tbuckley/cabot-search huggingface dataset:
Abstract B25: Colorectal cancer-associated anaerobic bacteria proliferate in tumor spheroids and alter the microenvironment
Authors: Stephen H. Kasper, Carolina Morell-Perez, Thomas P. Wyche, Theodore R. Sana, Linda A. Lieberman, Erik C. Hett
Journal: Cancer Research (2020)

Abstract Recent reports show that colorectal tumors contain microbiotas that are distinct from those that reside in a “normal” colon environment and that these microbiotas can contribute to cancer progression. Fusobacterium nucleatum is the most commonly observed species in the colorectal tumor microenvironment and reportedly influences disease progression through numerous mechanisms. However, a detailed understanding of the role of this organism in cancer progression is limited, in part due to challenges in maintaining F. nucleatum viability under standard aerobic cell culture conditions. Herein we describe the development of a 3-dimensional (3D) tumor spheroid model that can harbor and promote the growth of anaerobic bacteria. Bacteria-tumor cell interactions and metabolic crosstalk were extensively studied by measuring the kinetics of bacterial growth, cell morphology and lysis, cancer-related gene expression, and metabolomics. We observed that viable F. nucleatum assembles biofilm-like structures in the tumor spheroid microenvironment, whereas heat-killed F. nucleatum is internalized and sequestered in the cancer cells. Lastly, we use the model to coculture 28 Fusobacterium clinical isolates and demonstrate that the model successfully supports coculture with diverse fusobacterial species. This bacteria-spheroid coculture model enables mechanistic investigation of the role of anaerobic bacteria in the tumor microenvironment. Citation Format: Stephen H. Kasper, Carolina Morell-Perez, Thomas P. Wyche, Theodore R. Sana, Linda A. Lieberman, Erik C. Hett. Colorectal cancer-associated anaerobic bacteria proliferate in tumor spheroids and alter the microenvironment [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr B25.
Concurrent Definitive Immunoradiotherapy for Patients with Stage III–IV Head and Neck Cancer and Cisplatin Contraindication
Authors: Jared Weiss, Siddharth Sheth, Allison M. Deal, Juneko E. Grilley Olson, Samip Patel, Trevor G. Hackman, Jeffrey M. Blumberg, Thomas J. Galloway, Shetal Patel, Adam M. Zanation, Colette J. Shen, D. Neil Hayes, Christopher Hilliard, Ranee Mehra, Karen P. McKinnon, Hsing-Hui Wang, Mark Christian Weissler, Jessica R. Bauman, Bhishamjit S. Chera, Benjamin G. Vincent
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Although cisplatin plus radiotherapy is a standard treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC), cisplatin contraindication is common. Radiation elicits and promotes tumor-directed immune stimulation, which may potentiate anti–PD-1 therapy. We provide the first efficacy report of combined pembrolizumab and definitive radiotherapy in LA-HNSCC. Patients and Methods: This single-arm, multi-institution, phase II study (NCT02609503) enrolled 29 cisplatin-ineligible patients. Patients received radiotherapy concurrently with three cycles of pembrolizumab 200 mg every 3 weeks followed by three adjuvant cycles. The primary endpoint was a progression-free survival (PFS) of ≥16 months. Correlative studies included peripheral blood flow cytometry and Luminex cytokine profiling. Results: Reasons for cisplatin ineligibility included otopathy (69.0%), nephropathy (20.7%), and neuropathy (6.9%). With median follow-up of 21 months, estimated 24-month PFS and overall survival rates were 71% (95% confidence interval, 49%–84%) and 75% (51%–88%). The primary PFS endpoint has exceeded the hypothesis and its median has not been reached. Toxicities were typical of radiotherapy; however, high rates of grade 3/4 lymphopenia (58.6%) were observed. Flow cytometry revealed a relative decline in CD4 T cells and B cells, but not CD8 T cells. Upon treatment, frequencies of transitional B cells and tissue-like memory B cells increased, while resting memory B cells decreased. Patients with progression had greater percentages of baseline naïve B cells and fewer marginal zone B cells. Conclusions: Pembrolizumab and radiotherapy is efficacious in LA-HNSCC and should be evaluated in a randomized trial. The observed changes in B-cell markers deserve further study both as potential biomarkers and as therapeutic targets.
Vulnerability to reservoir reseeding due to high immune activation after allogeneic hematopoietic stem cell transplantation in individuals with HIV-1
Authors: Johanna M. Eberhard, Mathieu Angin, Caroline Passaes, Maria Salgado, Valerie Monceaux, Elena Knops, Guido Kobbe, Björn Jensen, Maximilian Christopeit, Nicolaus Kröger, Linos Vandekerckhove, Jon Badiola, Alessandra Bandera, Kavita Raj, Jan van Lunzen, Gero Hütter, Jürgen H. E. Kuball, Carolina Martinez-Laperche, Pascual Balsalobre, Mi Kwon, José L. Díez-Martín, Monique Nijhuis, Annemarie Wensing, Javier Martinez-Picado, Julian Schulze zur Wiesch, Asier Sáez-Cirión
Journal: Science Translational Medicine (2020)

Heterogenous immune reconstitution and de novo priming of HIV-specific T cells characterize allo-HSCT recovery in HIV-infected individuals.
The Antiphospholipid Syndrome
Authors: Jerrold S. Levine, D. Ware Branch, Joyce Rauch
Journal: New England Journal of Medicine (2002)

The antiphospholipid syndrome is an autoimmune disorder of hypercoagulability characterized by the presence of autoantibodies to various phospholipids or phospholipid-binding proteins. The autoantibodies include anticardiolipin antibodies, lupus anticoagulant antibodies, and antibodies to β2-glycoprotein I (a phospholipid-binding protein). These autoantibodies have both procoagulant and anticoagulant effects, but the procoagulant effects predominate, resulting in syndromes of venous and arterial thrombosis and pregnancy loss.
Protective humoral immunity in SARS-CoV-2 infected pediatric patients
Authors: Yaguang Zhang, Jin Xu, Ran Jia, Chunyan Yi, Wangpeng Gu, Pengcheng Liu, Xinran Dong, Hao Zhou, Bo Shang, Shipeng Cheng, Xiaoyu Sun, Jing Ye, Xuezhen Li, Jia Zhang, Zhiyang Ling, Liyan Ma, Bingbing Wu, Mei Zeng, Wenhao Zhou, Bing Sun
Journal: Cellular and Molecular Immunology (2020)
Infographic. Doping without drugs: how para-athletes may self-harm to boost performance
Authors: Cameron M Gee, Tom E Nightingale, Christopher R West, Andrei V Krassioukov
Journal: British Journal of Sports Medicine (2020)

This infographic provides a summary of the use of boosting by athletes with spinal cord injury (SCI); its causes, warning signs and dangers, and the current approach of the International Paralympic Committee (IPC) to testing.

Boosting is the intentional induction of autonomic dysreflexia (AD) to enhance performance. AD is a potentially life-threatening condition experienced by many individuals with a SCI, typically at or above the T6 spinal level. It is characterised by a sudden increase in systolic blood pressure (SBP) >20 mm Hg above baseline due to a noxious or non-noxious stimuli below the level of injury, that excites sympathetic preganglionic neurons resulting in vasoconstriction of blood vessels in the lower extremities and trunk.1 Triggers include, but are not limited to, bladder distension, injury or an innocuous stimulus (eg, a tight …
Cardiovascular Risk Reduction With Liraglutide: An Exploratory Mediation Analysis of the LEADER Trial
Authors: John B. Buse, Stephen C. Bain, Johannes F.E. Mann, Michael A. Nauck, Steven E. Nissen, Stuart Pocock, Neil R. Poulter, Richard E. Pratley, Martin Linder, Tea Monk Fries, David D. Ørsted, Bernard Zinman
Journal: Diabetes Care (2020)

The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial (ClinicalTrials.gov reg. no. NCT01179048) demonstrated a reduced risk of cardiovascular (CV) events for patients with type 2 diabetes who received the glucagon-like peptide 1 receptor agonist liraglutide versus placebo. The mechanisms behind this CV benefit remain unclear. We aimed to identify potential mediators for the CV benefit observed with liraglutide in the LEADER trial.
Vitamin C- and Valproic Acid-Induced Fetal RPE Stem-like Cells Recover Retinal Degeneration via Regulating SOX2
Authors: Han Shen, Chenyue Ding, Songtao Yuan, Ting Pan, Duo Li, Hong Li, Boxian Huang, Qinghuai Liu
Journal: Molecular Therapy (2020)

Retinal pigment epithelial (RPE) cell replacement therapy has provided promising outcomes in the treatment of retinal degenerative diseases (RDDs), but the resulting limited visual improvement has raised questions about graft survival and differentiation. Through combined treatment with vitamin C and valproic acid (together, VV), we activated human fetal RPE (fRPE) cells to become highly proliferative fetal RPE stem-like cells (fRPESCs). In this study, we report that SOX2 (SRY-box 2) activation contributed to mesenchymal-epithelial transition and elevated the retinal progenitor and mesenchymal stromal markers expressions of fRPESCs. These fRPESCs could differentiate into RPE cells, rod photoreceptors, and mesenchymal lineage progenies under defined conditions. Finally, fRPESCs were transplanted into the subretinal space of an RDD mouse model, and a photoreceptor rescue benefit was demonstrated. The RPE and rod photoreceptor differentiation of transplanted fRPESCs may account for the neural retinal recovery. This study establishes fRPESCs as a highly proliferative, multi-lineage differentiation potential (including RPE, rod photoreceptor, and mesenchymal lineage differentiation), mesenchymal-to-epithelial-transitioned retinal stem-like cell source for cell-based therapy of RDDs. Retinal pigment epithelial (RPE) cell replacement therapy has provided promising outcomes in the treatment of retinal degenerative diseases (RDDs), but the resulting limited visual improvement has raised questions about graft survival and differentiation. Through combined treatment with vitamin C and valproic acid (together, VV), we activated human fetal RPE (fRPE) cells to become highly proliferative fetal RPE stem-like cells (fRPESCs). In this study, we report that SOX2 (SRY-box 2) activation contributed to mesenchymal-epithelial transition and elevated the retinal progenitor and mesenchymal stromal markers expressions of fRPESCs. These fRPESCs could differentiate into RPE cells, rod photoreceptors, and mesenchymal lineage progenies under defined conditions. Finally, fRPESCs were transplanted into the subretinal space of an RDD mouse model, and a photoreceptor rescue benefit was demonstrated. The RPE and rod photoreceptor differentiation of transplanted fRPESCs may account for the neural retinal recovery. This study establishes fRPESCs as a highly proliferative, multi-lineage differentiation potential (including RPE, rod photoreceptor, and mesenchymal lineage differentiation), mesenchymal-to-epithelial-transitioned retinal stem-like cell source for cell-based therapy of RDDs.
EM-mosaic detects mosaic point mutations that contribute to congenital heart disease
Authors: Alexander Hsieh, Sarah U. Morton, Jon A. L. Willcox, Joshua M. Gorham, Angela C. Tai, Hongjian Qi, Steven DePalma, David McKean, Emily Griffin, Kathryn B. Manheimer, Daniel Bernstein, Richard W. Kim, Jane W. Newburger, George A. Porter, Deepak Srivastava, Martin Tristani-Firouzi, Martina Brueckner, Richard P. Lifton, Elizabeth Goldmuntz, Bruce D. Gelb, Wendy K. Chung, Christine E. Seidman, J. G. Seidman, Yufeng Shen
Journal: Genome Medicine (2020)

Abstract Background The contribution of somatic mosaicism, or genetic mutations arising after oocyte fertilization, to congenital heart disease (CHD) is not well understood. Further, the relationship between mosaicism in blood and cardiovascular tissue has not been determined. Methods We developed a new computational method, EM-mosaic (Expectation-Maximization-based detection of mosaicism), to analyze mosaicism in exome sequences derived primarily from blood DNA of 2530 CHD proband-parent trios. To optimize this method, we measured mosaic detection power as a function of sequencing depth. In parallel, we analyzed our cohort using MosaicHunter, a Bayesian genotyping algorithm-based mosaic detection tool, and compared the two methods. The accuracy of these mosaic variant detection algorithms was assessed using an independent resequencing method. We then applied both methods to detect mosaicism in cardiac tissue-derived exome sequences of 66 participants for which matched blood and heart tissue was available. Results EM-mosaic detected 326 mosaic mutations in blood and/or cardiac tissue DNA. Of the 309 detected in blood DNA, 85/97 (88%) tested were independently confirmed, while 7/17 (41%) candidates of 17 detected in cardiac tissue were confirmed. MosaicHunter detected an additional 64 mosaics, of which 23/46 (50%) among 58 candidates from blood and 4/6 (67%) of 6 candidates from cardiac tissue confirmed. Twenty-five mosaic variants altered CHD-risk genes, affecting 1% of our cohort. Of these 25, 22/22 candidates tested were confirmed. Variants predicted as damaging had higher variant allele fraction than benign variants, suggesting a role in CHD. The estimated true frequency of mosaic variants above 10% mosaicism was 0.14/person in blood and 0.21/person in cardiac tissue. Analysis of 66 individuals with matched cardiac tissue available revealed both tissue-specific and shared mosaicism, with shared mosaics generally having higher allele fraction. Conclusions We estimate that ~ 1% of CHD probands have a mosaic variant detectable in blood that could contribute to cardiac malformations, particularly those damaging variants with relatively higher allele fraction. Although blood is a readily available DNA source, cardiac tissues analyzed contributed ~ 5% of somatic mosaic variants identified, indicating the value of tissue mosaicism analyses.
シクロホスファミドとその活性代謝体4-ヒドロキシシクロホスファミド,ホスホラミドマスタードおよびアクロレインの変異誘起および催奇形性の比較 | 文献情報 | J-GLOBAL 科学技術総合リンクセンター
Authors: Hales B F
Journal: Cancer Research (1982)
Highly Efficient Gene Editing of Cystic Fibrosis Patient-Derived Airway Basal Cells Results in Functional CFTR Correction
Authors: Shingo Suzuki, Ana M. Crane, Varada Anirudhan, Cristina Barillà, Nadine Matthias, Scott H. Randell, Andras Rab, Eric J. Sorscher, Jenny L. Kerschner, Shiyi Yin, Ann Harris, Matthew Mendel, Kenneth Kim, Lei Zhang, Anthony Conway, Brian R. Davis
Journal: Molecular Therapy (2020)

There is a strong rationale to consider future cell therapeutic approaches for cystic fibrosis (CF) in which autologous proximal airway basal stem cells, corrected for CFTR mutations, are transplanted into the patient's lungs. We assessed the possibility of editing the CFTR locus in these cells using zinc-finger nucleases and have pursued two approaches. The first, mutation-specific correction, is a footprint-free method replacing the CFTR mutation with corrected sequences. We have applied this approach for correction of ΔF508, demonstrating restoration of mature CFTR protein and function in air-liquid interface cultures established from bulk edited basal cells. The second is targeting integration of a partial CFTR cDNA within an intron of the endogenous CFTR gene, providing correction for all CFTR mutations downstream of the integration and exploiting the native CFTR promoter and chromatin architecture for physiologically relevant expression. Without selection, we observed highly efficient, site-specific targeted integration in basal cells carrying various CFTR mutations and demonstrated restored CFTR function at therapeutically relevant levels. Significantly, Omni-ATAC-seq analysis revealed minimal impact on the positions of open chromatin within the native CFTR locus. These results demonstrate efficient functional correction of CFTR and provide a platform for further ex vivo and in vivo editing.
Insulin secretion and plasma levels of glucose-dependent insulinotropic peptide and glucagon-like peptide 1 67?36 amide9 after oral glucose in cirrhosis*1
Authors: Y KRUSZYNSKA
Journal: Hepatology (1995)

A blunted initial insulin secretory response may contribute to oral glucose intolerance in cirrhosis. Oral glucose is a better stimulant to insulin secretion than intravenous (IV) glucose in part because of release of gut peptides, notably glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 [7–36 amide] (GLP-1 [7–36 amide]). Because impaired release of or resistance to these gut peptides could explain impaired insulin secretion after oral glucose, we measured insulin secretion, plasma GIP, and GLP-1 [7–36 amide] levels, basally and after 75 g oral glucose, in 10 cirrhotics and 10 controls. Insulin secretion was calculated from a two-compartment analysis of serum C-peptide levels using kinetic parameters derived from IV injection of recombinant human C-peptide. C-peptide metabolic clearance rate, and the fractional rate constants for C-peptide (using the two-compartment model) were not significantly different, but the volume of the central compartment was 15% greater in cirrhotics (P < .01). Fasting blood glucose levels were similar (cirrhotics, 4.9 ± 0.2; controls, 4.6 ± 0.1 mmol/L) but serum insulin was six times higher in cirrhotics (P < .001). Cirrhotics had higher fasting GIP (215 ± 72 vs. 42 ± 18 pmol/L) and GLP-1 [7–36 amide] levels (25 ± 3 vs. 16 ± 1 pmol/L) (both P < .05). After oral glucose, blood glucose levels were significantly higher in cirrhotics. The timing of the gut peptide response to oral glucose was similar in the two groups, but peak levels of both peptides were ∼x2 higher in the cirrhotics. For the 1st 30 minutes, C-peptide levels and insulin secretion were similar in the two groups. In controls, insulin secretion peaked at 20 to 25 minutes and coincided with the GLP-1 [7–36 amide] peak; insulin secretion then decreased despite a persistent elevation in plasma GIP and glucose levels. In cirrhotics, peak insulin secretion was delayed until 50 to 55 minutes (coincident with the glucose peak). Total insulin secretion during the 4 hours after glucose ingestion was 55% higher in the cirrhotics, but peak insulin secretion rates were similar despite higher gut peptide and glucose levels in cirrhotics. The study shows that, after oral glucose, cirrhotics have a blunted serum C-peptide response and insulin secretion rate. This is not attributable to reduced levels of GIP or GLP-1 [7–36 amide] but could be attributable to resistance to their action.
Outline of Orthopaedics
Authors: D R L Newton
Journal: Annals of the Rheumatic Diseases (1988)

Book reviews 85 carried about by other people owing to gout .... Is it not disgraceful that a person should, by reason of that extraordinary thing arthritis, be unable to use his hands and should need somebody else to bring food to his mouth and to perform his toilet necessities for him... And even if one overlooks the disgraceful aspect of this, yet one cannot overlook the pain these people suffer, night and day, as though their maladies were torturers twisting them on the rack ... And the cause of all this must be referred to dissipation or ignorance or both.'6Modern rheumatologists may recognise their rheuma- toid patients in this powerful description, which clearly separates generalised arthritis from gout.It can obviously be argued that several other arthropathies could result in similar pain and disability, emphasising the difficulty in interpreting early descriptions of arthritic diseases.Perhaps the most important aspect of this quotation is not in its diagnostic value, or its contribution to the debate on the antiquity of rheumatoid arthritis.Galen appears to be making a political as well as a medical point-'Is it not disgraceful' is a question that remains pertinent today, and should not be purely rhetorical.At the recent 11th European Congress of Rheumatology, held in Athens, this little known quote was highlighted by Professor Bartsocas of Greece and by me.The continuing plight of those with chronic rheumatic disease, the inadequacies of treatment, and relative lack of funding of rheumatology were also addressed at this conference.If Galen had been allowed to return to his home country as a conference delegate what would he have thought of 1800 years of 'progress'?What adjective, other than 'disgraceful' would he have been tempted to use? Would he be accusing us of dissipation, or ignorance, or both?
Abstract 320: Statewide Implementation of the Prehospital Traumatic Brain Injury Guidelines in Children: The EPIC4Kids Study
Authors: Daniel W Spaite, Bentley Bobrow, Joshua B Gaither, Samuel M Keim, Bruce J Barnhart, Vatsal Chikani, Kurt Denninghoff, Terry Mullins, David Adelson, Amber D Rice, Chad Viscusi, Chengcheng Hu
Journal: Circulation (2019)

Introduction: The EPIC Study implemented the national EMS TBI Guidelines in a massive, statewide initiative (&gt;11,000 providers trained, 133 agencies). While implementation was not associated with improved survival to discharge in moderate or critically-severe TBI in the primary (all-age) study, the adjusted odds of survival doubled in severe TBI and tripled in severe, intubated TBI. We now report the preplanned pediatric subgroup analysis (“EPIC4Kids”-NIH R01NS071049). Methods: Multisystem, intention-to-treat study using a before/after controlled design in patients with moderate to critically severe TBI. Interventions: Prevention/treatment of hypoxia, hypotension, and hyperventilation by EMS providers. Inclusion: Age&lt;18; CDC Barell Matrix Type 1; 1/07-6/15. Severity subgroups [Head Region Severity Score (IDC-based AIS equivalent)]: Moderate=1-2; Severe=3-4; Critical=5-6. The pre-implementation (P1) and post-implementation (P3) cohorts were compared using logistic regression (Firth’s approach when comparisons had small event numbers), adjusting for risk factors/confounders. Results: Included were 2801 cases [P1=2041 (72.9%), P3=760 (27.1%); median age 11 (IQR 2, 15); 62.9% male]. The all-severity P3 vs P1 cohort analysis yielded adjusted odds (aOR) of 1.16 (95%CI 0.697, 1.92, p=0.57) for survival. In severe TBI (P1=1405, P3=605; 80% of P3 cases), but not moderate or critical TBI, adjusted survival was significantly improved after implementation (Figure; p=0.049). Improvement in survival for those with severe, intubated TBI (P1=174, P3=44) approached significance (Fig; p=0.11). Conclusion: In the first controlled study of its kind, implementation of the EMS TBI guidelines was independently associated with a dramatic increase in adjusted survival among children with severe TBI. The aOR for survival was even larger than that of the overall (all-age) EPIC Study and supports widespread implementation of the guidelines in children.
A clinically significant bronchodilator response in children: how should it be measured?
Authors: Carmen C.M. de Jong, Eva S.L. Pedersen, R. Mozun, Myrofora Goutaki, Daniel Trachsel, Juerg Barben, Claudia E. Kuehni
Journal: European Respiratory Journal (2020)

<b>More research is needed to evaluate the usefulness of diagnostic tests for asthma in children and cut-offs should be critically questioned and defined based on evidence from the patient population of interest</b>https://bit.ly/33xjLVW
Abstract 10831: Echolucency of Carotid Plaque is Useful for Selecting High-risk Patients With Chronic Coronary Artery Disease
Authors: Manabu Uematsu, Takamitsu Nakamura, Juntaro Deyama, Takeo Horikoshi, Aki Kobayashi, Toru Yoshizaki, Yosuke Watanabe, Tsuyoshi Kobayashi, Daisuke Fujioka, Yukio Saito, Kazuto Nakamura, Kenichi Kawabata, Jun-ei Obata, Kiyotaka Kugiyama
Journal: Circulation (2019)

Ultrasound assessment of either intima-media thickness (IMT) or plaque echolucency of the carotid artery provides prognostic information on cardiovascular events. Although high risk patients are re...