tbuckley/cabot-search huggingface dataset:
Abstract PS17-57: Breast cancer patients have reduced levels of short chain fatty acid producing beneficial gut bacteria
Authors: Praveen Vikas, Nicole Cady, Jessica Knobbe, Jemmie Hoang, Meeta Yadav, Melissa Curry, Cathernine Cherwin, Sonia Sugg, Sneha Phadke, Edward Filardo, Ashuthosh Mangalam
Journal: Cancer Research (2021)

Abstract The role of the human gut microbiome has been increasingly appreciated in respect to its influence on human health and disease. It has been proposed that dysbiosis in the gut microbiome and subsequent induction of chronic inflammatory state might have an influence on breast cancer development and prognosis. Therefore this study was undertaken to determine the role of gut microbiome in breast cancer. The Breast Molecular Epidemiology Resource (BMER) resources of the Holden Comprehensive Cancer Center (HCCC) were used to recruit 23 women with breast cancer. Fecal samples were used to characterize the gut microbiome of our patient population using 16S rRNA amplification and Illumina sequencing. Reads were then mapped back to amplicon sequence variant using DADA2 pipeline and compared to a cohort of race, age, and gender matched cohort of regional healthy controls. In our preliminary analysis, we observed that breast cancer patients have distinct microbiota compared to age and gender matched healthy controls. We identified depletion of the anti-inflammatory short chain fatty acid producing bacteria specifically Faecalibacterium, Anaerostipes, Parabacteroides and Phascolarctobacterium in feces from BC patients. Additionally, breast cancer cohort showed enrichment of the pro-inflammatory bacteria such as Eubacterium (dolichum), Bifidobacterium, and Blautia. These bacteria have been previously been identified to change with clinical disease stage and/or BMI, as has genus Bifidobacterium (increased in BC cohort). Within BC group, patients with high grade showed lower levels of Eggerthella lenta and Desulfovibrio whereas patients receiving chemotherapy showed depletion of Sulphur reducing Desulfovibrio and methane producing archaea Methanobrevibacter. Further analysis may lead to insights into the interplay between gut microbiome and breast cancer, as well as the feasibility of therapeutic strategies in the form of novel and existing probiotics. Citation Format: Praveen Vikas, Nicole Cady, Jessica Knobbe, Jemmie Hoang, Meeta Yadav, Melissa Curry, Cathernine Cherwin, Sonia Sugg, Sneha Phadke, Edward Filardo, Ashuthosh Mangalam. Breast cancer patients have reduced levels of short chain fatty acid producing beneficial gut bacteria [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-57.
Abstract PS7-05: Estrogen-based hormone replacement therapy [E-HRT] reduces all-cause, breast cancer, and Alzheimer's dementia mortality
Authors: Joseph Ragaz, Shayan Shakeraneh, Hong Qian, Hubert Wong, John J. Spinelli, Kenneth S. Wilson
Journal: Cancer Research (2021)

Abstract OBJECTIVES. To evaluate the long-term population-level impact of E-HRT on cause-specific and all-cause mortality in postmenopausal women in the USA, using the results of the 2017 Women’s Health Initiative HRT Trial 2 update.1 Of particular interest was the significantly reduced Breast Cancer [BrCa] mortality rates [RR=0.55, 95% C.I.=0.33-0.92].1 METHODOLOGY. In the WHI HRT Trial 2, women were randomized to receive estrogen (E) or placebo (P).1 For our analyses, the Annualized mortality rates (AR) were extracted for women aged 50-59, 60-69, 70-79, for breast cancer, Alzheimer's dementia, and all-cause mortality. The Median follow-up was 18 years. The Annualized Mortality Rate Difference (ARD) between the two groups was calculated as a difference of the AR between the P vs. E (AR in P - [minus] AR in E), expressed per 100,000 person-years. Subsequently, the Number of Avoided Deaths per year (NAD/year) was calculated using the number of women in each age group from the 2010 US census data. RESULTS. The annualized number of deaths avoided by the use of E-HRT in the US population was estimated as follows: BrCa, 9,292; Alzheimer’s dementia: 18,966; and all cause-mortality: 50,008 (Table). CONCLUSIONS. These data show a major beneficial impact of E-HRT, with over 50,000 deaths/year prevented in the USA alone. While these gains, sustained throughout the follow-up, represent undoubtedly major multi-organ metabolic benefits of estrogen, the most striking and unexpected findings involve BrCa, with over 9,000 BrCa deaths potentially avoided each year, just in the USA alone. RECOMMENDATION. Adoption and implementation of E-based HRT to the current HRT medical guidelines, to extend the health benefits to millions of women, and to prevent thousands of deaths each year in the USA alone. REFERENCE.1.Manson JE et al. Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women’s Health Initiative Randomized Trials. J Am Med Assoc 2017; 318(10): 927-938. AgesAge 50 – 59(N=21,506,008)Age 60 – 69(N=15,323,140)Age 70 – 79(N=9,169,601)ALL ages(N=45,998,749)ARD / 100,000NAD / YearARD / 100,000NAD / YearARD / 100,000NAD / YearNAD / YearBreast Cancer204,301233,524161,4679,292Alzheimer’s Dementia00406,12914012,83718,966All-Cause Mortality15032,259507,66211010,08750,008 Citation Format: Joseph Ragaz, Shayan Shakeraneh, Hong Qian, Hubert Wong, John J. Spinelli, Kenneth S. Wilson. Estrogen-based hormone replacement therapy [E-HRT] reduces all-cause, breast cancer, and Alzheimer's dementia mortality [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-05.
Short-Chain Fatty Acids Outpace Ketone Oxidation in the Failing Heart
Authors: Andrew N. Carley, Santosh K. Maurya, Matthew Fasano, Yang Wang, Craig H. Selzman, Stavros G. Drakos, E. Douglas Lewandowski
Journal: Circulation (2021)

Background: The failing heart is energy starved with impaired oxidation of long-chain fatty acids (LCFAs) at the level of reduced CPT1 (carnitine palmitoyltransferase 1) activity at the outer mitochondrial membrane. Recent work shows elevated ketone oxidation in failing hearts as an alternate carbon source for oxidative ATP generation. We hypothesized that another short-chain carbon source, short-chain fatty acids (SCFAs) that bypass carnitine palmitoyltransferase 1, could similarly support energy production in failing hearts. Methods: Cardiac hypertrophy and dysfunction were induced in rats by transverse-aortic constriction (TAC). Fourteen weeks after TAC or sham operation, isolated hearts were perfused with either the 4 carbon, 13 C-labeled ketone (D3-hydroxybutyrate) or the 4 carbon, 13 C-labeled SCFA butyrate in the presence of glucose and the LCFA palmitate. Oxidation of ketone and SCFA was compared by in vitro 13 C nuclear magnetic resonance spectroscopy, as was the capacity for short-chain carbon sources to compensate for impaired LCFA oxidation in the hypertrophic heart. Adaptive changes in enzyme expression and content for the distinct pathways of ketone and SCFA oxidation were examined in both failing rat and human hearts. Results: TAC produced pathological hypertrophy and increased the fractional contributions of ketone to acetyl coenzyme-A production in the tricarboxylic acid cycle (0.60±0.02 sham ketone versus 0.70±0.02 TAC ketone; P &lt;0.05). However, butyrate oxidation in failing hearts was 15% greater (0.803±0.020 TAC SCFA) than ketone oxidation. SCFA was also more readily oxidized than ketone in sham hearts by 15% (0.693±0.020 sham SCFA). Despite greater SFCA oxidation, TAC did not change short-chain acyl coenzyme-A dehydrogenase content. However, failing hearts of humans and the rat model both contain significant increases in acyl coenzyme-A synthetase medium-chain 3 enzyme gene expression and protein content. The increased oxidation of SCFA and ketones occurred at the expense of LCFA oxidation, with LCFA contributing less to acetyl coenzyme-A production in failing hearts perfused with SCFA (0.190±0.012 TAC SCFA versus 0.3163±0.0360 TAC ketone). Conclusions: SCFAs are more readily oxidized than ketones in failing hearts, despite both bypassing reduced CPT1 activity and represent an unexplored carbon source for energy production in failing hearts.
Long-standing enteroenteric anastomosis with lumen-apposing metal stents to access bilioenteric anastomotic strictures: yes we can!
Authors: Guido Costamagna
Journal: Endoscopy (2021)

Endoscopic retrograde cholangiopancreatography (ERCP) in patients with post-surgical altered upper gastrointestinal anatomy has been challenging since the early days of the technique. Until recent years, before the advent of proton pump inhibitors and the recognition of Helicobacter pylori as the etiologic factor of peptic ulcers, the vast majority of patients with altered gastrointestinal anatomy requiring an ERCP had undergone a partial gastrectomy with gastrojejunal anastomosis, commonly known as Billroth II gastrectomy. In these patients, the hurdles of ERCP were to progress with the endoscope into the afferent loop and reach the duodenal stump (especially when using a side-viewing duodenoscope), and then to cannulate the papilla in a reverse position. Performing the sphincterotomy was also a problem, and several different techniques to overcome the difficulties related to the upside-down position of the papilla were described [1].
Impact of Telemedicine on Pediatric Cardiac Center's Ambulatory Response to the 2019 Novel Coronavirus Disease (covid-19) Pandemic
Authors: K. M. Mehrtens, A. Krishnan, J. P. Moak, C. A. Sable, R. Selekman, C. I. Berul, I. Hovis, C. Helmandollar, T. A. Pender, C. Safo, C. Arroyo, J. A. Becker, R. A. Munoz, A. S. Harahsheh
Journal: Circulation (2020)
Protecting children and young people from developing sport associated dementia
Authors: Tanveer Rob, Peter Flannery
Journal: BMJ (2021)

As the intensity and volume of training in professional contact sports continue to increase, chronic traumatic encephalopathy (CTE) is going to become more prevalent.1 We need to keep things in perspective, however. The long term health benefits of playing sports in childhood are plentiful and well documented.2

Exercise in children …
The <scp>Heart Failure Association Atlas</scp>: <scp>Heart Failure Epidemiology and Management Statistics</scp> 2019
Authors: Petar M. Seferović, Panagiotis Vardas, Ewa A. Jankowska, Aldo P. Maggioni, Adam Timmis, Ivan Milinković, Marija Polovina, Chris P. Gale, Lars H. Lund, Yuri Lopatin, Mitja Lainscak, Gianluigi Savarese, Radu Huculeci, Dzianis Kazakiewicz, Andrew J.S. Coats
Journal: European Journal of Heart Failure (2021)
Establishing anchor-based minimally important differences for the EORTC QLQ-C30 in glioma patients
Authors: Linda Dirven, Jammbe Z Musoro, Corneel Coens, Jaap C Reijneveld, Martin J B Taphoorn, Florien W Boele, Mogens Groenvold, Martin J van den Bent, Roger Stupp, Galina Velikova, Kim Cocks, Mirjam A G Sprangers, Madeleine T King, Hans-Henning Flechtner, Andrew Bottomley
Journal: Neuro-Oncology (2021)

Abstract Background Minimally important differences (MIDs) allow interpretation of the clinical relevance of health-related quality of life (HRQOL) results. This study aimed to estimate MIDs for all European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) scales for interpreting group-level results in brain tumor patients. Methods Clinical and HRQOL data from three glioma trials were used. Clinical anchors were selected for each EORTC QLQ-C30 scale, based on correlation (&amp;gt;0.30) and clinical plausibility of association. Changes in both HRQOL and the anchors were calculated, and for each scale and time period, patients were categorized into one of the three clinical change groups: deteriorated by one anchor category, no change, or improved by one anchor category. Mean change method and linear regression were applied to estimate MIDs for interpreting within-group change and between-group differences in change over time, respectively. Distribution-based methods were applied to generate supportive evidence. Results A total of 1687 patients were enrolled in the three trials. The retained anchors were performance status and eight Common Terminology Criteria for Adverse Events (CTCAE) scales. MIDs for interpreting within-group change ranged from 4 to 12 points for improvement and −4 to −14 points for deterioration. MIDs for between-group difference in change ranged from 4 to 9 for improvement and −4 to −16 for deterioration. Most anchor-based MIDs were closest to the 0.3 SD distribution-based estimates (range: 3-10). Conclusions MIDs for the EORTC QLQ-C30 scales generally ranged between 4 and 11 points for both within-group mean change and between-group mean difference in change. These results can be used to interpret QLQ-C30 results from glioma trials.
Lonafarnib: First Approval
Authors: Sohita Dhillon
Journal: Drugs (2021)

Lonafarnib (Zokinvy™) is an orally active farnesyltransferase inhibitor developed by Eiger BioPharmaceuticals under license from Merck & Co. for the treatment of hepatitis D virus (HDV) infections, and progeria and progeroid laminopathies. The drug was originally discovered by Merck & Co as an investigational drug in oncology. In progeria, lonafarnib inhibits farnesyltransferase to prevent farnesylation and subsequent accumulation of progerin and progerin-like proteins in the nucleus and cellular cytoskeleton. In November 2020, lonafarnib received its first approval in the USA to reduce the risk of mortality in Hutchinson-Gilford Progeria Syndrome (HGPS) and for the treatment of processing-deficient progeroid laminopathies (with either heterozygous LMNA mutation with progerin-like protein accumulation, or homozygous or compound heterozygous ZMPSTE24 mutations) in patients ≥ 12 months of age with a body surface area (BSA) of ≥ 0.39 m2. Lonafarnib is under regulatory review in the European Union. Clinical development for the treatment of HDV infections is underway in multiple countries. This article summarizes the milestones in the development of lonafarnib leading to this first approval.
Corilagin inhibits SARS-CoV-2 replication by targeting viral RNA-dependent RNA polymerase
Authors: Quanjie Li, Dongrong Yi, Xiaobo Lei, Jianyuan Zhao, Yongxin Zhang, Xiangling Cui, Xia Xiao, Tao Jiao, Xiaojing Dong, Xuesen Zhao, Hui Zeng, Chen Liang, Lili Ren, Fei Guo, Xiaoyu Li, Jianwei Wang, Shan Cen
Journal: Acta Pharmaceutica Sinica B (2021)

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has become one major threat to human population health. The RNA-dependent RNA polymerase (RdRp) presents an ideal target of antivirals, whereas nucleoside analogs inhibitor is hindered by the proofreading activity of coronavirus. Herein, we report that corilagin (RAI-S-37) as a non-nucleoside inhibitor of SARS-CoV-2 RdRp, binds directly to RdRp, effectively inhibits the polymerase activity in both cell-free and cell-based assays, fully resists the proofreading activity and potently inhibits SARS-CoV-2 infection with a low 50% effective concentration (EC50) value of 0.13 μmol/L. Computation modeling predicts that RAI-S-37 lands at the palm domain of RdRp and prevents conformational changes required for nucleotide incorporation by RdRp. In addition, combination of RAI-S-37 with remdesivir exhibits additive activity against anti-SARS-CoV-2 RdRp. Together with the current data available on the safety and pharmacokinetics of corilagin as a medicinal herbal agent, these results demonstrate the potential of being developed into one of the much-needed SARS-CoV-2 therapeutics.
Vaccinating children to prevent long covid? More caution is needed in interpreting current epidemiological data
Authors: Sunil S Bhopal, Michael Absoud
Journal: BMJ (2021)

We are used to supporting children with chronic illness and have followed closely concerns raised by Simpson and Lokugamage regarding long covid in children.12 Media reports following the All Party Parliamentary Group on Coronavirus meeting on schools34 stated that “scientists called for reconsideration of covid-19 vaccinations for children” because of fears regarding the prevalence of the condition.5 The Office for National Statistics (ONS) prevalence of 12.9% (primary school age) …
Reply to John T. Lafin, Aditya Bagrodia’s Letter to the Editor re: Lucia Nappi, Marisa Thi, Nabil Adra, et al. Integrated Expression of Circulating miR375 and miR371 to Identify Teratoma and Active Germ Cell Malignancy Components in Malignant Germ Cell Tumors. Eur Urol 2021;79:16–9
Authors: Lucia Nappi, Craig Nichols, Christian Kollmannsberger
Journal: European Urology (2020)
Ethnic variability associating gut and oral microbiome with obesity in children
Authors: Baskar Balakrishnan, Vaithinathan Selvaraju, Jun Chen, Priscilla Ayine, Lu Yang, Jeganathan Ramesh Babu, Thangiah Geetha, Veena Taneja
Journal: Gut Microbes (2021)

Obesity is a growing worldwide problem that generally starts in the early years of life and affects minorities more often than Whites. Thus, there is an urgency to determine factors that can be used as targets as indicators of obesity. In this study, we attempt to generate a profile of gut and oral microbial clades predictive of disease status in African American (AA) and European American (EA) children. 16S rDNA sequencing of the gut and saliva microbial profiles were correlated with salivary amylase, socioeconomic factors (e.g., education and family income), and obesity in both ethnic populations. Gut and oral microbial diversity between AA and EA children showed significant differences in alpha-, beta-, and taxa-level diversity. While gut microbial diversity between obese and non-obese was not evident in EA children, the abundance of gut Klebsiella and Magasphaera was associated with obesity in AA children. In contrast, an abundance of oral Aggregatibacter and Eikenella in obese EA children was observed. These observations suggest an ethnicity-specific association with gut and oral microbial profiles. Socioeconomic factors influenced microbiota in obesity, which were ethnicity dependent, suggesting that specific approaches to confront obesity are required for both populations.
Novel Variant Findings and Challenges Associated With the Clinical Integration of Genomic Testing
Authors: Jill L. Maron, Stephen F. Kingsmore, Kristen Wigby, Shimul Chowdhury, David Dimmock, Brenda Poindexter, Kristen Suhrie, Jerry Vockley, Thomas Diacovo, Bruce D. Gelb, Annemarie Stroustrup, Cynthia M. Powell, Andrea Trembath, Matthew Gallen, Thomas E. Mullen, Pranoot Tanpaiboon, Dallas Reed, Anne Kurfiss, Jonathan M. Davis
Journal: JAMA Pediatrics (2021)

<h3>Importance</h3> A targeted genomic sequencing platform focused on diseases presenting in the first year of life may minimize financial and ethical challenges associated with rapid whole-genomic sequencing. <h3>Objective</h3> To report interim variants and associated interpretations of an ongoing study comparing rapid whole-genomic sequencing with a novel targeted genomic platform composed of 1722 actionable genes targeting disorders presenting in infancy. <h3>Design, Setting, and Participants</h3> The Genomic Medicine in Ill Neonates and Infants (GEMINI) study is a prospective, multicenter clinical trial with projected enrollment of 400 patients. The study is being conducted at 6 US hospitals. Hospitalized infants younger than 1 year of age suspected of having a genetic disorder are eligible. Results of the first 113 patients enrolled are reported here. Patient recruitment began in July 2019, and the interim analysis of enrolled patients occurred from March to June 2020. <h3>Interventions</h3> Patient (proband) and parents (trios, when available) were tested simultaneously on both genomic platforms. Each laboratory performed its own phenotypically driven interpretation and was blinded to other results. <h3>Main Outcomes and Measures</h3> Variants were classified according to the American College of Medical Genetics and Genomics standards of pathogenic (P), likely pathogenic (LP), or variants of unknown significance (VUS). Chromosomal and structural variations were reported by rapid whole-genomic sequencing. <h3>Results</h3> Gestational age of 113 patients ranged from 23 to 40 weeks and postmenstrual age from 27 to 83 weeks. Sixty-seven patients (59%) were male. Diagnostic and/or VUS were returned for 51 patients (45%), while 62 (55%) had negative results. Results were concordant between platforms in 83 patients (73%). Thirty-seven patients (33%) were found to have a P/LP variant by 2 or both platforms and 14 (12%) had a VUS possibly related to phenotype. The median day of life at diagnosis was 22 days (range, 3-313 days). Significant alterations in clinical care occurred in 29 infants (78%) with a P/LP variant. Incidental findings were reported in 7 trios. Of 51 positive cases, 34 (67%) differed in the reported result because of technical limitations of the targeted platform, interpretation of the variant, filtering discrepancies, or multiple causes. <h3>Conclusions and Relevance</h3> As comprehensive genetic testing becomes more routine, these data highlight the critically important variant detection capabilities of existing genomic sequencing technologies and the significant limitations that must be better understood.