tbuckley/cabot-search huggingface dataset:
Diminished AHR Signaling Drives Human Acute Myeloid Leukemia Stem Cell Maintenance
Authors: Michelle Ly, Stefan Rentas, Ana Vujovic, Nicholas Wong, Steven Moreira, Joshua Xu, Nicholas Holzapfel, Sonam Bhatia, Damian Tran, Mark D. Minden, Jonathan S. Draper, Kristin J. Hope
Journal: Cancer Research (2019)

Eliminating leukemic stem cells (LSC) is a sought after therapeutic paradigm for the treatment of acute myeloid leukemia (AML). While repression of aryl hydrocarbon receptor (AHR) signaling has been shown to promote short-term maintenance of primitive AML cells in culture, no work to date has examined whether altered AHR signaling plays a pathologic role in human AML or whether it contributes at all to endogenous LSC function. Here, we show AHR signaling is repressed in human AML blasts and preferentially downregulated in LSC-enriched populations within leukemias. A core set of AHR targets are uniquely repressed in LSCs across diverse genetic AML subtypes. In vitro and in vivo administration of the specific AHR agonist FICZ significantly impaired leukemic growth, promoted differentiation, and repressed self-renewal. Furthermore, LSCs suppressed a set of FICZ-responsive AHR target genes that function as tumor suppressors and promoters of differentiation. FICZ stimulation did not impair normal hematopoietic stem and progenitor (HSPC) function, and failed to upregulate a prominent LSC-specific AHR target in HSPCs, suggesting that differential mechanisms govern FICZ-induced AHR signaling manifestations in HSCs versus LSCs. Altogether, this work highlights AHR signaling suppression as a key LSC-regulating control mechanism and provides proof of concept in a preclinical model that FICZ-mediated AHR pathway activation enacts unique transcriptional programs in AML that identify it as a novel chemotherapeutic approach to selectively target human LSCs. SIGNIFICANCE: The AHR pathway is suppressed in leukemic stem cells (LSC), therefore activating AHR signaling is a potential therapeutic option to target LSCs and to treat acute myeloid leukemia.
5-year outcome after complete mesocolic excision for right-sided colon cancer: a population-based cohort study
Authors: Claus A Bertelsen, Anders U Neuenschwander, Jens E Jansen, Jutaka R Tenma, Michael Wilhelmsen, Anders Kirkegaard-Klitbo, Else R Iversen, Birgitte Bols, Peter Ingeholm, Leif A Rasmussen, Lars V Jepsen, Pernille W Born, Bent Kristensen, Jakob Kleif
Journal: The Lancet Oncology (2019)
The 2018 Diagnosis of Idiopathic Pulmonary Fibrosis Guidelines: Surgical Lung Biopsy for Radiological Pattern of Probable Usual Interstitial Pneumonia Is Not Mandatory
Authors: Ganesh Raghu, Martine Remy-Jardin, Jeffrey Myers, Luca Richeldi, Kevin C. Wilson
Journal: American Journal of Respiratory and Critical Care Medicine (2019)
Non-myeloablative allogeneic stem cell transplantation (NST) for metastatic melanoma: nondurable chemotherapy responses without clinically meaningful graft-vs-tumor (GVT) effects.
Authors: R Childs, K Bradstock, D Gottlieb, D Blaise, E Leifer, N Geller, M Mohty, C Faucher, R Srinivasan, R Kefford, U Hegenbart, D Niederwieser, AJ Barrett
Journal: Blood (2002)
NHS opens eight walk-in FGM clinics across England
Authors: Elisabeth Mahase
Journal: BMJ (2019)

Adult survivors of female genital mutilation (FGM) will be able to access expert care and support through eight NHS specialist clinics opening on 12 September.1

NHS England said the walk-in clinics—which will be led by specialist doctors, midwives, and nurses—would assist more than 1300 women (aged 18 and over) in Birmingham, Bristol, Leeds, and London.

Women’s health groups welcomed the clinics, but also highlighted the “major gap” in services for those under 18, and called on the NHS to meet the “desperate need” of these girls and young women.

Latest figures show that between April and …
Non-transmissible MV Vector with Segmented RNA Genome Establishes Different Types of iPSCs from Hematopoietic Cells
Authors: Takafumi Hiramoto, Maino Tahara, Jiyuan Liao, Yasushi Soda, Yoshie Miura, Ryo Kurita, Hiroshi Hamana, Kota Inoue, Hiroshi Kohara, Shohei Miyamoto, Yasuki Hijikata, Shinji Okano, Yoshiyuki Yamaguchi, Yoshinao Oda, Kenji Ichiyanagi, Hidehiro Toh, Hiroyuki Sasaki, Hiroyuki Kishi, Akihide Ryo, Atsushi Muraguchi, Makoto Takeda, Kenzaburo Tani
Journal: Molecular Therapy (2019)

Recent advances in gene therapy technologies have enabled the treatment of congenital disorders and cancers and facilitated the development of innovative methods, including induced pluripotent stem cell (iPSC) production and genome editing. We recently developed a novel non-transmissible and non-integrating measles virus (MV) vector capable of transferring multiple genes simultaneously into a wide range of cells through the CD46 and CD150 receptors. The MV vector expresses four genes for iPSC generation and the GFP gene for a period of time sufficient to establish iPSCs from human fibroblasts as well as peripheral blood T cells. The transgenes were expressed differentially depending on their gene order in the vector. Human hematopoietic stem/progenitor cells were directly and efficiently reprogrammed to naive-like cells that could proliferate and differentiate into primed iPSCs by the same method used to establish primed iPSCs from other cell types. The novel MV vector has several advantages for establishing iPSCs and potential future applications in gene therapy.
Niraparib Maintenance Treatment Improves Time Without Symptoms or Toxicity (TWiST) Versus Routine Surveillance in Recurrent Ovarian Cancer: A TWiST Analysis of the ENGOT-OV16/NOVA Trial
Authors: Ursula A. Matulonis, Lydia Walder, Trine J. Nøttrup, Paul Bessette, Sven Mahner, Marta Gil-Martin, Elsa Kalbacher, Jonathan A. Ledermann, Robert M. Wenham, Kathrine Woie, Susie Lau, Frederik Marmé, Antonio Casado Herraez, Anne-Claire Hardy-Bessard, Susana Banerjee, Gabriel Lindahl, Benedict Benigno, Joseph Buscema, Karin Travers, Holly Guy, Mansoor R. Mirza
Journal: Journal of Clinical Oncology (2019)

PURPOSE This study estimated time without symptoms or toxicity (TWiST) with niraparib compared with routine surveillance (RS) in the maintenance treatment of patients with recurrent ovarian cancer. PATIENTS AND METHODS Mean progression-free survival (PFS) was estimated for niraparib and RS by fitting parametric survival distributions to Kaplan-Meier data for 553 patients with recurrent ovarian cancer who were enrolled in the phase III ENGOT-OV16/NOVA trial. Patients were categorized according to the presence or absence of a germline BRCA mutation—g BRCAmut and non-g BRCAmut cohorts. Mean time with toxicity was estimated based on the area under the Kaplan-Meier curve for symptomatic grade 2 or greater fatigue, nausea, and vomiting adverse events (AEs). Time with toxicity was the number of days a patient experienced an AE post–random assignment and before disease progression. TWiST was estimated as the difference between mean PFS and time with toxicity. Uncertainty was explored using alternative PFS estimates and considering all symptomatic grade 2 or greater AEs. RESULTS In the g BRCAmut and non-g BRCAmut cohorts, niraparib treatment resulted in a mean PFS benefit of 3.23 years and 1.44 years, respectively, and a mean time with toxicity of 0.28 years and 0.10 years, respectively, compared with RS. Hence, niraparib treatment resulted in a mean TWiST benefit of 2.95 years and 1.34 years, respectively, compared with RS, which is equivalent to more than four-fold and two-fold increases in mean TWiST between niraparib and RS in the g BRCAmut and non-g BRCAmut cohorts, respectively. This TWiST benefit was consistent across all sensitivity analyses, including modeling PFS over 5-, 10-, and 15-year time horizons. CONCLUSION Patients who were treated with niraparib compared with RS experienced increased mean TWiST. Thus, patients who were treated with niraparib in the ENGOT-OV16/NOVA trial experienced more time without symptoms or symptomatic toxicities compared with control.
Role of FOXC1 in regulating APSCs self-renewal via STI-1/PrP<sup>C</sup> signaling
Authors: Yi-Hui Lee, Hsu-Tung Lee, Chien-Lin Chen, Chi-Hao Chang, Chung Y. Hsu, Woei-Cherng Shyu
Journal: Theranostics (2019)

Forkhead box protein C1 (FOXC1) is known to regulate developmental processes in the skull and brain.Methods: The unique multipotent arachnoid-pia stem cells (APSCs) isolated from human and mouse arachnoid-pia membranes of meninges were grown as 3D spheres and displayed a capacity for self-renewal.Additionally, APSCs also expressed the surface antigens as mesenchymal stem cells.By applying the FOXC1 knockout mice and mouse brain explants, signaling cascade of FOXC1-STI-1-PrP C was investigated to demonstrate the molecular regulatory pathway for APSCs self-renewal.Moreover, APSCs implantation in stroke model was also verified whether neurogenic property of APSCs could repair the ischemic insult of the stroke brain.Results: Activated FOXC1 regulated the proliferation of APSCs in a cell cycle-dependent manner, whereas FOXC1-mediated APSCs self-renewal was abolished in FOXC1 knockout mice (FOXC1 -/-mice).Moreover, upregulation of STI-1 regulated by FOXC1 enhanced cell survival and self-renewal of APSCs through autocrine signaling of cellular prion protein (PrP C ). Mouse brain explants STI-1 rescues the cortical phenotype in vitro and induces neurogenesis in the FOXC1 -/-mouse brain.Furthermore, administration of APSCs in ischemic brain restored the neuroglial microenvironment and improved neurological dysfunction. Conclusion:We identified a novel role for FOXC1 in the direct regulation of the STI-1-PrP C signaling pathway to promote cell proliferation and self-renewal of APSCs.
Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy
Authors: Marin L. Gantner, Kevin Eade, Martina Wallace, Michal K. Handzlik, Regis Fallon, Jennifer Trombley, Roberto Bonelli, Sarah Giles, Sarah Harkins-Perry, Tjebo F.C. Heeren, Lydia Sauer, Yoichiro Ideguchi, Michelle Baldini, Lea Scheppke, Michael I. Dorrell, Maki Kitano, Barbara J. Hart, Carolyn Cai, Takayuki Nagasaki, Mehmet G. Badur, Mali Okada, Sasha M. Woods, Catherine Egan, Mark Gillies, Robyn Guymer, Florian Eichler, Melanie Bahlo, Marcus Fruttiger, Rando Allikmets, Paul S. Bernstein, Christian M. Metallo, Martin Friedlander
Journal: New England Journal of Medicine (2019)

Identifying mechanisms of diseases with complex inheritance patterns, such as macular telangiectasia type 2, is challenging. A link between macular telangiectasia type 2 and altered serine metabolism has been established previously.Through exome sequence analysis of a patient with macular telangiectasia type 2 and his family members, we identified a variant in SPTLC1 encoding a subunit of serine palmitoyltransferase (SPT). Because mutations affecting SPT are known to cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), we examined 10 additional persons with HSAN1 for ophthalmologic disease. We assayed serum amino acid and sphingoid base levels, including levels of deoxysphingolipids, in patients who had macular telangiectasia type 2 but did not have HSAN1 or pathogenic variants affecting SPT. We characterized mice with low serine levels and tested the effects of deoxysphingolipids on human retinal organoids.Two variants known to cause HSAN1 were identified as causal for macular telangiectasia type 2: of 11 patients with HSAN1, 9 also had macular telangiectasia type 2. Circulating deoxysphingolipid levels were 84.2% higher among 125 patients with macular telangiectasia type 2 who did not have pathogenic variants affecting SPT than among 94 unaffected controls. Deoxysphingolipid levels were negatively correlated with serine levels, which were 20.6% lower than among controls. Reduction of serine levels in mice led to increases in levels of retinal deoxysphingolipids and compromised visual function. Deoxysphingolipids caused photoreceptor-cell death in retinal organoids, but not in the presence of regulators of lipid metabolism.Elevated levels of atypical deoxysphingolipids, caused by variant SPTLC1 or SPTLC2 or by low serine levels, were risk factors for macular telangiectasia type 2, as well as for peripheral neuropathy. (Funded by the Lowy Medical Research Institute and others.).
Instincts or gadgets? Not the debate we should be having
Authors: Dan Sperber
Journal: Behavioral and Brain Sciences (2019)

Abstract I argue, with examples, that most human cognitive skills are neither instincts nor gadgets but mechanisms shaped both by evolved dispositions and by cultural inputs. This shaping can work either through evolved skills fulfilling their function with the help of cultural skills that they contribute to shape, or through cultural skills recruiting evolved skills and adjusting to them.
Platelet Extracellular Vesicles Drive Inflammasome–IL-1β–Dependent Lung Injury in Sickle Cell Disease
Authors: Ravi Vats, Tomasz Brzoska, Margaret F. Bennewitz, Maritza A. Jimenez, Tirthadipa Pradhan-Sundd, Egemen Tutuncuoglu, Jude Jonassaint, Edgar Gutierrez, Simon C. Watkins, Sruti Shiva, Melanie J. Scott, Adrian E. Morelli, Matthew D. Neal, Gregory J. Kato, Mark T. Gladwin, Prithu Sundd
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Intraerythrocytic polymerization of Hb S promotes hemolysis and vasoocclusive events in the microvasculature of patients with sickle cell disease (SCD). Although platelet-neutrophil aggregate-dependent vasoocclusion is known to occur in the lung and contribute to acute chest syndrome, the etiological mechanisms that trigger acute chest syndrome are largely unknown.
Piperacillin/Tazobactam and Antibiotic-Associated Acute Kidney Injury in Critically Ill Children
Authors: Emily L. Joyce, Sandra L. Kane-Gill, Priyanka Priyanka, Dana Y. Fuhrman, John A. Kellum
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement Antibiotic-associated AKI is prevalent and contributes to substantial morbidity and mortality in critically ill pediatric patients. Little is known about how empiric use of broad-spectrum antibiotics affects development of AKI. The authors show that treatment of critically ill children with piperacillin/tazobactam within the first 48 hours of intensive care unit admission is associated with subsequent development of AKI. They demonstrate a weaker, nonsignificant association between AKI and piperacillin/tazobactam used in combination with vancomycin in this population. This second finding adds to uncertainty about the nephrotoxicity of piperacillin/tazobactam in this highly susceptible population. Cefepime, a potential alternative antibiotic, which was not associated with AKI in the study, may be a suitable alternative for some indications. Background There continues to be uncertainty about whether piperacillin/tazobactam (TZP) increases the risk of AKI in critically ill pediatric patients. We sought to compare rates of AKI among critically ill children treated with TZP or cefepime, an alternative frequently used in intensive care units, with and without vancomycin. Methods We conducted a retrospective cohort study assessing the risk of AKI in pediatric intensive care unit patients after exposure to vancomycin, TZP, and cefepime, alone or in combination, within 48 hours of admission. The primary outcome was development of stage 2 or 3 AKI or an increase in AKI stage from 2 to 3 within the 6 days after the 48-hour exposure window. Secondary outcomes included lengths of stay, need for RRT, and mortality. Results Of 5686 patients included, 494 (8.7%) developed stage 2 or 3 AKI. The adjusted odds of developing AKI after medication exposure were 1.56 for TZP (95% confidence interval [95% CI], 1.23 to 1.99), 1.13 for cefepime (95% CI, 0.79 to 1.64), and 0.86 for vancomycin (95% CI, 0.69 to 1.07). The adjusted odds of developing AKI for vancomycin plus TZP versus vancomycin plus cefepime was 1.38 (95% CI, 0.85 to 2.24). Conclusions Observational data in critically ill children show that TZP use is associated with increased odds of AKI. A weaker, nonsignificant association between vancomycin plus TZP and AKI compared with vancomycin plus cefepime, creates some uncertainty about the nature of the association between TZP and AKI. However, cefepime is an alternative not associated with AKI.
Cognitive gadgets: A provocative but flawed manifesto
Authors: Marco Del Giudice
Journal: Behavioral and Brain Sciences (2019)

The argument against innatism at the heart of Cognitive Gadgets is provocative but premature, and is vitiated by dichotomous thinking, interpretive double standards, and evidence cherry-picking. I illustrate my criticism by addressing the heritability of imitation and mindreading, the relevance of twin studies, and the meaning of cross-cultural differences in theory of mind development. Reaching an integrative understanding of genetic inheritance, plasticity, and learning is a formidable task that demands a more nuanced evolutionary approach.
Targeting epigenetic machinery: Emerging novel allosteric inhibitors
Authors: Fei Ye, Jing Huang, Hongbo Wang, Cheng Luo, Kehao Zhao
Journal: Pharmacology & Therapeutics (2019)

Epigenetics has emerged as an extremely exciting fast-growing area of biomedical research in post genome era. Epigenetic dysfunction is tightly related with various diseases such as cancer and aging related degeneration, potentiating epigenetics modulators as important therapeutics targets. Indeed, inhibitors of histone deacetylase and DNA methyltransferase have been approved for treating blood tumor malignancies, whereas inhibitors of histone methyltransferase and histone acetyl-lysine recognizer bromodomain are in clinical stage. However, it remains a great challenge to discover potent and selective inhibitors by targeting catalytic site, as the same subfamily of epigenetic enzymes often share high sequence identity and very conserved catalytic core pocket. It is well known that epigenetic modifications are usually carried out by multi-protein complexes, and activation of catalytic subunit is often tightly regulated by other interactive protein component, especially in disease conditions. Therefore, it is not unusual that epigenetic complex machinery may exhibit allosteric regulation site induced by protein-protein interactions. Targeting allosteric site emerges as a compelling alternative strategy to develop epigenetic drugs with enhanced druggability and pharmacological profiles. In this review, we highlight recent progress in the development of allosteric inhibitors for epigenetic complexes through targeting protein-protein interactions. We also summarized the status of clinical applications of those inhibitors. Finally, we provide perspectives of future novel allosteric epigenetic machinery modulators emerging from otherwise undruggable single protein target.
Mutations in RUNX1 and TP53 Genes Predict Progression in Patients with Lower-Risk Myelodysplastic Syndrome
Authors: Monika Hruba, Jitka Vesela, Hana Votavova, Michaela Dostalova Merkerova, Katarina Szikszai, Marie Lauermannova, Zuzana Zemanova, Anna Jonasova, Jaroslav Cermak, Monika Belickova
Journal: Blood (2018)
Gene Expression Modularity Reveals Footprints of Polygenic Adaptation in Theobroma cacao
Authors: Tuomas Hämälä, Mark J Guiltinan, James H Marden, Siela N Maximova, Claude W dePamphilis, Peter Tiffin
Journal: Molecular Biology and Evolution (2019)

Separating footprints of adaptation from demography is challenging. When selection has acted on a single locus with major effect, this issue can be alleviated through signatures left by selective sweeps. However, as adaptation is often driven by small allele frequency shifts at many loci, studies focusing on single genes are able to identify only a small portion of genomic variants responsible for adaptation. In face of this challenge, we utilize coexpression information to search for signals of polygenetic adaptation in Theobroma cacao, a tropical tree species that is the source of chocolate. Using transcriptomics and a weighted correlation network analysis, we group genes with similar expression patterns into functional modules. We then ask whether modules enriched for specific biological processes exhibit cumulative effects of differential selection in the form of high FST and dXY between populations. Indeed, modules putatively involved in protein modification, flowering, and water transport show signs of polygenic adaptation even though individual genes that are members of those groups do not bear strong signatures of selection. Modeling of demography, background selection, and the effects of genomic features reveal that these patterns are unlikely to arise by chance. We also find that specific modules are enriched for signals of strong or relaxed purifying selection, with one module bearing signs of adaptive differentiation and an excess of deleterious mutations. Our results provide insight into polygenic adaptation and contribute to understanding of population structure, demographic history, and genome evolution in T. cacao.
Association of Grit Scores With Treatment Adherence and Biomarkers in Patients With Type 2 Diabetes
Authors: Pablo A. Peña, Iván Pérez-Díaz, Ana K. Pulido-Ayala, Hillary K. Osorio-Landa, Juan M. López-Navarro, Angela L. Duckworth, Anupam B. Jena
Journal: JAMA Network Open (2019)

health challenges, such as managing diabetes.Study limitations include the analysis of observational data, which precludes a causal interpretation of the association between grit and treatment adherence, a focus on patients with type 2 diabetes, and analyses performed in a single center.
Ambient heat and hospitalisation for COPD in Brazil: a nationwide case-crossover study
Authors: Qi Zhao, Shanshan Li, Micheline de Sousa Zanotti Staglior Coelho, Paulo Hilário Nascimento Saldiva, Rongbin Xu, Rachel R Huxley, Michael J Abramson, Yuming Guo
Journal: Thorax (2019)

Background Heat exposure has been related to increased morbidity and mortality for several health outcomes. There is little evidence whether this is also true for COPD. This study quantified the relationship between ambient heat and hospitalisation for COPD in the Brazilian population. Methods Data on hospitalisations for COPD and weather conditions were collected from 1642 cities during the 2000–2015 hot seasons. A time-stratified, case-crossover design was used for city-specific analyses, which were then pooled at the regional and national levels using random-effect meta-analyses. Stratified analyses were performed by sex, age group and early/late hot season. Annual change in the association was examined using a random-effect meta-regression model. Results The OR of hospitalisation was 1.05 (95% CI 1.04 to 1.06) for every 5℃ increase in daily mean temperature at the national level, with the effect estimate stronger in the late hot season compared with the early hot season. The effect was similar in women and in men but was greatest for those aged ≥75 years. The association was stronger in the central west and southeast regions and minimal in the northeast. Assuming a causal relationship, 7.2% of admissions were attributable to heat exposure. There was no significant temporal decline in the impact of ambient heat over the 16-year study period. Conclusion In Brazil, exposure to ambient heat was positively associated with hospitalisation for COPD, particularly during the late hot season. These data add to the growing evidence base implicating global warming as being an important contributor to the future healthcare burden.