obese black South African women and tested the hypothesis that 12-week exercise training alters gene expression patterns in a depot-specific manner. Twelve young women performed 12-weeks of supervised aerobic and resistance training. Pre- and post-intervention measurements included peak oxygen consumption (VO2peak), whole-body composition and unbiased gene expression analysis of SAT depots. VO2peakincreased, body weight decreased, and body fat distribution improved with exercise training (p < 0.05). The expression of 15 genes, mainly associated with embryonic development, differed between SAT depots at baseline, whereas 318 genes were differentially expressed post-training (p < 0.05). Four developmental genes were differentially expressed between these depots at both time points (HOXA5, DMRT2,DMRT3andCSN1S1). Exercise training induced changes in the expression of genes associated with immune and inflammatory responses, and lipid metabolism in gSAT, and muscle-associated processes in aSAT. This study showed differences in developmental processes regulating SAT distribution and expandability of distinct depots, and depot-specific adaptation to exercise training in black South African women with obesity.
ssGSEA score-based Ras dependency indexes derived from gene expression data reveal potential Ras addiction mechanisms with possible clinical implications
Authors: Yi Ming , Nissley Dwight V. , McCormick Frank , Stephens Robert M. 
Published: June 2020

AbstractFor nearly a decade, the difficulties associated with both the determination and reproducibility of Ras-dependency indexes (RDIs) have limited their application and further delineation of the biology underlying Ras dependency. In this report, we describe the application of a computational single sample gene set enrichment analysis (ssGSEA) method to derive RDIs with gene expression data. The computationally derived RDIs across the Cancer Cell Line Encyclopedia (CCLE) cell lines show excellent agreement with the experimentally derived values and high correlation with a previous in-house siRNA effector node (siREN) study and external studies. Using EMT signature-derived RDIs and data from cell lines representing the extremes in RAS dependency, we identified enriched pathways distinguishing these classes, including the Fas signaling pathway and a putative Ras-independent pathway first identified in NK cells. Importantly, extension of the method to patient samples from The Cancer Genome Atlas (TCGA) showed the same consensus differential expression patterns for these two pathways across multiple tissue types. Last, the computational RDIs displayed a significant association with TCGA cancer patients’ survival outcomes. Together, these lines of evidence confirm that our computationally derived RDIs faithfully represent a measure of Ras dependency in both cancer cell lines and patient samples. The application of such computational RDIs can provide insights into Ras biology and potential clinical applications.
Serum branched-chain amino acids are associated with leukocyte telomere length and frailty based on residents from Guangxi longevity county
Authors: Zhang Ying , Zhou Qi , Yang Ruiyue , Hu Caiyou , Huang Zezhi , Zheng Chenguang , Liang Qinghua , Gong Ranhui , Zhu Xiaoquan , Gong Huan , Yuan Huiping , Chen Chen , Li Xianghui , Zhang Nan , Yang Ze , Sun Liang 
Published: June 2020

AbstractBranched-chain amino acids (BCAAs) and telomere length are biologically associated with healthy aging. However, the association between them and their interaction on frailty remain unclear in humans. Here, a cross-sectional study based on residents from Guangxi longevity county was conducted to investigate the association of serum BCAAs, peripheral leukocyte telomere length (LTL) and frailty. A total of 1,034 subjects aged 20 to 110 years were recruited in the study. The real-time qPCR method and a targeted metabolomics approach based on isotope dilution liquid chromatography tandem mass spectrometry (LC/MS/MS) method were used for measurement of LTL and BCAAs, respectively. A frailty score defined as the proportion of accumulated deficits based on 24 aging-related items was used assess the health status of elderly subjects. First, we found that a higher concentration of BCAAs was significantly associated with longer LTL only in middle-aged subjects, independent of age and BMI (P < 0.05). In the oldest-old subjects, we identified a significantly inverse association between BCAAs and frailty score (P < 0.001), even after adjustment for age and BMI (P < 0.05). Additionally, we recognized a statistically significant synergetic interaction between BCAAs and LTL on frailty score in the oldest-old subjects by the general linear model (P = 0.042), although we did not find any significant association between LTL and frailty score. In summary, our findings suggest a potentially protective effect of circulating BCAAs on LTL and frailty based on the subjects from longevity county in East Asia and indicate a potential synergetic interaction between BCAAs and LTL in healthy aging.
Transformation of terahertz vibrational modes of cytosine under hydration
Authors: Lee Donggun , Cheon Hwayeong , Jeong Seo-Yeon , Son Joo-Hiuk 
Published: June 2020

AbstractCytosine and cytosine monohydrate are representative biomolecules for investigating the effect of hydrogen bonds in deoxyribonucleic acid. To better understand intermolecular interactions, such as hydrogen bonds, between nucleobases it is necessary to identify the low-frequency vibrational modes associated with intermolecular interactions and crystalline structures. In this study, we investigated the characteristic low-frequency vibrational modes of cytosine and cytosine monohydrate using terahertz time-domain spectroscopy (THz-TDS). The crystal geometry was obtained by the powder X-ray diffraction technique. The optimized atomic positions and the normal modes in the terahertz region were calculated using density functional theory (DFT), which agreed well with the experimental results. We found that overall terahertz absorption peaks of cytosine and cytosine monohydrate consist of collective vibrations mixed with intermolecular and intramolecular vibrations in mode character analysis, and that the most intense peaks of both samples involve remarkable intermolecular translational vibration. These results indicate that THz-TDS combined with DFT calculations including mode character analysis can be an effective method for understanding how water molecules contribute to the characteristics of the low-frequency vibrational modes by intermolecular vibrations with hydrogen bonding in biological and biomedical applications.