tbuckley/cabot-search huggingface dataset:
Blood Biomarkers for Use in Alzheimer Disease—Moving From “If” to “How?”
Authors: Sid E. O’Bryant
Journal: JAMA Neurology (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal
Abstract 18942: Inhibition of β-arrestin 1 Prevents post-MI Maladaptive Ventricular Remodeling
Authors: Md Abdur Razzaque, Xianyao Xu, Abbasali Badami, Peter Klepacz, Mei Han, Jennifer L Philip, Shahab A Akhter
Journal: Circulation (2015)

Remote (non-infarct) territory fibrosis is a significant cause of post-myocardial infarction (MI) heart failure (HF). We have previously shown that increased activity of β-arrestin 1 in adult human cardiac fibroblasts (CF) isolated from failing hearts is an important mechanism of cardiac fibrosis. This study investigates the potential therapeutic role of β-arrestin 1 inhibition on CF biology in vivo. Adult male rats underwent LAD ligation to induce post-MI HF. β-arrestin 1 was inhibited by intra-coronary adenoviral-mediated delivery of a β-arrestin 1 inhibitor (Ad-Barr1ct) immediately following LAD ligation (n=11). Ad-Barr1ct contains a rat β-arrestin 1 C-terminal fragment (aa. 369-418). Control rats received a null adenovirus (n=10). Animals were studied prior to and up to 8 weeks (wks) post-MI and adenoviral delivery. There was a significant decline in LV function at 8 wks post-MI in Ad-null rats vs. pre-MI. Remote territory (non-infarct area) fibrosis increased by 8 wks post-MI consistent with adverse remodeling. Intra-coronary delivery of Ad-Barr1ct following LAD ligation significantly inhibited post-MI LV dysfunction vs. Ad-Null as measured by improved fractional shortening and ejection fraction. Ad-Barr1ct also decreased peri-infarct and remote territory fibrosis. Consistent with these findings, Ad-arr1ct resulted in decreased α-SMA, collagen I, collegen III and fibronectin expression in CF isolated 8 wks post-MI vs. Ad-Null providing evidence of decreased post-MI CF activation and myofibroblast transformation with Ad-Barr1ct. Targeted inhibition of β-arrestin 1 in the heart may represent a novel therapeutic approach to prevent pathological fibrosis and maladaptive remodeling post-MI.
OSCA: a tool for omic-data-based complex trait analysis
Authors: Futao Zhang, Wenhan Chen, Zhihong Zhu, Qian Zhang, Marta F. Nabais, Ting Qi, Ian J. Deary, Naomi R. Wray, Peter M. Visscher, Allan F. McRae, Jian Yang
Journal: Genome biology (2019)

The rapid increase of omic data has greatly facilitated the investigation of associations between omic profiles such as DNA methylation (DNAm) and complex traits in large cohorts. Here, we propose a mixed-linear-model-based method called MOMENT that tests for association between a DNAm probe and trait with all other distal probes fitted in multiple random-effect components to account for unobserved confounders. We demonstrate by simulations that MOMENT shows a lower false positive rate and more robustness than existing methods. MOMENT has been implemented in a versatile software package called OSCA together with a number of other implementations for omic-data-based analyses.
Emerging Concepts in Precision Medicine and Cardiovascular Diseases in Racial and Ethnic Minority Populations
Authors: George A. Mensah, Cashell Jaquish, Pothur Srinivas, George J. Papanicolaou, Gina S. Wei, Nicole Redmond, Megan C. Roberts, Cheryl Nelson, Larissa Aviles-Santa, Mona Puggal, Melissa C. Green Parker, Mollie A. Minear, Whitney Barfield, Kathleen N. Fenton, Cheryl Anne Boyce, Michael M. Engelgau, Muin J. Khoury
Journal: Circulation Research (2019)

Cardiovascular diseases remain the leading cause of mortality and a major contributor to preventable deaths worldwide. The dominant modifiable risk factors and the social and environmental determinants that increase cardiovascular risk are known, and collectively, are as important in racial and ethnic minority populations as they are in majority populations. Their prevention and treatment remain the foundation for cardiovascular health promotion and disease prevention. Genetic and epigenetic factors are increasingly recognized as important contributors to cardiovascular risk and provide an opportunity for advancing precision cardiovascular medicine. In this review, we explore emerging concepts at the interface of precision medicine and cardiovascular disease in racial and ethnic minority populations. Important among these are the lack of racial and ethnic diversity in genomics studies and biorepositories; the resulting misclassification of benign variants as pathogenic in minorities; and the importance of ensuring ancestry-matched controls in variant interpretation. We address the relevance of epigenetics, pharmacogenomics, genetic testing and counseling, and their social and cultural implications. We also examine the potential impact of precision medicine on racial and ethnic disparities. The National Institutes of Health’s All of Us Research Program and the National Heart, Lung, and Blood Institute’s Trans-Omics for Precision Medicine Initiative are presented as examples of research programs at the forefront of precision medicine and diversity to explore research implications in minorities. We conclude with an overview of implementation research challenges in precision medicine and the ethical implications in minority populations. Successful implementation of precision medicine in cardiovascular disease in minority populations will benefit from strategies that directly address diversity and inclusion in genomics research and go beyond race and ethnicity to explore ancestry-matched controls, as well as geographic, cultural, social, and environmental determinants of health.
Cardiovascular Corner
Authors: Jennifer Abbasi
Journal: JAMA (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Recent advances inde novo design strategy for practical lead identification
Authors: Teruki Honma
Journal: Medicinal Research Reviews (2003)

Abstract De novo design programs such as LEGEND, LUDI, and LeapFrog can identify novel structures that are predicted to fit the active site of a target protein. However, in the conventional de novo design strategy, the output structures obtained from the programs can be problematic with regard to synthetic accessibility and binding affinity prediction. Thus it has been practically difficult to obtain novel lead compounds that are appropriate for medicinal chemists through the de novo design strategy. Since the late 1990s, several new strategies for lead identification have been reported and the successful examples have been disclosed. One of the strategies is validation of small fragments, which can be substructures of de novo ligands, by using NMR, X‐ray, or MS spectra. Another method is prioritization of output structures obtained from de novo design programs by chemical accessibility. This review describes these new strategies with practical applications and future perspectives of de novo design. © 2003 Wiley Periodicals, Inc. Med Res Rev, 23, No. 5, 606–632, 2003
Francis John Bennett
Authors: Jennifer Bennett, Jian Farhoumand
Journal: BMJ (2019)

Francis John Bennett (known as John) devoted his life to the improvement of public health throughout Africa, and is regarded as the “Father of Primary Health Care in Africa.” He was born in Sesheke, Barotseland (now Zambia), a rural village surrounded by swamps and forests. When John was 5 years old he was sent to boarding school in a neighbouring country by way of dug-out canoe on the river, then narrow-gauge railway through a logging plantation, and finally a steam train. Thanks to this childhood, John became a true renaissance man. Outside medicine his wider interests and knowledge spanned anthropology, zoology, ornithology, herpetology, botany, and geology. Some of …
PB2424 AUGMENTED AND SYNERGISTIC EFFECT OF FACTOR V LEIDEN (FVL) AND MTHFR GENES POLYMORPHISMS AND PLATELET ACTIVITY AND REACTIVITY AS RISK FACTORS FOR ISCHEMIC CEREBROVASCULAR STROKE (IS)
Authors: A.E.S. Abdelhamid, H.‐A. Hassan Nashaat, A. Sayed Ahmed, A. O. Hosny, A.M. Hassan, M.A.A. ELSamahy, M.A.S. Abdelhamid
Journal: HemaSphere (2019)

Background: Ischemic cerebrovascular stroke (IS) is a polygenic multifactorial disease; effect of thrombotic gene polymorphism, platelet activation and reactivation synergistic risk effect are plausible postulation. Aims: To assess synergistic effect of FVL and MTHFR genes polymorphisms and platelet activity and reactivity as risk factors for ischemic cerebrovascular stroke Methods: A hospital‐based case‐control study; approvered by Suez Canal University (SCU) ethical committee, after obtaining an informed consent. 120 individuals were included: 60 acute IS patients, subdivided into 2 subgroups regarding the vascular risk factors recruited from neurology department, SCU Hospital; and 60 matched healthy individuals. FVL G1691A, FVLA4070G, FVL A5279G, MTHFRC677T, and MTHFR A1298C were assessed using multiplex real‐time PCR assay (AnyplexTM II Thrombosis SNP Panel Assay, seegene); platelet ex vivo activity &amp; reactivity (CD62P; after ADP provocation) were assessed by four‐colors flow cytometry, FACS Caliber, BD‐Biosciences). Results: Both FVLG1691A &amp; FVL A4070G (OR 19.6; 95 % CI = 2.5 to 154.4; p = 0.0001), (OR 7.6; 95 % CI = 1.13 to 178; p = 0.012), and MTHFRC677T (OR 10; 95 % CI = 1.16to 85.8; p = 0.03) and MTHFRA1298C (OR 11.6; 95 % CI = 1.35to 100.7; p = 0.03) &amp; the presence of &gt;1 mutation (p &lt; 0.0001) showed a statistically significant association with IS. Multivariate logistic regression models showed that studied SNPs add synergistic effect on the vascular risk factors. A statistically significant difference was detected in platelet CD62p % after adding ADP (IS patients: 72.95 ± 14.8 ‐ controls: 62.2 ± 11.39), MFI IS patients: 248 ± 101‐controls 215 ± 75.8). both FVLG1691A and MTHFRC677T were significantly associated with higher baseline platelet activation in the co‐dominant and recessive models for FVLG1691A and in the dominant model for MTHFRC677T Summary/Conclusion: FVLG1691A, FVL14070G, MTHFRC677T &amp; MTHFRA1298C were independent risk factors for IS especially in younger patients &amp; existence of &gt;1 mutation significantly increased IS risk, platelet activity and reactivity and genetic polymorphism play a potential synergistic role increasing the risk of IS. image
PB2174 EPIDEMIOLOGY OF MULTIPLE MYELOMA (MM) IN MOSCOW (RUSSIA)
Authors: V. Ptushkin, O. Vinogradova, M. Chernikov, Y. Kochkareva, V. Zherebtsova, Y. Kobzev, E. Markova, D. Shikhbabaeva
Journal: HemaSphere (2019)

Background: The incidence of MM varies greatly between countries, but since 1990 it has increased steadily. Despite improvements in the care of patients with MM, these advances have largely delivered better outcomes to patients in high‐income countries. Moscow is a big city (12.6 million inhabitants in 2018) with relatively identical protocols for the diagnosis, staging and treatment of MM. Aims: To evaluate the incidence and mortality of MM depending on age, gender and year of observation in Moscow in 2009–2019. Methods Data of 3,942 MM patients (pts) who reside in Moscow and were treated at Moscow City Hematology Center (Botkin Hospital) have been studied. It was collected from out‐ and in‐patient clinical records and state registries. The period from 2009 through 2019 was analyzed. The median follow up of patients since the diagnosis of MM was 34 (1 ‐ 423) months. Results: Among the registered 3,942 patients with MM, 1,707 were men (43%) and 2,241 women (57%). The median age at diagnosis was 65 (23–93) years. For men, it was 63 (23–93), for women ‐ 66 (29–92) years. Most of the patients were older than 65 ‐ 2047 (51.9%). Over the 10‐year period, the median age at diagnosis has increased by 3 years ‐ from 64 to 67 years. The average annual MM incidence recorded for 10 years increased by 60.52% ‐ from 1.9 to 3.05 per 100,000 population. However, such increase in the incidence was observed only for a cohort of patients older than 50 years, achieving a peak in the age range of 60 ‐ 69 years. Prevalence rate (PR) of MM has grown from 8.0 per 100,000 population in 2009 to 15.2 in 2018, mostly due to improved therapy outcomes. 2‐year overall survival was 76%, 5‐year ‐ 49%, and 10‐year ‐27%. Median overall survival of pts younger than 65 years of age at diagnosis was 79 months, 65 and older–48 months. Summary/Conclusion: Significant changes in MM epidemiology in the City of Moscow were observed. In the last 10 years, the incidence has increased mostly due to the increase of life expectancy, whereas improved MM diagnostics and treatment resulted in substantial increase in OS. In turn, this have caused MM PR increase, and this trend will most likely continue in the future.
FRI0200 REVIEW OF HYDROXYCHLOROQUINE USE AND DEVELOPMENT OF A REGIONAL STRATEGY TO MINIMISE RETINAL TOXICITY
Authors: Ursula Laverty, Gerard Reid, Julie Silvestri, Adrian Pendleton
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Guidelines from the Royal College of Opthalmologists in February 2018 were developed for retinal screening for patients on hydroxychloroquine, as recent evidence suggests the risk of retinal toxicity is higher than previously reported. The prevalence of retinal toxicity in long term use appears to be 7.5% and depending on dose and duration of therapy can increase to 20-50% after 20 years of therapy. Risk is increased for patients taking more than 5mg per kg per day of hydroxychloroquine, patients on Tamoxifen and those with renal impairment. The guidelines recommend the use of a standardised referral proforma to help identify patients who are high risk. <h3>Objectives:</h3> 1. Audit of Hydroxychloroquine use and retinal screening in the Belfast Health and Social Care Trust (BHSCT) 2. Develop a regional referral proforma and screening service for retinal toxicity <h3>Methods:</h3> Patients who were treated with hydroxychloroquine, under the care of a consultant rheumatologist were identified on the database. A proforma was used to aid data collection and patients' electronic records were reviewed. We audited the use of hydroxychloroquine and retinal screening against current Royal College of Ophthalmology (RCO) guidelines. We designed a standardised referral proforma and regional screening strategy in conjunction with ophthalmology colleagues. <h3>Results:</h3> There were 151 patients identified on hydroxychloroquine on the database. 40 of these patients had stopped hydroxychloroquine, 2 of which had retinal toxicity. Therefore the rate of retinal toxicity in this sample was 1.3% (2/151). There were 111 patients who remained on hydroxychloroquine treatment with a female: male ratio of 9:1. Age range was from 22 to 84, with a mean age of 55. There were 44% of patients on hydroxychloroquine for rheumatoid arthritis, 25% had systemic lupus erythematosus, 8% had Sjogrens syndrome, 6% had pallindromic rheumatoid arthritis and 13% had other connective tissue diseases. The majority (79%) of patients were on 200mg hydroxychloroquine daily and 19% were on 400mg daily. 6% of patients had an eGFR&lt;60. No patients were on tamoxifen. 73% of patients were on hydroxychloroquine treatment for over 5 years. Retinal screening was overdue in 64% of patients. <h3>Conclusion:</h3> In this sample, only 1.3% of patients had evidence of retinal toxicity, although 64% of patients were overdue retinal screening. We developed a referral proforma and a regional screening strategy in line with RCO guidelines. In order to meet the RCO guidelines, we recognise the need for substantial investment in regional ophthalmology services. <h3>References:</h3> [1] Royal College of Ophthalmologists. (2018) Clinical Guidelines. Hydroxychloroquine and Chloroquine Retinopathy:Recommendations on Screening. <h3>Disclosure of Interests:</h3> None declared
Interim safety analysis of a compassionate-use program (CUP) and early-access program (EAP) providing cabazitaxel (Cbz) plus prednisone (P) to patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel.
Authors: Zafar I. Malik, Giuseppe Di Lorenzo, Mert Basaran, Alexandros Ardavanis, Phillip Parente, Wito de Schultz, Fred Saad, Inge van Oort, Winald R. Gerritsen, Luis M. Antón Aparicio, Geoffrey Matus, Simon Hitier, Axel Heidenreich, Amit Bahl
Journal: Journal of Clinical Oncology (2013)

5055 Background: Cbz + P provides a significant survival benefit vs mitoxantrone + P in pts with mCRPC (Phase III TROPIC study [NCT00417079]; hazard ratio 0.70; p &lt; 0.0001). These findings supported the initiation of ongoing Sanofi-funded CUP and EAP (NCT01254279) to provide access to Cbz prior to commercialization and to collect real-life safety data. Methods: Expected enrollment is ~1600 pts with mCRPC from 250 centers worldwide. Pts receive Cbz (25 mg/m 2 Q3W) + P (10 mg oral QD) until progressive disease (PD), death, unacceptable toxicity, physician/pt decision or Cbz commercial availability. Pts are followed until 30 days after last dose. Granulocyte colony-stimulating factor (G-CSF) use is recommended as per ASCO guidance. Results: Interim baseline and safety data from the first 1301 pts treated in 37 countries are now available. Mean age was 68 yrs (22% were ≥ 75 yrs). All pts had an ECOG performance status ≤ 2. Median time from initial prostate cancer diagnosis was 57.6 months and 60% of pts had ≥ 2 metastatic sites; the most common were bone (91%) and lymph nodes (regional 30%, distant 27%). In total, 17% had PD whilst on docetaxel. The median number of Cbz cycles was 6 (range 1–22); median relative dose intensity was 99%. Overall, 837 pts (64%) received G-CSF (n = 123 curative [C], n = 765 prophylactic [P] and n = 99 [C + P]). Of 1142 pts (88%) who discontinued Cbz + P, the most common reasons were PD (44%), adverse event (AE; 27%), physician decision (13%) and commercial availability of Cbz (7%). Grade 3–4 AEs possibly related to Cbz + P occurred in 43% of pts; the most frequent were clinical neutropenia (18%), febrile neutropenia (FN; 7%) and diarrhea (4%). Of 80 pts (6%) with AEs leading to death, the AE was related to Cbz + P in 39 pts (3%). Conclusions: These results provide valuable data on Cbz + P treatment in routine clinical practice, confirming the safety results of clinical trials and showing that treatment with Cbz + P is associated with a manageable safety profile. The incidence of FN seems slightly lower than in TROPIC, owing to more frequent use of G-CSF prophylaxis in the CUP and EAP. Clinical trial information: NCT01254279.
PF199 TARGETING BRD4 IN MLL‐PTD AML
Authors: F. Pepe, B. McNeil, H.G. Ozer, M. Karunasiri, M. Bill, R. Garzon, A. Dorrance
Journal: HemaSphere (2019)

Background: Mixed lineage leukemia (MLL) gene encodes for a nuclear protein that regulates genes involved in development and hematopoiesis. De‐regulation of MLL by chromosome translocations causes acute myeloid leukemia (AML). In addition, about 5–11% of AML patients have MLL‐partial tandem duplication (PTD) mutations. MLL‐PTD is associated with poor prognosis and shorter remission duration in AML. Preliminary studies from our group indicate that when MLL‐PTD is knockdown in AML blasts we observe a mRNA expression profile that is very similar to that of bromodomain 4 (BRD4) inhibition in AML. Aims: We hypothesized that MLL‐PTD interacts with BRD4 forming a complex that regulate key genes in MLL‐PTD positive AML. Therefore treatment with BRD4 inhibitors, such as JQ1, could be a valid therapeutic strategy for MLL‐PTD AML patients. Methods: To identify proteins forming the transcriptional complex regulated by BRD4 and MLL, we conducted a Rapid Immunoprecipitation Mass spectrometry of Endogenous protein (RIME) study using BRD4 and MLL antibodies. Successively, we treated MLL‐PTD positive primary patient cells and CD34 + cord blood from healthy donors as controls with JQ1, and conducted RNA‐seq and ChIP‐seq studies. Finally, we conducted in vitro and in vivo studies on MLL‐PTD harboring samples to assess JQ1 treatment efficiency in inducing cell death in MLL‐PTD AML. Results: RIME analysis using BRD4 and MLL antibodies showed that the 75% of the proteins were in common between the two groups. PANTHER gene ontology analysis identified common pathways between them, suggesting that MLL and BRD4 could be part of similar protein complexes. Next, we treated MLL‐PTD + primary patient cells, and CD34 + cord blood cells as controls with JQ1 or vehicle, and conducted RNA‐seq and ChIP‐seq studies. RNA expression and peak intensity on promoter region results were combined to identify genes aberrantly expressed in MLL‐PTD + samples. We identified 98 up‐regulated and 32 down‐regulated genes that were differentially expressed d by JQ1 treatment only in AML samples. The top deregulated genes were validated by RT‐qPCR and ChIP in both human and murine MLL‐PTD + samples. Next, we treated the MLL‐PTD + AML cell line (EOL1) and primary murine AML cells from Mll‐PTD/Flt3‐ITD model with JQ1 and showed that JQ1 treatment induced more apoptosis and reduction of living cells in MLL‐PTD + models respect the relative controls (fold change living cells at 48 hours WT: 0.81, Mll‐PTD + : 0.42, p‐value: 0.0247). Last, treatment of the Mll‐PTD/Flt3‐ITD xenotranplanted BoyJ mice with JQ1 significantly increased their survival compared with controls (median survival CTRL: 75 days, JQ1: 109 days, Mantel‐Cox p‐value: 0.0195). In addition, we observed a reduced engraftment in serial re‐transplantation assays. Summary/Conclusion: Our data support developing a therapeutic strategy to target BRD4 in MLL‐PTD AML. image