tbuckley/cabot-search huggingface dataset:
The miR-561-5p/CX<sub>3</sub>CL1 Signaling Axis Regulates Pulmonary Metastasis in Hepatocellular Carcinoma Involving CX<sub>3</sub>CR1<sup>+</sup> Natural Killer Cells Infiltration
Authors: Er-Bao Chen, Zheng-Jun Zhou, Kun Xiao, Gui-Qi Zhu, Yi Yang, Biao Wang, Shao-Lai Zhou, Qing Chen, Dan Yin, Zheng Wang, Ying-Hong Shi, Dong-Mei Gao, Jie Chen, Yan Zhao, Wei-Zhong Wu, Jia Fan, Jian Zhou, Zhi Dai
Journal: Theranostics (2019)

Natural killer (NK) cell can inhibit tumor initiation and regulates metastatic dissemination, acting as key mediators of the innate immune response. Intrinsic factors modulating NK cells infiltration and its anticancer activity remain poorly characterized. We investigated the roles of dysregulation of micro(mi)RNAs and NK cells in progression of hepatocellular carcinoma (HCC). Methods: Small RNA sequencing were used to detect the miRNA profiles of tumor tissues from HCC patients with (n=14) or without (n=13) pulmonary metastasis and HCC cell lines with different pulmonary metastatic potentials. Chemokine expression profiling and bioinformatics were used to detect the downstream target of candidate target. In gain- and loss-of-function assays were used to investigate the role of miRNA in HCC progression. Different subsets of NK cells were isolated and used for chemotaxis and functional assays in vivo and in vitro. In situ hybridization and immunohistochemical analyses were performed to detect the expression of miRNA in tumor tissues from 242 HCC patients undergoing curative resection from 2010. Results: Three miRNAs (miR-137, miR-149-5p, and miR-561-5p) were identified to be associated with pulmonary metastasis in patients with HCC. miR-561-5p was most highly overexpressed in metastatic HCC tissues and high-metastatic-potential HCC cell lines. In gain- and loss-of-function assays in a murine model, miR-561-5p promoted tumor growth and spread to the lungs. Yet, miR-561-5p did not appear to affect cellular proliferation and migration in vitro. Bioinformatics and chemokine expression profiling identified chemokine (C-X3-C motif) ligand 1 (CX3CL1) as a potential target of miR-561-5p. Furthermore, miR-561-5p promoted tumorigenesis and metastasis via CX3CL1-dependent regulation of CX3CR1+ NK cell infiltration and function. CX3CR1+ NK cells demonstrated stronger in vivo anti-metastatic activity relative to CX3CR1- NK cells. CX3CL1 stimulated chemotactic migration and cytotoxicity in CX3CR1+ NK cells via STAT3 signaling. Blockade of CX3CL1, CX3CR1, or of pSTAT3 signaling pathways attenuated the antitumor responses. Clinical samples exhibited a negative correlation between miR-561-5p expression and levels of CX3CL1 and CX3CR1+ NK cells. High miR-561-5p abundance, low CX3CL1 levels, and low numbers of CX3CR1+ NK cells were associated with adverse prognosis. Conclusion: We delineated a miR-561-5p/CX3CL1/NK cell axis that drives HCC metastasis and demonstrated that CX3CR1+ NK cells serve as potent antitumor therapeutic effectors.
De novo biosynthesis of liquiritin in Saccharomyces cerevisiae
Authors: Yan Yin, Yanpeng Li, Dan Jiang, Xianan Zhang, Wei Gao, Chunsheng Liu
Journal: Acta Pharmaceutica Sinica B (2019)

Liquiritigenin (LG), isoliquiritigenin (Iso-LG), together with their respective glycoside derivatives liquiritin (LN) and isoliquiritin (Iso-LN), are the main active flavonoids of Glycyrrhiza uralensis, which is arguably the most widely used medicinal plant with enormous demand on the market, including Chinese medicine prescriptions, preparations, health care products and even food. Pharmacological studies have shown that these ingredients have broad medicinal value, including anti-cancer and anti-inflammatory effects. Although the biosynthetic pathway of glycyrrhizin, a triterpenoid component from G. uralensis, has been fully analyzed, little attention has been paid to the biosynthesis of the flavonoids of this plant. To obtain the enzyme-coding genes responsible for the biosynthesis of LN, analysis and screening were carried out by combining genome and comparative transcriptome database searches of G. uralensis and homologous genes of known flavonoid biosynthesis pathways. The catalytic functions of candidate genes were determined by in vitro or in vivo characterization. This work characterized the complete biosynthetic pathway of LN and achieved the de novo biosynthesis of liquiritin in Saccharomyces cerevisiae using endogenous yeast metabolites as precursors and cofactors for the first time, which provides a possibility for the economical and sustainable production and application of G. uralensis flavonoids through synthetic biology.
Tumoral MET/HGF expression and MET gene amplification in patients with ALK 2p23 fusion driven lung cancer.
Authors: Yan Feng, Eugen C. Minca, Wei Zhang, Lihong Yin, Nathan A. Pennell, Carol Farver, Angen Liu, Raymond R. Tubbs, Patrick C. Ma
Journal: Journal of Clinical Oncology (2013)

11091 Background: MET receptor and its ligand HGF are both promising targets in non-small cell lung cancer (NSCLC) therapy. Crizotinib, a recently approved ALK inhibitor for NSCLC harboring oncogenic ALK 2p23 fusion (ALK+), was initially developed as a bona fide MET inhibitor. The role of MET/HGF pathway in ALK+ NSCLC is still unknown. Methods: The study included 73 NSCLC patients tested for ALK rearrangements at Cleveland Clinic (2000-2012), including 21 ALK+ and 52 ALK-. Immunohistochemistry (IHC) on FFPE tumor tissue was performed for c-MET using a monoclonal CONFIRM antibody (SP44, Ventana) with Ventana Benchmark XT automated immunostainer and for HGF using a polyclonal antibody (R&amp;D) following a manual protocol. IHC scoring was interpreted on a 4-tier system (0, 1+, 2+, 3+). MET gene amplification by MET/Chromosome 7 dual probe in-situ hybridiazation (DISH) (Ventana) was also performed. Statistical analysis was performed using Fisher exact test in JMP. Results: Of the tested tumors, 61 were adenocarcinoma (21 ALK+ and 40 ALK-), 6 squamous cell, 4 large cell and 2 NSCLC-NOS. None received any MET inhibitor prior to tissue collection. MET expression by IHC score 0-3 was: 35%, 33%, 15% and 17% in ALK-, and 5%, 37%, 42% and 16% in ALK+ tumor group, respectively. HGF IHC score 0-3 was 34%, 55%, 11% and 0% in ALK-, and 0%, 63%, 32% and 5% in ALK+ tumor group, respectively. The percentages of high MET or HGF expression (2+ or 3+) were higher in ALK+ group compared to ALK- (58% vs 32%, p=0.06, and 37% vs 11%, p=0.03). The correlation coefficient between MET and HGF expression was 0.48. MET gene amplification by DISH was detected in 15% (7/47) ALK- tumors but 0% (0/15) ALK+ tumors (difference not statistically significant, p=0.18). The correlation coefficient between MET IHC and MET gene amplification was 0.33. Conclusions: MET and HGF expression is commonly seen in NSCLC, with more frequent high expression levels in ALK+ than ALK- tumors. Using a newly developed DISH method, we show that MET gene amplification tend to be less frequent in ALK+ tumor. A prospective study with larger sample size is warranted to further define the role of MET/HGF as biomarkers in the biology of NSCLC with ALK rearrangements and their targeted therapy.
Ivermectin safety in infants and children under 15 kg treated for scabies: a multicentric observational study
Authors: M. Levy, L. Martin, A.‐C. Bursztejn, C. Chiaverini, J. Miquel, E. Mahé, A. Maruani, F. Boralevi
Journal: British Journal of Dermatology (2019)

Scabies is a frequent condition seen in infants and children. Only topical treatments have been approved in infants, but some of them are poorly tolerated. Oral ivermectin is approved for the treatment of scabies in several countries, but its use in infants and children weighing < 15 kg is off label. To assess the safety of ivermectin in infants and young children, and to collect data on ivermectin efficacy in these age groups. This study was performed in the dermatology and paediatric dermatology departments of 28 French centres between July 2012 and November 2015. Physicians treating an infant or child weighing < 15 kg for scabies with oral ivermectin were asked to send back a completed standardized and anonymous questionnaire, and the data were analysed. Data were collected on 170 infants and children aged 1–64 months, with a body weight of 4–14·5 kg, who were treated with oral ivermectin. The mean dose received was 223 μg kg–1 and 89% of the patients received a systematic second dose. Concomitant topical treatment was administered to 73% of patients. Adverse events were reported in seven patients (4%) and were not severe. At the follow‐up visit, 139 (85%) patients had achieved healing. Factors significantly associated with healing were an ivermectin dose > 200 μg kg–1 (P < 0·001), and a delay between those two doses of < 10 days (P = 0·025). Our findings suggest the safety and efficacy of ivermectin for the treatment of scabies in infants and young children. What's already known about this topic? Scabies is a frequent condition in small children and infants, but the therapeutic options are limited. Ivermectin has been approved for the treatment of scabies in adults and children > 15 kg, but its use is off‐label in infants and children weighing < 15 kg. Safety data on the use of ivermectin in children weighing < 15 kg are limited. What does this study add? Of 170 infants and children weighing < 15 kg who were treated for scabies with oral ivermectin, there were only seven reported mild adverse events and no serious ones. Our results show that ivermectin is effective in treating scabies in 85% of patients. Efficacy is higher when the received dose exceeds 200 μg kg–1 and when the delay between the two doses is < 10 days. Respond to this article
Risk of therapy-related myelodysplastic syndrome/acute myeloid leukemia after childhood cancer: a population-based study
Authors: Pragati G. Advani, Sara J. Schonfeld, Rochelle E. Curtis, Graça M. Dores, Martha S. Linet, Byron S. Sigel, Clara J. K. Lam, Margaret A. Tucker, Stephen J. Chanock, Lindsay M. Morton
Journal: Leukemia (2019)
Automatic CNN-based detection of cardiac MR motion artefacts using k-space data augmentation and curriculum learning
Authors: Ilkay Oksuz, Bram Ruijsink, Esther Puyol-Antón, James R. Clough, Gastao Cruz, Aurelien Bustin, Claudia Prieto, Rene Botnar, Daniel Rueckert, Julia A. Schnabel, Andrew P. King
Journal: Medical Image Analysis (2019)

Good quality of medical images is a prerequisite for the success of subsequent image analysis pipelines. Quality assessment of medical images is therefore an essential activity and for large population studies such as the UK Biobank (UKBB), manual identification of artefacts such as those caused by unanticipated motion is tedious and time-consuming. Therefore, there is an urgent need for automatic image quality assessment techniques. In this paper, we propose a method to automatically detect the presence of motion-related artefacts in cardiac magnetic resonance (CMR) cine images. We compare two deep learning architectures to classify poor quality CMR images: 1) 3D spatio-temporal Convolutional Neural Networks (3D-CNN), 2) Long-term Recurrent Convolutional Network (LRCN). Though in real clinical setup motion artefacts are common, high-quality imaging of UKBB, which comprises cross-sectional population data of volunteers who do not necessarily have health problems creates a highly imbalanced classification problem. Due to the high number of good quality images compared to the relatively low number of images with motion artefacts, we propose a novel data augmentation scheme based on synthetic artefact creation in k-space. We also investigate a learning approach using a predetermined curriculum based on synthetic artefact severity. We evaluate our pipeline on a subset of the UK Biobank data set consisting of 3510 CMR images. The LRCN architecture outperformed the 3D-CNN architecture and was able to detect 2D+time short axis images with motion artefacts in less than 1ms with high recall. We compare our approach to a range of state-of-the-art quality assessment methods. The novel data augmentation and curriculum learning approaches both improved classification performance achieving overall area under the ROC curve of 0.89.
Patterns of paternal investment predict cross-cultural variation in jealous response
Authors: Brooke A. Scelza, Sean P. Prall, Tami Blumenfield, Alyssa N. Crittenden, Michael Gurven, Michelle Kline, Jeremy Koster, Geoff Kushnick, Siobhán M. Mattison, Elizabeth Pillsworth, Mary K. Shenk, Kathrine Starkweather, Jonathan Stieglitz, Chun-Yi Sum, Kyoko Yamaguchi, Richard McElreath
Journal: Nature Human Behaviour (2019)
Cost-effectiveness of first-line pembrolizumab plus chemotherapy for metastatic squamous non-small cell lung cancer (NSCLC).
Authors: Ashley Kim, Beth Devine, Joshua A. Roth
Journal: Journal of Clinical Oncology (2019)

e20703 Background: Trial results from KEYNOTE-407 have recently led to the FDA approval for pembrolizumab + carboplatin + paclitaxel/nab-paclitaxel (pembrolizumab+chemo) in previously untreated metastatic squamous NSCLC. This is the only first-line indication for squamous NSCLC regardless of tumor expression status. Our objective was to evaluate the cost-effectiveness of pembrolizumab combination therapy in this setting from the US payer perspective. Methods: Using data from KEYNOTE-407, we developed a partitioned survival decision model to estimate the lifetime costs and effectiveness of pembrolizumab+chemo vs. chemo alone in the first-line treatment of metastatic squamous NSCLC. The base case used a Weibull curve selected based on minimum AIC/BIC and best graphical fit to extrapolate in-trial survival to a lifetime horizon. First- and second-line therapy resource use and adverse event (AE) rates were derived from KEYNOTE-407. Utility data and AE management were obtained from published literature and national sources. Direct medical costs were adjusted to 2018 US dollars, and future costs and outcomes were discounted at 3% per year. We estimated life years (LY), quality-adjusted life years (QALYs), and costs over a lifetime horizon. One-way and probabilistic sensitivity analyses were also conducted. Results: In the base case, pembrolizumab+chemo resulted in 0.51 more LYs, 0.36 more QALYs, and $233,246 in healthcare costs vs. chemo alone. Costs per LY and QALY gained were $216,180 and $309,004, respectively. One-way sensitivity analyses indicated that the results were most sensitive to survival and pre-progression utility inputs. In a threshold analysis, we found that the cost of pembrolizumab+chemo would need to be reduced by 24% per course of therapy ($176,175) in order to be cost-effective at $150,000/QALY. Conclusions: Based on current available data, our analysis suggests first-line pembrolizumab-based combination therapy in metastatic squamous NSCLC is unlikely to be cost-effective relative to implied willingness to pay in cancer in the U.S. (ie &lt; $150,000 per QALY). Future studies should reassess cost-effectiveness as trial data mature.
Characterization of 648 non-small cell lung cancer (NSCLC) cases with 28 unique <i>HER2</i> exon 20 insertions.
Authors: Sai-Hong Ignatius Ou, Russell Madison, Jacqulyne Ponville Robichaux, Jeffrey S. Ross, Vincent A. Miller, Siraj Mahamed Ali, Alexa Betzig Schrock, John Heymach
Journal: Journal of Clinical Oncology (2019)

9063 Background: EGFR and HER2 ( ERBB2) exon 20 insertion (ex20ins) mutations represent a subset of driver alterations in NSCLC, which historically have largely not responded to available targeted therapies. Recently, inhibitors specifically targeting ex20ins have shown efficacy in the clinic. Previous studies have described the landscape of EGFR ex20ins in NSCLC (PMID: 29981927), but similar descriptions of HER2 ex20ins are lacking. Methods: Hybrid capture-based comprehensive genomic profiling (CGP) was performed on 39,644 tissue and 4,062 blood-based circulating tumor DNA (ctDNA) samples from 43,706 unique patients with advanced NSCLC. Tumor mutational burden (TMB) was determined on 0.8-1.1 Mbp of sequenced DNA for tissue samples and reported as mutations/Mb. Results: HER2 ex20ins were detected in 1.5% (648/43,706) of NSCLC cases (614 tissue and 34 ctDNA). HER2 ex20ins represented 35% (648/1,845) of HER2-altered NSCLCs overall, while 46% (843/1,845) of cases had HER2 amplification (≥5 copies), 17% (320/1,845) had a non-ex20ins HER2 short variant (SV; most commonly S310F in 84 cases and V659E in 29 cases), and 1.8% (34/1,845) had HER2 amplification + SV. There were 28 unique ex20ins including most commonly A775_G776insYVMA (69%, 450/648), G776 &gt; VC (12%, 76/648) and P780_Y781insGSP (8.6%, 56/648). Cases with HER2 ex20ins were significantly enriched for adenocarcinoma histology (89% vs 66%), female gender (64% vs 51%) and low TMB (95% vs 65% TMB &lt; 10 mut/Mb) compared to HER2 wild-type cases (all p &lt; 0.0001). HER2 amplification (7 median copies, range 5-39) co-occurred in 16% (103/648) of HER2 ex20ins cases. Co-occurrence of other known NSCLC drivers in HER2 ex20ins cases was rare (0.8%, 5/648). In contrast, non- HER2ex20ins cases with HER2 amplification or other HER2 SVs each had co-occurring known driver alterations in ~30% of cases. There was no significant difference in histology, gender, age, HER2 co-amplification or TMB in cases with YVMA vs non-YVMA ex20ins. Conclusions: HER2 ex20ins are found in 1.5% of NSCLCs and are generally mutually exclusive of other known drivers. Detection of these alterations may be critical to identify matched targeted therapy options for this subset of patients.
Resistance of parvalbumin to gastrointestinal digestion is required for profound and long‐lasting prophylactic oral tolerance
Authors: Raphaela Freidl, Antonia Gstöttner, Ulrike Baranyi, Ines Swoboda, Frank Stolz, Margarete Focke‐Tejkl, Thomas Wekerle, Ronald van Ree, Rudolf Valenta, Birgit Linhart
Journal: Allergy (2019)

Early introduction of food allergens into children's diet is considered as a strategy for the prevention of food allergy. The major fish allergen parvalbumin exhibits high stability against gastrointestinal digestion. We investigated whether resistance of carp parvalbumin to digestion affects oral tolerance induction.Natural Cyp c 1, nCyp c 1, and a gastrointestinal digestion-sensitive recombinant Cyp c 1 mutant, mCyp c 1, were analyzed for their ability to induce oral tolerance in a murine model. Both antigens were compared by gel filtration, circular dichroism measurement, in vitro digestion, and splenocyte proliferation assays using synthetic Cyp c 1-derived peptides. BALB/c mice were fed once with high doses of nCyp c 1 or mCyp c 1, before sensitization to nCyp c 1. Immunological tolerance was studied by measuring Cyp c 1-specific antibodies and cellular responses by ELISA, basophil activation, splenocyte proliferations, and intragastric allergen challenge.Wild-type and mCyp c 1 showed the same physicochemical properties and shared the same major T-cell epitope. However, mCyp c 1 was more sensitive to enzymatic digestion in vitro than nCyp c 1. A single high-dose oral administration of nCyp c 1 but not of mCyp c 1 induced long-term oral tolerance, characterized by lack of parvalbumin-specific antibody and cellular responses. Moreover, mCyp c 1-fed mice, but not nCyp c 1-fed mice developed allergic symptoms upon challenge with nCyp c 1.Sensitivity to digestion in the gastrointestinal tract influences the capacity of an allergen to induce prophylactic oral tolerance.
Comparative effectiveness of treatments for recurrent ovarian cancer.
Authors: Nina A. Bickell, Partha Deb, Monica Prasad Hayes, Rebeca Franco, Elizabeth A. Howell, Juan P. Wisnivesky, Ruirui Sun, Natalia Egorova
Journal: Journal of Clinical Oncology (2013)

e16551 Background: Traditionally, recurrent ovarian cancer has been treated with chemotherapy. However, increasingly, secondary cytoreductive surgery (SCS) is being performed. We undertook this study to compare survival between SCS vs chemotherapy vs both or neither to treat recurrent ovarian cancer. Methods: Using SEER-Medicare 1997-2007, we identified women age 66+ years with primary late stage epithelial ovarian cancer with fee-for-service Medicare treated with surgery and chemotherapy for their primary cancer who experienced a recurrence. We defined recurrent cancer using claims for chemotherapy, hospice or SCS following a 6 month treatment free window after primary treatment. Survival time is calculated from time of first recurrence. We conducted parametric and semi-parametric multivariate survival analyses to assess comparative treatment survival rates and factors affecting survival. We use propensity score weighting methods to obtain robust estimates of comparative effectiveness. To address the risk that a fraction of patients classified by our algorithms as non-recurrent are, indeed, recurrent, we use finite mixture models. Results: Of the 1,623 women with recurrent cancer, 72% received secondary chemotherapy while 15% receive both chemotherapy and surgery. &lt;2% receive secondary surgery and 12% received hospice with no active treatment. Univariate analyses show that the mean survival time after first recurrence of ovarian cancer is 1,357 days. Multivariate survival models controlling for patient demographics, cancer type and comorbidities show that, compared to patients who received both surgery and chemotherapy, those who received only SCS (-569 days) as well as those who received only chemotherapy (-381 days) had significantly lower survival times. Survival time is negatively associated with black race and age at recurrence and positively associated with date of reoccurrence. Patients with greater comorbidities have significantly shorter survival times. Conclusions: Patients with recurrent ovarian cancer treated with both secondary surgery and chemotherapy survive longer than patients treated with either chemotherapy or surgery. Women who are Black, or older at time of recurrence have worse survival.