tbuckley/cabot-search huggingface dataset:
Design, synthesis, and biological evaluation of Bcr-Abl PROTACs to overcome T315I mutation
Authors: Liang Jiang, Yuting Wang, Qian Li, Zhengchao Tu, Sihua Zhu, Sanfang Tu, Zhang Zhang, Ke Ding, Xiaoyun Lu
Journal: Acta Pharmaceutica Sinica B (2020)

Bcr-Abl threonine 315 to isoleucine 315 (T315I) gatekeeper mutation induced drug resistance remains an unmet clinical challenge for the treatment of chronic myeloid leukemia (CML). Chemical degradation of Bcr-AblT315I protein has become a potential strategy to overcome drug resistance. Herein, we first described the design, synthesis, and evaluation of a new class of selective Bcr-AblT315I proteolysis-targeting chimeric (PROTAC) degraders based on GZD824 (reported as Bcr-AblT315I inhibitor by our group). One of the degrader 7o with 6-member carbon chain linkage with pomalidomide exhibits the most potent degradation efficacy with DR of 69.89% and 94.23% at 100 and 300 nmol/L, respectively, and has an IC50 value of 26.8 ± 9.7 nmol/L against Ba/F3T315I cells. Further, 7o also displays substantial tumor regression against Ba/F3-Bcr-AblT315I xenograft model in vivo.
Abstract 15488: Epidemiological Profile of Cardiovascular Risk Factors and Outcomes in Patients With Solid Organ and Haematological Malignancies
Authors: David Chandrakumar, Gary Gan, Urmi Jethwani, Cindy Li, Aaia Aladdin, Prajith Jeyaprakash, Aditya Bhat, Amanda Johnston, Fiona Kwok, Marielle Scherrer-crosbie, Timothy C Tan
Journal: Circulation (2020)

Introduction: Chemotherapy remains the cornerstone in the management of solid organ malignancies (SOM) and hematological malignancies (HM). Although life-prolonging, it is not without cost, with heart failure and arrhythmia becoming increasingly recognised complications of treatment. Although there is significant overlap in the chemotherapeutic management of SOM and HM, epidemiological information on the differential prevalence of baseline cardiovascular risk factors and outcomes in these populations is scarce. Hypothesis: A differential cardiovascular risk profile and clinical course will be appreciated in patients with SOM and HM undergoing chemotherapy. Methods: Retrospective observational study design. Patients admitted to our institution undergoing chemotherapy for SOM (2014-2018) or HM (2012-2015) were reviewed. Baseline demographic and clinical data was collated and patients were followed for up to five years following chemotherapy for occurrence of major adverse cardiac events (MACE) defined as the development of new-onset heart failure or arrhythmia. Results: 545 hematology and 435 oncology patients with malignancy were assessed. Compared to those with HM, those treated for SOM had a poorer cardiovascular risk profile (table 1). At mean follow-up period of 22.8±17.8 months, no significant difference in the incidence of the composite endpoint (9.4% vs 9.0%, p=0.45) or its components was observed. Higher rates of anthracycline therapy was observed in patients with HM (100% vs 17%, p &lt; 0.01), however its use did not have a differential effect on MACE (12% vs 9%, p=0.25). Conclusions: Compared to patients treated for HM, patients with SOM had a greater burden of cardiovascular risk factors and lower use of anthracycline chemotherapy. Despite this, MACE occurred at similar rates in both groups. The use of anthracyclines was not associated with the development of MACE, suggesting alternative pathways contributing to its development.
Abstract 14178: Characteristics and Outcomes of Young ST Segment Elevation Myocardial Infarction Patients Undergoing Primary Percutaneous Intervention
Authors: Benjamin W Tung, Zhe Yan Ng, William Kristanto, Kalyar W Saw, winnie C sia, Siew Pang Chan, Koo Hui Chan, Mark Chan, Ronald C Lee, Joshua Loh, Adrian F Low, Edgar Tay, Huay Cheem Tan, Tiong Cheng Yeo, Poay Huan Loh
Journal: Circulation (2020)

Introduction: ST-segment elevation myocardial infarction (STEMI) is associated with significant morbidity and mortality leading to loss of productivity and productive life years, especially in younger patients. Understanding the characteristics of younger patients with STEMI and their outcomes could help focus public health efforts in STEMI prevention within a population. Aim: This study aims to compare the characteristics and outcomes of younger versus older patients with STEMI undergoing primary percutaneous intervention (PPCI). Methods: Data from the Coronary Care Unit database of the National University Hospital between July 2015 to June 2019 was reviewed. Patients were divided into Young (&lt;50 years old) or Old (≥50 years old) groups. Results: Of the 1818 consecutive patients with STEMI and underwent PPCI, 465 (25.6%) were Young patients with mean age 43±4.9 years old as compared to Old patients with mean age 63.2±9.4 years old. Young patients were more likely to be male (94% vs. 85%, p&lt;0.0001), current smokers (61.1% vs. 42.6%, p&lt;0.0001), of Indian ethnicity (32% vs. 16.3%, p&lt;0.0001), and had family history of myocardial infarction (MI) (18.1% vs. 9.5%, p&lt;0.0001). Compared to Old patients, Young patients had better post-MI left ventricular ejection fraction (49.5±10.7 vs. 47.8±11.6, p=0.007) with fewer of them suffered from cardiogenic shock (7.1% vs. 13.2%, p&lt;0.0001), and had lower mortality at one year (3.4% vs. 10.4%, p&lt;0.0001). Although diabetes, hypertension and hyperlipidemia was less common among the Young patients when compared to the Old, the prevalence was high in the range of 28 to 38% (Table 1). Conclusions: A sizable proportion of STEMI patients are younger than 50 years old. The risk profile of these younger patients can be attributed to constitutional factors and smoking but other cardiovascular risk factors are also prevalent among them. Although mortality is lower among the younger than the older patients, it is not negligible.
Abstract 16994: Left Ventricle Accessory Antero-Septal Papillary Muscle Detected in the LVOT Vicinity by Means of Cardiac MRI and Echocardiography in HOCM and Control Patients
Authors: George O Angheloiu, Robert W Biederman
Journal: Circulation (2020)

Background: We studied by means of echocardiography (echo) and cardiac MRI the occurrence of an accessory papillary muscle that unites mostly the left ventricle (LV) apex with the basal or mid antero-septum. Methods: We included all good quality studies as reviewed by two cardiologists and assessed the occurrence of a contractile papillary muscle situated between the LV apex and antero-septum. Results: A contractile accessory papillary muscle situated between the LV apex and the antero-septum was seen in 100% of HOCM patients and 62% of control patients (p=0.05, panels 1-6 HOCM patients and 7-9 controls; panels 1, 4 and 7 - diastole; 2,5 and 8 - early-systole; 3, 6 and 9 - end-systole) in the cardiac MRI images acquired from a total of 22 HOCM (9) and control (13) patients. The same structure was observed in 241 patients representing 69.5% of all-comers echo studies. The age was 69 ± 17 years on average in the echo arm, patients harboring the antero-septal accessory muscle being older (71.6 + 15.7 years old vs 63.5 ± 18.1 for those without, p=0.0005). We exemplify this structure by parasternal long axis still echo images from 24 patients (panel 14) as well as more detailed images from 4 patients in the same group (panels 10-13). Red arrows point out the accessory antero-septal papillary muscle and white arrows the antero-septum. Pink and yellow dots neighbor the regular antero-lateral and postero-medial pap muscles and the white dots the mitral valve. Conclusion: A contractile accessory papillary muscle was observed in slightly more than half of the all-comer echo studies, and in all HOCM patients in the cardiac MRI arm. Further research is needed to fully characterize the anatomical and physiological significance of this structure attaching in the immediate vicinity of the LVOT in HOCM and control patients.
Airborne spread of SARS-CoV-2 while using high-flow nasal cannula oxygen therapy: myth or reality?
Authors: Andrew Haymet, Gianluigi Li Bassi, John F. Fraser
Journal: Intensive Care Medicine (2020)

In 2020, a new pandemic caused by SARS-CoV-2 was declared [1], and since the first cases of coronavirus disease 2019 (COVID-19), clinicians had to apply different modes of respiratory support, previously used on patients with severe respiratory failure from other etiologies. In particular, high-flow nasal cannulae (HFNC) and non-invasive ventilation (NIV) were variably applied in early reports from China [2] and Europe [3]. Yet, the extent of airborne contamination of clinical areas during the use of HFNC has sparked intense debate and highlighted the need for inclusive investigation in this area.
Abstract PO-014: Interleukin 17 induced- neutrophil extracellular traps (NETs) mediate resistance to checkpoint blockade in pancreatic cancer
Authors: Vidhi Chandra, Yu Zhang, Erick Riquelme, Prasanta Dutta, Pompeyo R. Quesada, Amanda Rakoski, Michelle Zoltan, Nivedita Arora, Seyda Baydogan, William Horne, Jared Burks, Hanwen Xu, Perwez Hussain, Huamin Wang, Sonal Gupta, Anirban Maitra, Jennifer M. Bailey, Seyed J. Moghaddam, Sulagna Banerjee, Ismet Sahin, Pratip Bhattacharya, Florencia McAllister
Journal: Cancer Research (2020)

Abstract Pancreatic ductal adenocarcinoma (PDAC) continues to be an aggressive disease with an immunosuppressive tumor microenvironment, which is recalcitrant to most therapies. Interleukin-17 (IL-17), a potent pro-inflammatory cytokine, has been implicated in initiation of pancreatic premalignant lesions but its role in invasive PDAC has not been widely explored. We hypothesized that IL-17 triggers and sustains immunosuppression during PDAC. We employed pharmacological and genetic strategies to inhibit IL-17/IL-17RA signaling axis and characterized the tumor microenvironment with RNA sequencing, mass &amp; flow cytometry and quantitative multiplex immunofluorescence. Our analysis revealed that IL-17 signaled through tumor cells to recruit neutrophils into the tumor microenvironment and spatially exclude cytotoxic CD8 T cells. Furthermore, IL-17 signaling in tumor cells triggered neutrophils to form extracellular traps (NETs), a primary mechanism mediating PDAC immunosuppression. Genetic or pharmacological inhibition of IL-17 overcame resistance to immune checkpoint blockade (PD-1, CTLA-4), in a CD8 T cell dependent manner. Inhibition of neutrophils or Padi4-dependent NETosis phenocopied IL-17 neutralization. Higher expression of IL-17 and PADI4 in human PDAC corresponded with poorer prognosis, according to TCGA data. Serum from PDAC patients had a higher capacity for NET formation and diminished ability for NET degradation in control neutrophils, in comparison to serum from healthy donors. In conclusion, the cross-talk of IL-17 with pancreatic cancer cells orchestrates neutrophil recruitment and activation of Padi4 dependent NETosis, ultimately resulting in spatial remodeling of the stroma and immunosuppression. IL-17 inhibition overcomes resistance to checkpoint blockade in a CD8 T cell dependent fashion. Clinical studies with IL-17 inhibitors and checkpoint blockade represent a promising novel combinatorial therapy for this lethal disease. Citation Format: Vidhi Chandra, Yu Zhang, Erick Riquelme, Prasanta Dutta, Pompeyo R. Quesada, Amanda Rakoski, Michelle Zoltan, Nivedita Arora, Seyda Baydogan, William Horne, Jared Burks, Hanwen Xu, Perwez Hussain, Huamin Wang, Sonal Gupta, Anirban Maitra, Jennifer M. Bailey, Seyed J. Moghaddam, Sulagna Banerjee, Ismet Sahin, Pratip Bhattacharya, Florencia McAllister. Interleukin 17 induced- neutrophil extracellular traps (NETs) mediate resistance to checkpoint blockade in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-014.
Why telemedicine diminishes the doctor-patient relationship
Authors: Janet Menage
Journal: BMJ (2020)

Stokel-Walker says that telemedicine is here to stay.1

“Tele” is from the Greek, meaning “far off,” and a clinician is “a doctor having direct contact with patients.”2 Telemedicine is therefore oxymoronic, unless medicine now refers solely to the distribution of drugs and not to the clinical activity of examining patients.

How does one detect hepatomegaly, feel for lymphadenopathy, percuss the chest, elicit rebound …
Incorporating Coronary Calcification Into Pre-Test Assessment of the Likelihood of Coronary Artery Disease
Authors: Simon Winther, Samuel Emil Schmidt, Thomas Mayrhofer, Hans Erik Bøtker, Udo Hoffmann, Pamela S. Douglas, William Wijns, Jeroen Bax, Louise Nissen, Vibeke Lynggaard, Jens Juel Christiansen, Antti Saraste, Morten Bøttcher, Juhani Knuuti
Journal: Journal of the American College of Cardiology (2020)
Abstract 14250: Semi-automated Analysis of Tricuspid Regurgitation Doppler Profile for Detection and Evaluation of Pulmonary Hypertension
Authors: Seraina A Dual, Myriam Amsallem, Doff McElhinney, Roham Zamanian, Jeffrey Feinstein, Francois Haddad, Alison Marsden
Journal: Circulation (2020)

Introduction: Non-invasive detection of pulmonary hypertension relies on the tricuspid regurgitant (TR) Doppler maximal velocity (Vmax). When the TR signal is incomplete, Vmax must be estimated by extrapolation, which is prone to error. Automatic extrapolation could improve robustness but requires an in-depth understanding of complete TR shape. Semi-automated analysis was used to test the hypothesis that all waveforms can be expressed with a small set of curve parameters. Methods: We retrospectively analyzed complete continuous Doppler TR signals from 76 patients (median 50 [39, 56] years-old, 77% female) with pulmonary arterial hypertension in whom echocardiography and invasive hemodynamics were available within 3 months. Semi-automated analysis divided Doppler images into heartbeats (three signals per patient) using the ECG and recognized segmented waveforms for shape analysis. Multiple linear regression modeling assessed the independent association between waveform features (Vmax, velocity-time integral, curve width, skewness (t1,t2), kurtosis and time scale) and age, sex, pulmonary vascular resistance (PVR), TR severity, right ventricular (RV) end-diastolic area index (size), RV strain (function) and right atrial volume index. Results: TR waveforms were non-Gaussian with varying skewness, width and kurtosis. Figure summarizes the covariates associated with TR waveform features. Vmax was directly related to PVR and RV strain, but not to TR severity. The RR-normalized width was correlated to heart rate, TR severity, RV strain and size (all p&lt;0.0001). Kurtosis was not only associated with heart rate but also with PVR, TR severity, RV strain and size (all p&lt;0.01). Conclusions: The non-Gaussian TR Doppler curve shape is influenced by TR severity, RV function and size. The high variability in shape limits the ability to extrapolate signals in the presence of an incomplete envelope. Machine learning algorithms may be valuable to address this issue.
Activity Within an Extraperitoneal Ureteral Herniation Detected on Bone Scan, Associated With a Partially Duplicated Collecting System
Authors: Robert Robbins, Roopa Bhat, Mohamed Baqar, Amolak Singh
Journal: Clinical Nuclear Medicine (2020)

Abstract A 64-year-old man with history of renal stones and prostate cancer presented for evaluation of osseous metastatic disease due to elevated prostate-specific antigen (13.7 ng/mL). A 99m Tc-labeled bone scan demonstrated unusual linear uptake projecting over the lower pelvis extending into the scrotum. Follow-up CT confirmed a rare case of inguinoscrotal extraperitoneal herniation of the ureter associated with a partially duplicated left renal collecting system. The left-sided inguinoscrotal uptake was within the herniated ureter, potentially mimicking disease within the pelvis.
THU0223 Treatment of a patient with nonclassified hla b27 associated destructive oligoarthritis with anti tnf: clinical outcome and effects on nf-kappa b activity in pbmc
Authors: T Geiler, R Voll, HM Lorenz, C Dechant, B Manger, JR Kalden
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> We report the case of a 38 years old HLA B27 positive male with a 11 year history of a destructive nonclassified oligoarthritis. While the first 6 years of the disease have been dominated by a relapsing nondestructive synovitis of the right knee joint and a asymptomatic sacroileitis treated with NSAID`s alone the disease began to spread in a destructive manner to the right wrist and foot (MTP I-V, PIP I-V, DIP I-V). Additionally, a painful tenosynovitis of the flexor and extensor tendons of both feet occured. Despite intensifying the pharmacological treatment by high doses of corticosteroides (up to 100 mg/d) and methotrexate (25 mg/week) for 9 month the disease showed significant clinical and radiological progress. No reduction of the constantly elevated ESR and CRP could be achieved. By initiating a therapy with anti TNF (Remicade<sup> TM</sup>) at a dose of 5 mg/kg body weight all clinical symptoms disappeared completely within 8 h after the first infusion of the antibody. ESR and CRP normalised within 6 days. The patient stayed completely free of symptoms since, side effects have not been detected by now. Repeated infusions after 2, 4, 6 and 14 weeks did not further improve the therapeutic benefit but were given to sustain the therapeutic effect. <h3>Objectives</h3> Since TNF is known as a strong activator of NF-κB which is strongly involved in the production of proinflammatory cytokines and matrix metalloproteinases we looked for the activity of this transcription factor in PBMC`s of this patient by electro mobility shift assays (EMSA). <h3>Methods</h3> Cells were obtained immediately before the infusions were started and 1 h and 24 h after end of infusions. Cell preparations and EMSA were done according standard protocols. <h3>Results</h3> There was substantial NF-κB activity in PBMC`s before first antibody treatment. Anti TNF treatment decreased NF-κB activity detectable already 1 h after first infusion. The NF-κB activity was further inhibited 24 h after first infusion and remained low during the whole treatment period in accordance to the persisting clinical improvement. <h3>Conclusion</h3> In the treatment of patients with progressive nonclassified HLA B27 oligoarthritis resistent to classical treatment with NSAID`s, corticosteroids and DMARD`s the use of TNF blocking agents should be considered. As in other destructive inflammatory joint diseases NF-κB might play a crucial role in the pathogenesis of joint destruction in HLA B27 associated arthritides. The clinical improvement appears to be associated with a persistent and marked inhibition of NF-kappa B.
Abstract 14345: <i>Cardiopulmonary Best Abstract Award:</i> Improves Right Ventricular - Pulmonary Arterial Coupling and Right Ventricular Function in the Pulsar Study: A Phase 2, Double-blind, Placebo-controlled, Randomized Study to Compare the Efficacy and Safety of Sotatercept versus Placebo When Added to Standard of Care for the Treatment of Pulmonary Arterial Hypertension (PAH)
Authors: Vallerie McLaughlin, Mardi Gomberg-maitland, Solaiappan Manimaran, Jonathan Lu, Simon Gibbs, Carrie Barron
Journal: Circulation (2020)

Background: The right ventricle (RV) and pulmonary arteries become uncoupled as RV function deteriorates in PAH, a consequence of pulmonary vascular remodeling which is ultimately fatal. Restoration of RV-PA coupling and RV function is a crucial aim of PAH treatment. Preclinically, sotatercept, a first-in-class fusion protein, has been shown to reverse right heart remodeling and improve right heart structure and function and acts by suppressing TGF-β signaling and rebalancing BMPR2 signaling. The PULSAR study (NCT03496207, EudraCT 2017-004738-27) released positive topline results earlier this year. Methods: The PULSAR study enrolled 106 patients with WHO Group 1 PAH and WHO functional classes (FC) II-III; age ≥18; pulmonary vascular resistance of ≥5 Wood units by right heart catheterization; stable PAH standard of care (SOC) therapy (all combinations allowed). Sotatercept was administered by SC injection every 21 days for a 24-week double-blind, placebo-controlled treatment period in 3 arms: placebo + SOC, 0.3 mg/kg sotatercept + SOC, 0.7 mg/kg sotatercept + SOC. 2D Doppler echocardiography was performed at baseline and 24 weeks and read in a central laboratory. RV-PA coupling was assessed by TAPSE/PASP. Results: Significant improvement was seen in LS mean (SE) change from baseline to week 24 in RV-PA coupling, RVFAC, RVEDA, RVESA, PASP, and RAP in both sotatercept dose level groups vs placebo. No changes were seen in TAPSE or, notably, in CO. For RV-PA coupling, all patients started below the 0.31 mm/mmHg prognostic threshold; both treatment arms improved above that threshold by 24 weeks while the placebo arm remained below. Conclusions: In the PULSAR study, treatment with sotatercept compared to placebo was associated with statistically significant improvements in RV-PA coupling and RV function. Sotatercept has the potential to be a new treatment option for PAH patients with consistent and encouraging effects on RV-PA coupling and RV function.
Abstract 275: Cardiac Arrest Etiology and Associated Cognitive Impairment in Survivors
Authors: Allison C Koller, Jon C Rittenberger, Thomas J Songer, Andrea L Rosso, Jessica E Salerno, Patrick J Coppler, Clifton W Callaway
Journal: Circulation (2020)

Background: Cardiac arrest is a significant public health problem, impacting over 500,000 people in the United States annually. The four major etiologies of arrest are cardiac, respiratory, traumatic, and other. The objective was to determine the impact of etiology on cognition in cardiac arrest survivors using the Montreal Cognitive Assessment (MOCA). Hypothesis: Cardiac arrest etiology impacts cognitive exam score, and patient demographics and characteristics modify that relationship. Methods: A retrospective cohort analysis was performed on all Pittsburgh Post Cardiac Arrest Service (PCAS) patients from 2012-18. Data were acquired through medical record review. T-tests, linear and logistic regression were used to assess the relationships between exam score and modifying factors. MOCA score was analyzed as a binomial variable using a pass/fail threshold of 26/30 points (86.7%) and above for normal cognition. For statistical significance, an alpha level of 0.05 was used. Results: In total, 192 patients completed the MOCA: 104 with cardiac etiology, 35 with respiratory, 4 with trauma, and 49 with other. Median age for all patients was 59.3 years, and 58% were male. Mean (SE) MOCA score for all patients was 72.8 (1.1) percent. When MOCA score was converted to a binomial indicator of normal cognition, respiratory, traumatic, and other etiologies were more likely to exhibit impairment than cardiac etiology arrest when age, sex, witnessed status, length of ICU stay and coma were controlled for (OR: 2.52, 3.43, 2.18 respectively). These findings were nullified when time from arrest to MOCA administration was included. Of the MOCA subcategories, delayed recall was the most severely impacted, with patients recalling an average of 1.67 of 5 words after 5 minutes. Additionally, respiratory arrests performed significantly worse than cardiac etiology arrests in attention (4.1 vs 4.9 points, p=0.004) and language domains (1.9 vs. 2.3, p=0.04). Conclusions: Respiratory, traumatic, and other etiologies were more likely to exhibit abnormal cognition on the MOCA than those with a cardiac etiology. The etiological findings were nullified when time to cognitive examination was controlled for. Timing appears to influence cognitive assessments more than etiology.