tbuckley/cabot-search huggingface dataset:
Ginseng polysaccharides alter the gut microbiota and kynurenine/tryptophan ratio, potentiating the antitumour effect of antiprogrammed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) immunotherapy
Authors: Jumin Huang, Di Liu, Yuwei Wang, Liang Liu, Jian Li, Jing Yuan, Zhihong Jiang, Zebo Jiang, WL Wendy Hsiao, Haizhou Liu, Imran Khan, Ying Xie, Jianlin Wu, Yajia Xie, Yizhong Zhang, Yu Fu, Junyi Liao, Wenjun Wang, Huanling Lai, Axi Shi, Jun Cai, Lianxiang Luo, Runze Li, Xiaojun Yao, Xingxing Fan, Qibiao Wu, Zhongqiu Liu, Peiyu Yan, Jingguang Lu, Mingrong Yang, Lin Wang, Yabing Cao, Hong Wei, Elaine Lai-Han Leung
Journal: Gut (2021)

Objective Programmed death 1 and its ligand 1 (PD-1/PD-L1) immunotherapy is promising for late-stage lung cancer treatment, however, the response rate needs to be improved. Gut microbiota plays a crucial role in immunotherapy sensitisation and Panax ginseng has been shown to possess immunomodulatory potential. In this study, we aimed to investigate whether the combination treatment of ginseng polysaccharides (GPs) and αPD-1 monoclonal antibody (mAb) could sensitise the response by modulating gut microbiota. Design Syngeneic mouse models were administered GPs and αPD-1 mAb, the sensitising antitumour effects of the combination therapy on gut microbiota were assessed by faecal microbiota transplantation (FMT) and 16S PacBio single-molecule real-time (SMRT) sequencing. To assess the immune-related metabolites, metabolomics analysis of the plasma samples was performed. Results We found GPs increased the antitumour response to αPD-1 mAb by increasing the microbial metabolites valeric acid and decreasing L-kynurenine, as well as the ratio of Kyn/Trp, which contributed to the suppression of regulatory T cells and induction of T eff cells after combination treatment. Besides, the microbial analysis indicated that the abundance of Parabacteroides distasonis and Bacteroides vulgatus was higher in responders to anti-PD-1 blockade than non-responders in the clinic. Furthermore, the combination therapy sensitised the response to PD-1 inhibitor in the mice receiving microbes by FMT from six non-responders by reshaping the gut microbiota from non-responders towards that of responders. Conclusion Our results demonstrate that GPs combined with αPD-1 mAb may be a new strategy to sensitise non-small cell lung cancer patients to anti-PD-1 immunotherapy. The gut microbiota can be used as a novel biomarker to predict the response to anti-PD-1 immunotherapy.
Abstract MP29: Combined Impact Of Chronic Kidney Disease And Hypertension On Lifetime Risk Of Cardiovascular Disease Death: A Pooled Analysis Of Data From The Evidence For Cardiovascular Prevention From Observational Cohorts In Japan Study
Authors: Yukiko Imai, Masaru Sakurai, Nakagawa Hideaki, Aya Hirata, Yoshitaka Murakami, Sachiko Tanaka, Yutaka Kiyohara, Toshiharu Ninomiya, Shizukiyo Ishikawa, Shigeyuki Saitoh, Fujiko Irie, Toshimi Sairenchi, Masahiko Kiyama, Katsuyuki Miura, Hirotsugu Ueshima, Tomonori Okamura
Journal: Circulation (2021)

Introduction: Those who are considered to be low risk in short term such as 10 year risk actually have high risk of cardiovascular disease for the remaining lifespan at younger age. Absolute risk of Lifetime risk (LTR) is more useful and understandable for lay audience compared with short term risk or relative risk. CKD (Chronic Kidney Disease) is global burden of cardiovascular disease (CVD) and hypertension is damaging complication of CKD for CVD. To date, there have been no reports of LTR with the outcome of CVD death based on CKD in Asian population. Hypothesis: We sought to estimate LTR of CVD death stratified by the status of CKD and hypertension. Methods: We used data from EPOCH-JAPAN (Evidence for Cardiovascular Prevention From Observational Cohorts in Japan) which is designed to pool data from nationwide and regional cohort studies in Japan. Modified Kaplan-Meier approach was used to estimate the remaining lifetime risk of cardiovascular death at each index age starting from 40 years according to CKD stratified by Hypertension. Participants were classified into four groups, which were those without CKD and hypertension (CKD-/HT-), those with CKD but without hypertension (CKD+/HT-), those without CKD but with hypertension (CKD-/HT+), and those with both CKD and hypertension (CKD+/HT+). Results: A total of 44,582 participants from 8 cohorts was included in the analysis. Mean follow-up period was 14.9 years with 662,488 person years and total CVD death was 1,035 in men and 1,160 in women. The LTRs at the index age of 40 years increased in groups with CKD and/or HT as follows: 12.6% (95% confidence interval: 9.4 - 14.5%) in CKD-/HT- group, 20.6% (11.4 - 25.9%) in CKD+/HT- group, 23.2% (19.9 - 25.2%) in CKD-/HT+ group, and 27.9% (21.7 - 32.9%) in CKD+/HT+ group for men; 11.3%(8.9 - 13.2%), 17.4%(13.2 - 20.4%) , 17.8%(15.3 - 19.8%) , and 22.7%(19.5 - 25.2%) for women. Conclusions: We observed that complication of CKD and hypertension are collectively responsible for lifetime risk due to CVD death. Management of blood pressure from an early age is important to reduce CVD mortality in CKD patients.
Comparing machine learning algorithms for predicting ICU admission and mortality in COVID-19
Authors: Sonu Subudhi, Ashish Verma, Ankit B. Patel, C. Corey Hardin, Melin J. Khandekar, Hang Lee, Dustin McEvoy, Triantafyllos Stylianopoulos, Lance L. Munn, Sayon Dutta, Rakesh K. Jain
Journal: npj Digital Medicine (2021)

Abstract As predicting the trajectory of COVID-19 is challenging, machine learning models could assist physicians in identifying high-risk individuals. This study compares the performance of 18 machine learning algorithms for predicting ICU admission and mortality among COVID-19 patients. Using COVID-19 patient data from the Mass General Brigham (MGB) Healthcare database, we developed and internally validated models using patients presenting to the Emergency Department (ED) between March-April 2020 ( n = 3597) and further validated them using temporally distinct individuals who presented to the ED between May-August 2020 ( n = 1711). We show that ensemble-based models perform better than other model types at predicting both 5-day ICU admission and 28-day mortality from COVID-19. CRP, LDH, and O 2 saturation were important for ICU admission models whereas eGFR &lt;60 ml/min/1.73 m 2 , and neutrophil and lymphocyte percentages were the most important variables for predicting mortality. Implementing such models could help in clinical decision-making for future infectious disease outbreaks including COVID-19.
Abstract 16461: Are Inducible Exercise Left Ventricular Outflow Tract Gradients Associated With Adverse Outcomes in Pediatric Hypertrophic Cardiomyopathy?
Authors: Mansi Gaitonde, Megan Simpson, Martha Wetzel, William L Border, Ritu Sachdeva, Matthew Ferguson, Robert Whitehill
Journal: Circulation (2020)

Introduction: Adverse outcomes in hypertrophic cardiomyopathy (HCM) includes arrhythmias, myocardial fibrosis, heart failure, and sudden cardiac arrest (SCA). These are well documented in children. Exercise stress echocardiography (ESE) can identify the severity and mechanism of left ventricular outflow tract (LVOT) obstruction that may not be present at rest. Our aim was to compare clinical outcomes in pediatric patients with varying severity of LVOT obstruction. Methods: We reviewed records of patients &lt; 22 years with HCM who underwent staged ESE Jan 2009 - Dec 2019 at our center. Patients were divided into 3 groups: no resting or exercise LVOT gradient (Group 1), no resting gradient with LVOT gradient &gt; 30 mmHg at peak exercise (Group 2), and resting LVOT gradient &gt; 30 mmHg (Group 3). We assessed echocardiographic indices, advanced imaging, and clinical data. Statistical analysis performed with p-value &lt;0.05. Results: 93 patients met inclusion criteria. 6 SCA events occurred, though not during ESE.. Patients in Group 3 were classified less often as NYHA Class 1 compared to Group 1 or Group 2, (p &lt; 0.01). Group 3 had the highest rate of myectomy (p=0.005) and ICD placement (p=0.003). There was no significant difference in exercise symptoms, peak oxygen consumption, or ischemic changes during ESE between the groups. Peak heart rate was also higher in Group 2 with no difference in blood pressure response. Groups were not associated with family history of disease, positive gene status, SCA, or the presence of fibrosis (Table). LVOT gradients differed as early as Stage 1 in Groups 1 &amp; 2. Inducible LVOT obstruction was most commonly midcavitary in Group 2. Conclusion: The presence of resting versus inducible LVOT obstruction in pediatric HCM does not appear associated with adverse outcomes. This may be hampered by the rarity of events in pediatrics. The predominant mechanism of inducible LVOT obstruction was midcavitary, which has a link to adverse long-term outcomes in adult HCM.
Comment on Gregory et al. COVID-19 Severity Is Tripled in the Diabetes Community: A Prospective Analysis of the Pandemic’s Impact in Type 1 and Type 2 Diabetes. Diabetes Care 2021;44:526–532
Authors: David M. Maahs, G. Todd Alonso, Mary Pat Gallagher, Osagie Ebekozien
Journal: Diabetes Care (2020)

We commend Gregory and colleagues for their well-designed prospective study to quantify and contextualize the risk for coronavirus disease 2019 (COVID-19)related hospitalization and illness severity in type 1 (and type 2) diabetes (1).High-quality data such as these are required to inform public health approaches, including defining the risk of severe acute respiratory syndrome coronavirus 2 infection and health outcomes in people with diabetes.Indeed, these data inform a JDRF campaign (https:// www.jdrf.org/coronavirus)advocating for prioritization of people with type 1 diabetes for COVID-19 vaccinations.However, as pointed out in a recent Diabetes Care Commentary (2), data
The metabesity factor HMG20A potentiates astrocyte survival and reactive astrogliosis preserving neuronal integrity
Authors: Petra I. Lorenzo, Eugenia Martin Vazquez, Livia López-Noriega, Esther Fuente-Martín, José M. Mellado-Gil, Jaime M. Franco, Nadia Cobo-Vuilleumier, José A. Guerrero Martínez, Silvana Y. Romero-Zerbo, Jesús A. Perez-Cabello, Sabrina Rivero Canalejo, Antonio Campos-Caro, Christian Claude Lachaud, Alejandra Crespo Barreda, Manuel Aguilar-Diosdado, Eduardo García Fuentes, Alejandro Martin-Montalvo, Manuel Álvarez Dolado, Franz Martin, Gemma Rojo-Martinez, David Pozo, Francisco J. Bérmudez-Silva, Valentine Comaills, José C. Reyes, Benoit R. Gauthier
Journal: Theranostics (2021)

Rationale:We recently demonstrated that the 'Metabesity' factor HMG20A regulates islet beta-cell functional maturity and adaptation to physiological stress such as pregnancy and pre-diabetes.HMG20A also dictates central nervous system (CNS) development via inhibition of the LSD1-CoREST complex but its expression pattern and function in adult brain remains unknown.Herein we sought to determine whether HMG20A is expressed in the adult CNS, specifically in hypothalamic astrocytes that are key in glucose homeostasis and whether similar to islets, HMG20A potentiates astrocyte function in response to environmental cues.Methods: HMG20A expression profile was assessed by quantitative PCR (QT-PCR), Western blotting and/or immunofluorescence in: 1) the hypothalamus of mice exposed or not to either a high-fat diet or a high-fat high-sucrose regimen, 2) human blood leukocytes and adipose tissue obtained from healthy or diabetic individuals and 3) primary mouse hypothalamic astrocytes exposed to either high glucose or palmitate.RNA-seq and cell metabolic parameters were performed on astrocytes treated or not with a siHMG20A.Astrocyte-mediated neuronal survival was evaluated using conditioned media from siHMG20A-treated astrocytes.The impact of ORY1001, an inhibitor of the LSD1-CoREST complex, on HMG20A expression, reactive astrogliosis and glucose metabolism was evaluated in vitro and in vivo in high-fat high-sucrose fed mice.Results: We show that Hmg20a is predominantly expressed in hypothalamic astrocytes, the main nutrient-sensing cell type of the brain.HMG20A expression was upregulated in diet-induced obesity and glucose intolerant mice, correlating with increased transcript levels of Gfap and Il1b indicative of inflammation and reactive astrogliosis.Hmg20a transcript levels were also increased in adipose tissue of obese non-diabetic Ivyspring International
14P Immunomodulatory effect of denosumab in early breast cancer: Preliminary results of a randomized window-opportunity clinical trial D-Biomark
Authors: A.C. Vethencourt, E.M. Trinidad, C. Gómez Aleza, S. Pernas Simon, A. Petit, T. Soler, A. Urruticoechea, A. Gumà Martinez, A. García-Tejedor, M.J. Pla, C. Capó, M. Gil Gil, A. Stradella, A. Fernádez, S. Recalde Penabad, M. Cejuela, S. Vazquez, A. Iserte, C. Falo, E. Gonzalez-Suarez
Journal: Annals of Oncology (2021)
プレβHDLの強力な産生物,FAMPはコレステロール逆転送を増強し,心筋梗塞モデルの生存率を改善する
Authors: Miura Shinichiro, Uehara Yoshinari, Tanigawa Hiroyuki, Yahiro Eiji, Saku Keijiro
Journal: Circulation (2011)
23P CDK4/6 inhibition and endocrine therapy (ET) in the HER2-enriched subtype (HER2-E) in hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer (ABC): A retrospective analysis of real-world data
Authors: O. Martínez-Sáez, P. Tolosa, A. Sánchez De Torre, T. Pascual, F. Brasó-Maristany, A. Rodriguez Hernandez, L. Parrilla, A.M. Roncero, Y. Ruano, N. Chic, F. Schettini, J.C. Laguna, E. Sanfeliu Torres, B. Gonzalez-Farre, M. Vidal, B. Adamo, M.C. Guillen Sacoto, M. Muñoz, A. Prat, E.M. Ciruelos
Journal: Annals of Oncology (2021)
149P Restricted mean survival time (RMST): A new tool for time to event analysis in young breast cancer patients (YBCP)
Authors: J.C. Sánchez, M. Mendez Garcia, B. Nunez Garcia, M. Blanco Clemente, J. Mucientes, M. López Valcárcel, R. Aguado, A. Royuela, M. Provencio Pulla, B. Cantos Sanchez de Ibarguen
Journal: Annals of Oncology (2021)
44O Characterization of venous thromboembolic events (VTE), elevated aminotransferases (EAT) and interstitial lung disease (ILD) in monarchE
Authors: M. Toi, N. Harbeck, J.M. Puig, J. Cruz, J.H. Seo, M. Takahashi, M. Hulstijn, E.A. Twum, A. Regev, B. San Antonio, D.M. Median, M. Campone
Journal: Annals of Oncology (2021)
DNMT3A haploinsufficiency causes dichotomous DNA methylation defects at enhancers in mature human immune cells
Authors: Jung-Yeon Lim, Sascha H. Duttke, Turner S. Baker, Jihye Lee, Kristyne J. Gambino, Nicholas J. Venturini, Jessica Sook Yuin Ho, Simin Zheng, Yesai S. Fstkchyan, Vinodh Pillai, David C. Fajgenbaum, Ivan Marazzi, Christopher Benner, Minji Byun
Journal: The Journal of Experimental Medicine (2021)

DNMT3A encodes an enzyme that carries out de novo DNA methylation, which is essential for the acquisition of cellular identity and specialized functions during cellular differentiation. DNMT3A is the most frequently mutated gene in age-related clonal hematopoiesis. As such, mature immune cells harboring DNMT3A mutations can be readily detected in elderly persons. Most DNMT3A mutations associated with clonal hematopoiesis are heterozygous and predicted to cause loss of function, indicating that haploinsufficiency is the predominant pathogenic mechanism. Yet, the impact of DNMT3A haploinsufficiency on the function of mature immune cells is poorly understood. Here, we demonstrate that DNMT3A haploinsufficiency impairs the gain of DNA methylation at decommissioned enhancers, while simultaneously and unexpectedly impairing DNA demethylation of newly activated enhancers in mature human myeloid cells. The DNA methylation defects alter the activity of affected enhancers, leading to abnormal gene expression and impaired immune response. These findings provide insights into the mechanism of immune dysfunction associated with clonal hematopoiesis and acquired DNMT3A mutations.
Abstract MP06: Healthy Diet Quality Is Associated With Epigenetic Age Deceleration
Authors: Youjin Kim, Jiantao Ma, Daniel Levy
Journal: Circulation (2021)

Introduction: Epigenetic age is a marker of healthy lifespan. Diet quality is known to be associated with the risk of developing chronic diseases; however, the relation between diet quality and epigenetic age remains to be investigated. Hypothesis: We tested the hypothesis that healthy diet quality is associated with favorable epigenetic age. Methods: Participants were drawn from the eighth examination of the Framingham Heart Study Offspring cohort ( n =1,995; mean age 67 years; 55% women). Diet quality was estimated using Alternative Healthy Eating Index (AHEI) and Mediterranean-style Diet Score (MDS) derived from food frequency questionnaire. A second generation of epigenetic age, DNA methylation GrimAge, was calculated. Epigenetic age acceleration (GrimAA) was derived as residual after adjustment for chronological age using linear regression model. Results and Conclusions: Higher AHEI and MDS (i.e., healthier diet) were associated with decreased GrimAA after adjusting for age, sex, body mass index, smoking, physical activity, alcohol consumption, and energy intake ( P &lt; 0.001). We observed that the association of diet quality with GrimAA was stronger in ever-smokers (i.e., former and current smokers) compared to that in never-smokers ( P interaction &lt; 0.001 for both scores). In ever-smokers, adjusted mean Grim AA was 3.95 years (95%CI: 3.47, 4.43) and 0.65 years (95%CI: 0.11, 1.19) in the lowest and highest AHEI quartile category, respectively, or GrimAA was reduced by 1.15 years (95%CI: 0.82, 1.48) per standard deviation (SD) increase in AHEI, P &lt; 0.001. In never-smokers, adjusted mean GrimAA was -1.73 years (95%CI: -2.19, -1.26) and -2.37 years (95%CI: -2.80, 1.94) in the lowest and highest AHEI quartile category, respectively, or GrimAA was reduced by 0.23 years (95%CI: 0.05, 0.40) per SD increase in AHEI, P = 0.01. Similarly, for one SD increase in MDS, the GrimAA was reduced by 0.92 years (95%CI: 0.56, 1.27; P &lt; 0.001) in ever-smokers, but by 0.19 years (95%CI: 0.01, 0.38; P = 0.04) in never-smokers. GrimAA significantly mediated the association between diet quality and all-cause mortality with the mean proportion of 37.0% for AHEI ( P mediation &lt; 0.001) and 25.5% for MDS ( P mediation = 0.001). The mediation effect of GrimAA was more prominent in ever-smokers, which was twice the proportion found in never-smokers for both AHEI and MDS. In conclusion, higher diet quality is associated with decelerated epigenetic aging, which partially explains the beneficial relation of diet quality and healthy lifespan. These results also suggest that better diet quality could be more beneficial in ever-smokers.
Conserved pan-cancer microenvironment subtypes predict response to immunotherapy
Authors: Alexander Bagaev, Nikita Kotlov, Krystle Nomie, Viktor Svekolkin, Azamat Gafurov, Olga Isaeva, Nikita Osokin, Ivan Kozlov, Felix Frenkel, Olga Gancharova, Nava Almog, Maria Tsiper, Ravshan Ataullakhanov, Nathan Fowler
Journal: Cancer Cell (2021)
Abstract 15735: Neonatal Cardiac Regeneration Depends on IGF1R-signaling
Authors: Thomas Schuetz, Theresa Dolejsi, Alexander Bild, Axel Bauer, Josef M Penninger, Bernhard J Haubner
Journal: Circulation (2020)

Introduction: In contrast to other adult tissues myocardium cannot be sufficiently regenerated following significant myocardial infarction (MI). Efficient cardiac regeneration was demonstrated in neonatal mouse myocardial injury models. Similar observations were reported in other neonatal mammals including newborn human babies suffering from MI. The mechanisms of neonatal mammalian cardiac regeneration remain unclear. Here we show the crucial role of IGF1R which was unraveled in a time-course transcriptome analysis of neonatal mouse hearts. Methods: IGF1R was specifically knocked-down (KD) in cardiomyocytes of wildtype postnatal day one (P1) mice using adeno-associated virus (rAAV9) delivered shRNAmirs. KD of Renilla served as control (REN-CTRL). 5x10 13 viral genomes per kg bodyweight were injected intrathoracally. Three batches of rAAV9 with different shRNAmirs were used for the IGF1R-KD groups. Viral transduction was confirmed by bioluminescence imaging on luciferase containing rAAV9 copies and by immunofluorescence staining of rAAV9 delivered GFP reporter. KD efficiency was confirmed in vitro using a retrovirus system and in vivo. On P2 mice underwent either left anterior descending artery (LAD) ligation for induction of MI or SHAM surgery. Cardiac function was subsequently assessed by echocardiography 1 day post injury (dpi) and 21 dpi. Thereafter, hearts were harvested and left ventricular fibrosis was analyzed histologically. Results: LAD ligation resulted in significant MI in both, IGF1R-KD and REN-CTRL, LAD groups as proven by a markedly reduced ejection fraction (EF) 1 dpi. Importantly, 21 dpi IGF1R-KD and REN-CTRL SHAM groups displayed normal cardiac function proving no effect on neonatal cardiac growth and development of only KD of IGF1R without LAD ligation. In contrast, LAD ligation IGF1R-KD mice presented significantly reduced EF 21dpi compared to the other 3 groups. Histological analysis revealed significant fibrosis in the IGF1R-KD LAD hearts compared to the other 3 groups. Conclusions: Whereas IGF1R-KD or control rAAV9 does not alter physiological cardiac development, KD of IGF1R markedly impairs neonatal cardiac regeneration in neonatal mice after MI suggesting a crucial role in neonatal cardiac regeneration.
Abstract 16893: Thrombotic Events During Extended Microaxial Mechanical Circulatory Support for Cardiogenic Shock
Authors: Mathew S Lopes, Danuzia Silva, Daniel Loriaux, David Berg, Michael Levangie, Erin A Bohula, David A Morrow
Journal: Circulation (2020)

Background: Percutaneous ventricular assist devices (VAD) are used in ~1/3 of patients (pts) with cardiogenic shock (CS). A percutaneous microaxial intracardiac VAD can offer hemodynamic support weighed against a risk of vascular complications. However, few studies have addressed the incidence of thrombotic complications, particularly in pts who require extended mechanical circulatory support (MCS). Methods: We conducted an observational cohort study to quantify the risk of thrombotic events during MCS in pts managed with a microaxial VAD for CS or mixed shock from 2015-2020 in a quaternary referral center. All consecutive pts were captured in a prospective registry of MCS and retrospectively reviewed for potentially device-related thrombotic events by 2 physician adjudicators. All pts received systemic anticoagulation with unfractionated heparin and/or bivalirudin. Results: The study included 106 pts (72% male, mean age 59.8). Peripheral artery disease, and a significant smoking history were present in 12% and 44% of cases respectively. The duration of microaxial VAD use was 5.3 days on average and &gt;7 days in 25%. A concurrent microaxial VAD and other MCS were used in 28% of cases. Thrombotic/ischemic events were observed in 24.5% and were subcategorized into limb ischemia with visualized thrombus (n=6), limb ischemia without visualized thrombus (n=6), systemic embolism (n=6), intraventricular thrombus (n=2), device thrombus (n=6), and device dysfunction (n=3). Three pts had more than one complication. Moderate to severe thrombocytopenia (&lt;100mcg/dL) was observed in 78% of pts. In-hospital mortality was 51% and was not higher in pts with thrombotic events (p=0.14). Conclusion: Thrombotic events are common with a microaxial intracardiac VAD with an observed rate that was higher than previously reported. Larger studies of all-comers with MCS for CS are needed to better define the rate of MCS-associated complications.