tbuckley/cabot-search huggingface dataset:
Single-cell analysis shows that adipose tissue of persons with both HIV and diabetes is enriched for clonal, cytotoxic, and CMV-specific CD4+ T cells
Authors: Celestine N. Wanjalla, Wyatt J. McDonnell, Ramesh Ram, Abha Chopra, Rama Gangula, Shay Leary, Mona Mashayekhi, Joshua D. Simmons, Christian M. Warren, Samuel Bailin, Curtis L. Gabriel, Liang Guo, Briana D. Furch, Morgan C. Lima, Beverly O. Woodward, LaToya Hannah, Mark A. Pilkinton, Daniela T. Fuller, Kenji Kawai, Renu Virmani, Aloke V. Finn, Alyssa H. Hasty, Simon A. Mallal, Spyros A. Kalams, John R. Koethe
Journal: Cell Reports Medicine (2021)

Persons with HIV are at increased risk for diabetes mellitus compared with individuals without HIV. Adipose tissue is an important regulator of glucose and lipid metabolism, and adipose tissue T cells modulate local inflammatory responses and, by extension, adipocyte function. Persons with HIV and diabetes have a high proportion of CX3CR1+ GPR56+ CD57+ (C-G-C+) CD4+ T cells in adipose tissue, a subset of which are cytomegalovirus specific, whereas individuals with diabetes but without HIV have predominantly CD69+ CD4+ T cells. Adipose tissue CD69+ and C-G-C+ CD4+ T cell subsets demonstrate higher receptor clonality compared with the same cells in blood, potentially reflecting antigen-driven expansion, but C-G-C+ CD4+ T cells have a more inflammatory and cytotoxic RNA transcriptome. Future studies will explore whether viral antigens have a role in recruitment and proliferation of pro-inflammatory C-G-C+ CD4+ T cells in adipose tissue of persons with HIV.
Near-infrared fluorescence-guided resection of micrometastases derived from esophageal squamous cell carcinoma using a c-Met-targeted probe in a preclinical xenograft model
Authors: Mingzhu Liang, Meilin Yang, Fen Wang, Xiaojin Wang, Bailiang He, Chaoming Mei, Jianzhong He, Yujing Lin, Qingdong Cao, Dan Li, Hong Shan
Journal: Journal of Controlled Release (2021)
The Innate Immune Response to<i>Mycobacterium tuberculosis</i>Infection
Authors: Mariëtta M. Ravesloot-Chávez, Erik Van Dis, Sarah A. Stanley
Journal: Annual Review of Immunology (2021)

Infection with Mycobacterium tuberculosis causes >1.5 million deaths worldwide annually. Innate immune cells are the first to encounter M. tuberculosis, and their response dictates the course of infection. Dendritic cells (DCs) activate the adaptive response and determine its characteristics. Macrophages are responsible both for exerting cell-intrinsic antimicrobial control and for initiating and maintaining inflammation. The inflammatory response to M. tuberculosis infection is a double-edged sword. While cytokines such as TNF-α and IL-1 are important for protection, either excessive or insufficient cytokine production results in progressive disease. Furthermore, neutrophils-cells normally associated with control of bacterial infection-are emerging as key drivers of a hyperinflammatory response that results in host mortality. The roles of other innate cells, including natural killer cells and innate-like T cells, remain enigmatic. Understanding the nuances of both cell-intrinsic control of infection and regulation of inflammation will be crucial for the successful development of host-targeted therapeutics and vaccines.
Real-world insights on preferred treatments for steroid-refractory immune checkpoint inhibitor-induced pneumonitis
Authors: Margaret Gatti-Mays, James L Gulley
Journal: Journal for ImmunoTherapy of Cancer (2021)

Immune checkpoint inhibitor (ICI)-induced pneumonitis has been considered a rare immune-related adverse event (irAE). Incidence is estimated at less than 5% of clinical trial patients, with high-grade pneumonitis occurring in less than 1% of patients who receive ICIs.[1 2][1] However, as ICIs gain
Hypothermic Machine Perfusion in Liver Transplantation — A Randomized Trial
Authors: Rianne van Rijn, Ivo J. Schurink, Yvonne de Vries, Aad P. van den Berg, Miriam Cortes Cerisuelo, Sarwa Darwish Murad, Joris I. Erdmann, Nicholas Gilbo, Robbert J. de Haas, Nigel Heaton, Bart van Hoek, Volkert A.L. Huurman, Ina Jochmans, Otto B. van Leeuwen, Vincent E. de Meijer, Diethard Monbaliu, Wojciech G. Polak, Jules J.G. Slangen, Roberto I. Troisi, Aude Vanlander, Jeroen de Jonge, Robert J. Porte
Journal: New England Journal of Medicine (2021)

Transplantation of livers obtained from donors after circulatory death is associated with an increased risk of nonanastomotic biliary strictures. Hypothermic oxygenated machine perfusion of livers may reduce the incidence of biliary complications, but data from prospective, controlled studies are limited.In this multicenter, controlled trial, we randomly assigned patients who were undergoing transplantation of a liver obtained from a donor after circulatory death to receive that liver either after hypothermic oxygenated machine perfusion (machine-perfusion group) or after conventional static cold storage alone (control group). The primary end point was the incidence of nonanastomotic biliary strictures within 6 months after transplantation. Secondary end points included other graft-related and general complications.A total of 160 patients were enrolled, of whom 78 received a machine-perfused liver and 78 received a liver after static cold storage only (4 patients did not receive a liver in this trial). Nonanastomotic biliary strictures occurred in 6% of the patients in the machine-perfusion group and in 18% of those in the control group (risk ratio, 0.36; 95% confidence interval [CI], 0.14 to 0.94; P = 0.03). Postreperfusion syndrome occurred in 12% of the recipients of a machine-perfused liver and in 27% of those in the control group (risk ratio, 0.43; 95% CI, 0.20 to 0.91). Early allograft dysfunction occurred in 26% of the machine-perfused livers, as compared with 40% of control livers (risk ratio, 0.61; 95% CI, 0.39 to 0.96). The cumulative number of treatments for nonanastomotic biliary strictures was lower by a factor of almost 4 after machine perfusion, as compared with control. The incidence of adverse events was similar in the two groups.Hypothermic oxygenated machine perfusion led to a lower risk of nonanastomotic biliary strictures following the transplantation of livers obtained from donors after circulatory death than conventional static cold storage. (Funded by Fonds NutsOhra; DHOPE-DCD ClinicalTrials.gov number, NCT02584283.).
Estimates of mortality attributable to COVID-19: a statistical model for monitoring COVID-19 and seasonal influenza, Denmark, spring 2020
Authors: Jens Nielsen, Naja Hulvej Rod, Lasse S Vestergaard, Theis Lange
Journal: Eurosurveillance (2021)

Background Timely monitoring of COVID-19 impact on mortality is critical for rapid risk assessment and public health action. Aim Building upon well-established models to estimate influenza-related mortality, we propose a new statistical Attributable Mortality Model (AttMOMO), which estimates mortality attributable to one or more pathogens simultaneously (e.g. SARS-CoV-2 and seasonal influenza viruses), while adjusting for seasonality and excess temperatures. Methods Data from Nationwide Danish registers from 2014-week(W)W27 to 2020-W22 were used to exemplify utilities of the model, and to estimate COVID-19 and influenza attributable mortality from 2019-W40 to 2020-W20. Results SARS-CoV-2 was registered in Denmark from 2020-W09. Mortality attributable to COVID-19 in Denmark increased steeply, and peaked in 2020-W14. As preventive measures and national lockdown were implemented from 2020-W12, the attributable mortality started declining within a few weeks. Mortality attributable to COVID-19 from 2020-W09 to 2020-W20 was estimated to 16.2 (95% confidence interval (CI): 12.0 to 20.4) per 100,000 person-years. The 2019/20 influenza season was mild with few deaths attributable to influenza, 3.2 (95% CI: 1.1 to 5.4) per 100,000 person-years. Conclusion AttMOMO estimates mortality attributable to several pathogens simultaneously, providing a fuller picture of mortality by COVID-19 during the pandemic in the context of other seasonal diseases and mortality patterns. Using Danish data, we show that the model accurately estimates mortality attributable to COVID-19 and influenza, respectively. We propose using standardised indicators for pathogen circulation in the population, to make estimates comparable between countries and applicable for timely monitoring.
Inhibition of RNA synthesis by 5-fluorouridine accounts for its cyto toxicity on colorectal cancer cells in vitro
Authors: Pochi R. Subbarayan, Zeming Deng, Philip Lee, Ardalan Bach
Journal: Cancer Research (2005)

1362  5-fluorouracil (5-FU) or occasionally fluorodeoxyuridine (FUdR) are used in combination therapy to treat patients with colorectal cancer (CRC). 5-FU and FUdR are metabolized to 5-fluro-2’-deoxyuridine monophosphate (FdUMP). FdUMP competes with deoxyuridine monophosphate (dUMP) to be the substrate for thymidylate synthase (TS), an important enzyme in the formation of dTMP. Incorporation of fluorinated analogues into DNA causes replication defect leading to eventual cell death. The other lesser-known fluoropyrimidine analogue is 5-fluorouridine (FUR). However, the mode of action of 5-FU, FUdR and FUR is not completely understood. Therefore we investigated the mechanisms of action of 5FU, FUdR and FUR. Here we compared their cytotoxicity in colorectal cancer cell lines Colo320HSR, CCL 221 and HT29. To unravel the mode of action of fluorouridines, we rescued the treated cells with deoxythymidine (dThd) or uridine (Urd). We established time and dose dependent cell kill for the listed fluoropyrimidine analogues. Following drug treatment we quantitated the TS transcript level in Colo320HSR cells in vitro. Additionally, we conducted in vivo animal toxicity studies with 5FU, FUdR and FUR. The in vitro studies showed that FUdR and FUR have very similar IC50 values of 19, 29, 14 & 23, 52, 41 nM in Colo320HSR, CCL 221 and HT29 cells respectively. In contrast, 5-FU required 3300, 8732, 6062 nM to obtain the same degree of cell kill. Rescue studies performed with 10 μM deoxythymidine (dThd) inhibited the cytotoxic effect of FUdR but not of FUR. On the other hand 1 mM Urd rescued the cells from the toxic effects of FUR only. This suggests that 5FU and FUdR interferes with DNA synthesis and FUR with transcription. Time and dose dependent cytotoxicity studies reveal existence of an inverse relationship between the duration of exposure and concentration of 5-FU used. Exposure of Colo320HSR cells to 1 μM of 5FU for 1 h was ineffective. Increasing the duration from 1h to 5 or 24 hrs and dosage from 1 μM to 5 or 10 μM resulted in 20% and 60% growth inhibition. Similar cytotoxic studies using FUdR demonstrated that it was more effective than 5FU. In contrast FUR inhibited cell growth at all concentrations and exposure times. Reverse transcriptase PCR analysis following drug treatment showed FUR exhibited maximum inhibition of TS transcription in vivo. Among the three fluoropyrimidine analogues FUR was found to be most toxic in BALB/C mice. Our studies demonstrated that FUR is the most potent anti tumor agent among the fluoropyrimidines. In general their cytotoxicity depends on dose and duration of treatment. Fluoropyrimidines exert dual regulation on TS gene expression. Initially they induce its expression with eventual suppression following prolonged exposure. Severe inhibitory effect of FUR on TS gene expression and its RNA mediated cell kill may explain its superiority over the other two fluoropyrimidine analogues tested.
The colorectal cancer-associated faecal microbiome of developing countries resembles that of developed countries
Authors: Caroline Young, Henry M. Wood, Ramakrishnan Ayloor Seshadri, Pham Van Nang, Carlos Vaccaro, Luis Contreras Melendez, Mayilvahanan Bose, Mai Van Doi, Tamara Alejandra Piñero, Camilo Tapia Valladares, Julieta Arguero, Alba Fuentes Balaguer, Kelsey N. Thompson, Yan Yan, Curtis Huttenhower, Philip Quirke
Journal: Genome Medicine (2021)

Abstract Background The incidence of colorectal cancer (CRC) is increasing in developing countries, yet limited research on the CRC- associated microbiota has been conducted in these areas, in part due to scarce resources, facilities, and the difficulty of fresh or frozen stool storage/transport. Here, we aimed (1) to establish a broad representation of diverse developing countries (Argentina, Chile, India, and Vietnam); (2) to validate a ‘resource-light’ sample-collection protocol translatable in these settings using guaiac faecal occult blood test (gFOBT) cards stored and, importantly, shipped internationally at room temperature; (3) to perform initial profiling of the collective CRC-associated microbiome of these developing countries; and (4) to compare this quantitatively with established CRC biomarkers from developed countries. Methods We assessed the effect of international storage and transport at room temperature by replicating gFOBT from five UK volunteers, storing two in the UK, and sending replicates to institutes in the four countries. Next, to determine the effect of prolonged UK storage, DNA extraction replicates for a subset of samples were performed up to 252 days apart. To profile the CRC-associated microbiome of developing countries, gFOBT were collected from 41 treatment-naïve CRC patients and 40 non-CRC controls from across the four institutes, and V4 16S rRNA gene sequencing was performed. Finally, we constructed a random forest (RF) model that was trained and tested against existing datasets from developed countries. Results The microbiome was stably assayed when samples were stored/transported at room temperature and after prolonged UK storage. Large-scale microbiome structure was separated by country and continent, with a smaller effect from CRC. Importantly, the RF model performed similarly to models trained using external datasets and identified similar taxa of importance ( Parvimonas , Peptostreptococcus , Fusobacterium , Alistipes , and Escherichia ). Conclusions This study demonstrates that gFOBT, stored and transported at room temperature, represents a suitable method of faecal sample collection for amplicon-based microbiome biomarkers in developing countries and suggests a CRC-faecal microbiome association that is consistent between developed and developing countries.
Abstract 10866: Cardioversion Outcomes After Left Atrial Appendage Occlusion With the Watchman Device
Authors: Simrat Kaur, Erika Hutt, Walid I Saliba, Mohamed H Kanj, Khaldoun Tarkaji, Bryan Baranowski, Daniel J Cantillon, John Rickard, Thomas J Dresing, Thomas D Callahan, Mandeep Bhargava, Oussama M Wazni, Samir R Kapadia, Ayman Hussein
Journal: Circulation (2019)

Introduction: The population of patients with Watchman devices (Boston Scientific,USA) for stroke prevention in atrial fibrillation (AF) is growing. Little is known about anti coagulation managemen...
Involvement of Transient Receptor Potential Vanilloid Channel 2 in the Induction of Lubricin and Suppression of Ectopic Endochondral Ossification in Mouse Articular Cartilage
Authors: Hideki Nakamoto, Yuki Katanosaka, Ryota Chijimatsu, Daisuke Mori, Fengjun Xuan, Fumiko Yano, Yasunori Omata, Yuji Maenohara, Yasutaka Murahashi, Kohei Kawaguchi, Ryota Yamagami, Hiroshi Inui, Shuji Taketomi, Yuki Taniguchi, Motoi Kanagawa, Keiji Naruse, Sakae Tanaka, Taku Saito
Journal: Arthritis & Rheumatology (2021)

Objective Transient receptor potential vanilloid channel 2 (TRPV2) is a Ca 2+ ‐permeable channel and plays a role in mediating intracellular Ca 2+ current via mechanical stimuli. This study was undertaken to examine the expression and role of TRPV2 in adult articular cartilage and the development of osteoarthritis (OA). Methods We examined TRPV2 expression in mouse and human articular cartilage. We analyzed the development of OA in Col2a1‐Cre ERt2 ; Trpv2 fl/fl mice and Trpv2 fl/fl littermates in the resection of the medial meniscus and medial collateral ligament model (n = 5 each), the destabilization of the medial meniscus model (n = 5 each), and the aging mouse model (n = 8–9 each). We examined marker protein expression in these joints, Ca 2+ influx by mechanical stimuli, and downstream pathways in vitro. Results TRPV2 was expressed in mouse and human articular cartilage and ectopic ossification lesions. In all mouse models of OA examined, Col2a1‐Cre ERt2 ; Trpv2 fl/fl mice were observed to have enhanced degradation of articular cartilage accompanied by decreased expression of lubricin/ Prg 4 , and marked formation of periarticular ectopic ossification. Mechanical stress–induced Ca 2+ influx was decreased by Trpv2 knockout (KO). Prg4 induction by fluid‐flow shear stress was diminished in Trpv2 ‐KO mouse chondrocytes, and this was mediated by the Ca 2+ /calmodulin‐dependent protein kinase kinase‐cyclic AMP response element binding protein axis. Hypertrophic differentiation was enhanced in Trpv2 ‐KO mouse chondrocytes. Increased activity of calcineurin and nuclear translocation of nuclear factor in activated T cells 1 induced by fluid‐flow shear stress or TRP agonist treatment was reversed by Trpv2 knockout. Conclusion Our findings demonstrate regulation of articular cartilage by TRPV2 through Prg4 induction and suppression of ectopic ossification.
ACCF/ASNC/ACR/AHA/ASE/SCCT/SCMR/SNM 2009 Appropriate Use Criteria for Cardiac Radionuclide Imaging. A Report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, the American Society of Nuclear Cardiology, the America
Authors: Handel Rc, Berman Ds, Di Carli Mf, Paul A. Heidenreich, Henkin Re, Pellikka Pa, Pohost Gm, Williams Ka
Journal: Circulation (2009)
Abstract 15737: Deficiency of Mitochondrial Calcium Uniporter Protects Mouse Hearts From Iron Overload by Attenuating Ferroptosis
Authors: Nadezhda Fefelova, Suwakon Wongjaikam, Natthaphat Siri-Angkul, Judith Gwathmey, Nipon Chattipakorn, Siriporn Chattipakorn, Lai-Hua Xie
Journal: Circulation (2020)

Iron (Fe) plays essential roles in many physiological processes. Hereditary hemochromatosis and frequent blood transfusions result in iron overload (IO) and dysfunction of iron-deposited organs including the heart. Although IO-induced cardiomyopathy remains a significant clinical challenge, the underlying mechanism is not well defined. In the present study, we aim to assess the involvement of the mitochondrial Ca uniporter (mCU) in IO-induced cardiac contractile dysfunction and ferroptosis. In a chronic IO model, after receiving Fe (dextran, i.p. 0.6 mg/g, 3 days/wk) for 6 weeks, systolic function (LVEF and LVFS) was reduced in mCU +/+ (WT) compared to mCU -/- (mCU KO). This observation was confirmed in isolated ventricular myocytes where we similarly detected a significant decrease in cell shortening in WT, but not mCU KO myocytes. We found lower Fe levels in mitochondria from mCU KO myocytes compared to WT, while observing the same level of Fe deposition in heart tissue from both groups. The mitochondrial ROS level was lower in mCU KO myocytes vs. WT. Long term cardiac dysfunction may result in myocyte cell death, however, we did not detect apoptosis (TUNEL) in either mCU KO or in WT hearts with cardiac dysfunction after chronic IO. The lipid oxidation level was increased with Fe load suggesting ferroptosis may be involved in IO-induced cardiomyopathy, which was supported by the observation that administration of the selective ferroptosis inhibitor ferrostatin-1 reduced lipid oxidation (4-HNE) and maintained heart function. To further determine the role of mCU in IO-mediated ferroptosis in the heart, we used isolated myocytes from WT and mCU KO and conducted Live/Dead cell viability assays. While Fe (FAC, 0.1-5 mM) induced ferroptosis in a dose-dependent manner, it was prevented by ferrostatin-1 (10 μM), the Fe chelator 2,2'-bipyridyl (2 mM), and MitoTEMPO (5 μM), respectively. Fe-induced ferroptosis in mCU KO myocytes did not occur while the lipid oxidation level (Liperfluo) remained low. In conclusion, mitochondrial Fe uptake, presumably mediated by mCU, accounts for the molecular/cellular mechanisms for Fe-induced myocyte ferroptosis and cardiomyopathy. Cardiac-specific deficiency of mCU prevents the development of Fe induced cardiomyopathy.
Abstract 120: Epidemiology and Outcomes of Cardiopulmonary Resuscitation Events in the Neonatal Intensive Care Unit
Authors: Kaashif A Ahmad, Steven G Velasquez, Cody L Henderson, Katy L Kohlleppel, Jaclyn M LeVan, Christina M Stine, Utpal S Bhalala
Journal: Circulation (2018)

Introduction: Limited data exists regarding cardiopulmonary resuscitation (CPR) in infants in the Neonatal Intensive Care Unit (NICU). Objectives included determining the incidence, demographics, diagnoses, and outcomes of infants who require CPR across 10 NICUs in San Antonio, Texas. Methods: We conducted a retrospective review of in-NICU CPR events requiring chest compressions for 1 minute from 2012 - 2017. Included NICUs provided the following levels of care: two level IV, two high acuity level III, four low acuity level III, and two level II. Case identification occurred by reviewing death summaries and CPR coding in the electronic medical record. Results: In total, 139 infants (81 or 58% male) required 211 episodes of CPR. CPR incidence per 1000 patient days was 0.68, 0.37, 0.02 and 0 among level IV, high acuity level III, low acuity level III, and level II NICUs, respectively. Median birth weight was 945 (IQR 630, 2243) grams, gestational age at birth 27 (IQR 24, 34) weeks and age at CPR 11 (IQR 1, 42) days. Only 27 events (13%) occurred in term infants. Ninety-three CPR events (44%) had a primary respiratory etiology, 38 (18%) circulatory, 36 (17%) infectious, and 24 (11%) metabolic. Term and preterm infants had significantly different CPR etiologies (p=0.036). Circulatory etiologies were more common in term infants (37% vs 15%) with respiratory etiologies being less common (33.3% vs 46.2%). The most common rhythm documented leading to initiation of CPR was bradycardia (63%), followed by asystole (19%), and pulseless electrical activity (14%). The median duration of CPR was 10 (IQR 4, 25.5) minutes and chest compressions 8 (IQR 3, 18) minutes. While 135 of 211 CPR events (64%) had ROSC, only 22 of 139 patients (16%) survived to hospital discharge. The rate of ROSC among Level IV NICUs was significantly higher than in high acuity level III NICUs (68.2% vs 51.9%, p = 0.034). Conclusions: NICU CPR events occur most commonly in premature infants and are respiratory in origin. Bradycardia is the most common initial rhythm requiring CPR in the NICU. The incidence of CPR and the rate of ROSC are higher in level IV than level III NICUs. Further investigation is needed into factors associated with ROSC for in-NICU CPR.
Coronial necropsies show the indirect damage from covid-19
Authors: Sebastian B Lucas
Journal: BMJ (2021)

The SARS-CoV-2 pandemic is impacting non-covid care to a greater extent than reducing normal in-hospital care for cancer and urgent cardiac surgery. 1 It is associated with excess deaths in the community from diseases that would normally be diagnosed and treated by GPs and emergency hospital doctors.Pathologists performing medico-legal necropsies see these: Pell and colleagues identified acute myocardial infarction, diabetic ketoacidosis, alcoholism, and suicide in this category. 2I add to this list, as consequences of fear of attending hospital, falciparum malaria, venous thromboembolism, and maternal death following self-delivery at home.Such data will not be identified from Office for National Statistics cause of death certification alone, and many of these indirect deaths from covid-19 will not be subject to an inquest.Epidemiologists must examine the detailed necropsy reports to identify and quantify these deaths as the collateral damage from the pandemic.Coroners and fiscals should be making the reports available, rather than-as at present-confidential.
TP53 Mutations Are a Rare Event in Primary Myelofibrosis, Associated with TET2 Mutations, and Suggest Poor Clinical Outcome
Authors: Mohammad Omar Hussaini, Jinming Song, Rami S. Komrokji, David A Sallman, Andrew Kuykendall, Eric Padron, Sayeef Mirza, Ling Zhang
Journal: Blood (2017)