tbuckley/cabot-search huggingface dataset:
Exploration of Target Spaces in the Human Genome for Protein and Peptide Drugs
Authors: Zhongyang Liu, Honglei Li, Zhaoyu Jin, Yang Li, Feifei Guo, Yangzhige He, Xinyue Liu, Yaning Qi, Liying Yuan, Fuchu He, Dong Li
Journal: Genomics Proteomics & Bioinformatics (2022)

After decades of development, protein and peptide drugs have now grown into a major drug class in the marketplace. Target identification and validation are crucial for the discovery of protein and peptide drugs, and bioinformatics prediction of targets based on the characteristics of known target proteins will help improve the efficiency and success rate of target selection. However, owing to the developmental history in the pharmaceutical industry, previous systematic exploration of the target spaces has mainly focused on traditional small-molecule drugs, while studies related to protein and peptide drugs are lacking. Here, we systematically explore the target spaces in the human genome specifically for protein and peptide drugs. Compared with other proteins, both successful protein and peptide drug targets have many special characteristics, and are also significantly different from those of small-molecule drugs in many aspects. Based on these features, we develop separate effective genome-wide target prediction models for protein and peptide drugs. Finally, a user-friendly web server, Predictor Of Protein and PeptIde drugs' therapeutic Targets (POPPIT) (http://poppit.ncpsb.org.cn/), is established, which provides not only target prediction specifically for protein and peptide drugs but also abundant annotations for predicted targets.
Moving Beyond Race-Based Medicine
Authors: Mack Roach III
Journal: Annals of Internal Medicine (2022)

LettersMarch 2022Moving Beyond Race-Based MedicineMack Roach III, MDMack Roach III, MDSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L21-0778 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR: I found Jones' editorial (1) to be extremely problematic. For more than 20 years, I and others have contended that race is not a biological construct and therefore is not the driving force that explains the observed disparity in cancer outcomes between Black and White persons (2–4). As such, I agree that at some point we need to “move beyond” race-based medicine. Unfortunately, that time has not yet arrived.I believe that a large portion of the health disparity experienced by Black persons is due to racism—a system of structuring opportunity and assigning value on the basis ...References1. Jones DS. Moving beyond race-based medicine. Ann Intern Med. 2021;174:1745-6. [PMID: 34662149] doi:10.7326/M21-3804 LinkGoogle Scholar2. Roach M 3rd, Alexander M. The prognostic significance of race and survival from breast cancer: a model for assessing the reliability of reported survival differences. J Natl Med Assoc. 1995;87:214-9. [PMID: 7731072] MedlineGoogle Scholar3. Roach M 3rd, Cirrincione C, Budman D, et al. Race and survival from breast cancer: based on Cancer and Leukemia Group B trial 8541. Cancer J Sci Am. 1997 Mar-Apr;3:107-12. [PMID: 9099461] MedlineGoogle Scholar4. Roach M 3rd, Forte D, Alexander M. Re: Race, prostate cancer survival, and membership in a large health maintenance organization [Letter]. J Natl Cancer Inst. 1999;91:801-3. [PMID: 10328112] CrossrefMedlineGoogle Scholar5. Chapman CH, Schechter CB, Cadham CJ, et al. Identifying equitable screening mammography strategies for black women in the United States using simulation modeling. Ann Intern Med. 2021;174:1637-46. [PMID: 34662151] doi:10.7326/M20-6506 LinkGoogle Scholar Author, Article, and Disclosure InformationAffiliations: Disclosures: The author has reported no disclosures of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L21-0778. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoMoving Beyond Race-Based Medicine David S. Jones Moving Beyond Race-Based Medicine David S. Jones Moving Beyond Race-Based Medicine Ashok V. Daftary Metrics March 2022Volume 175, Issue 3Page: W20KeywordsMammographyRacial and ethnic issuesRacismResearch designStructural racism ePublished: 15 March 2022 Issue Published: March 2022 Copyright & PermissionsCopyright © 2022 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Cultural concepts of distress and complex PTSD: Future directions for research and treatment
Authors: Eva Heim, Thanos Karatzias, Andreas Maercker
Journal: Clinical Psychology Review (2022)

Complex post-traumatic stress disorder (CPTSD) was introduced as a new diagnostic category in ICD-11. It encompasses PTSD symptoms along with disturbances in self-organisation (DSO), i.e., affect dysregulation, negative self-concept, and disturbances in relationships. Quantitative research supports the validity of CPTSD across different cultural groups. At the same time, evidence reveals cultural variation in the phenomenology of PTSD, which most likely translates into cultural variation with regard to DSO. This theoretical review aims to set the ground for future research on such cultural aspects in the DSO. It provides a theoretical introduction to cultural clinical psychology, followed by a summary of evidence on cultural research related to PTSD and DSO. This evidence suggests that the way how DSO symptoms manifest, and the underlying etiological processes, are closely intertwined with cultural notions of the self, emotions, and interpersonal relationships and interpersonal relationships. We propose directions for future research and implications for culturally sensitive clinical practice.
Publisher Correction: The endothelial Dll4–muscular Notch2 axis regulates skeletal muscle mass
Authors: Shin Fujimaki, Tomohiro Matsumoto, Masashi Muramatsu, Hiroshi Nagahisa, Naoki Horii, Daiki Seko, Shinya Masuda, Xuerui Wang, Yoko Asakura, Yukie Takahashi, Yuta Miyamoto, Shingo Usuki, Kei-ichiro Yasunaga, Yasutomi Kamei, Ryuichi Nishinakamura, Takashi Minami, Takaichi Fukuda, Atsushi Asakura, Yusuke Ono
Journal: Nature Metabolism (2022)
MACHINE LEARNING IDENTIFIED SUBSET OF AF PATIENTS WHO BENEFIT FROM LEFT ATRIAL APPENDAGE OCCLUSION VERSUS NOAC
Authors: Xiaoxi Yao, Che Ngufor, Nan Zhang, Holly Van Houten, Neena Abraham, Jonathan Graff-Radford, Mohamad Adnan Alkhouli, Trevor Simard, Ammar M. Killu, Alejandro Rabinstein, Paul A. Friedman, David R. Holmes, Peter Noseworthy
Journal: Journal of the American College of Cardiology (2022)
Error in Figure
Authors: Nora Pashayan, Paul Pharoah
Journal: JAMA Oncology (2022)

Shawn H. R. Lee, MBBS; Federico Antillon-Klussmann, MD; Deqing Pei, MS; Wenjian Yang, PhD; Kathryn G. Roberts, PhD; Zhenhua Li, PhD; Meenakshi Devidas, PhD; Wentao Yang, PhD; Cesar Najera, BS; Hai Peng Lin, MBBS; Ah Moy Tan, MBBS; Hany Ariffin, MBBS; Cheng Cheng, PhD; William E. Evans, PharmD; Stephen P. Hunger, MD; Sima Jeha, MD; Charles G. Mullighan, MD; Mignon L. Loh, MD; Allen E. J. Yeoh, MBBS; Ching-Hon Pui, MD; Jun J. Yang, PhD
Phase II Trial of Cabozantinib Plus Nivolumab in Patients With Non–Clear-Cell Renal Cell Carcinoma and Genomic Correlates
Authors: Chung-Han Lee, Martin H. Voss, Maria Isabel Carlo, Ying-Bei Chen, Mark Zucker, Andrea Knezevic, Robert A. Lefkowitz, Natalie Shapnik, Chloe Dadoun, Ed Reznik, Neil J. Shah, Colette Ngozi Owens, Deaglan Joseph McHugh, David Henry Aggen, Andrew Leonard Laccetti, Ritesh Kotecha, Darren R. Feldman, Robert J. Motzer
Journal: Journal of Clinical Oncology (2022)

PURPOSE To assess the efficacy and safety of cabozantinib plus nivolumab in a phase II trial in patients with non–clear-cell renal cell carcinoma (RCC). PATIENTS AND METHODS Patients had advanced non–clear-cell renal carcinoma who underwent 0-1 prior systemic therapies excluding prior immune checkpoint inhibitors. Patients received cabozantinib 40 mg once daily plus nivolumab 240 mg once every 2 weeks or 480 mg once every 4 weeks. Cohort 1 enrolled patients with papillary, unclassified, or translocation-associated RCC; cohort 2 enrolled patients with chromophobe RCC. The primary end point was objective response rate (ORR) by RECIST 1.1; secondary end points included progression-free survival, overall survival, and safety. Next-generation sequencing results were correlated with response. RESULTS A total of 47 patients were treated with a median follow-up of 13.1 months. Objective response rate for cohort 1 (n = 40) was 47.5% (95% CI, 31.5 to 63.9), with median progression-free survival of 12.5 months (95% CI, 6.3 to 16.4) and median overall survival of 28 months (95% CI, 16.3 to not evaluable). In cohort 2 (n = 7), no responses were observed; one patient had stable disease &gt; 1 year. Grade 3/4 treatment-related adverse events were observed in 32% treated patients. Cabozantinib and nivolumab were discontinued because of toxicity in 13% and 17% of patients, respectively. Common mutations included NF2 and FH in cohort 1 and TP53 and PTEN in cohort 2. Objective responses were seen in 10/12 patients with either NF2 or FH mutations. CONCLUSION Cabozantinib plus nivolumab showed promising efficacy in most non–clear-cell RCC variants tested in this trial, particularly those with prominent papillary features, whereas treatment effects were limited in chromophobe RCC. Genomic findings in non–clear-cell RCC variants warrant further study as predictors of response.
BASELINE CHARACTERISTICS OF SMIDT HEART INSTITUTE TAKOTSUBO REGISTRY PARTICIPANTS
Authors: Okezi Obrutu, Jenna Maughan, Benita Tjoe, Romana Herscovici, Prizzi Moy, Natalie Rojas, Paul Marano, Janet Wei, Chrisandra Shufelt, Thomas Rutledge, C. Noel Bairey Merz
Journal: Journal of the American College of Cardiology (2022)
Abstract WS2-1: Genome editing in human organoids as new models for discovery
Authors: JM Rosenbluth
Journal: Cancer Research (2022)

Abstract Use of human organoids as new models for discovery. Despite significant advances, there are circumstances where mouse models remain inadequate to model cancer. Human organoid cultures are becoming established as a useful adjunct to mouse models because they enable the propagation of both normal and cancerous tissues in the lab for functional studies, disease modeling, and drug screening. Organoids can be generated from induced pluripotent stem cells or directly from donor tissue samples (e.g. normal breast tissue or tumors). In the latter approach, breast organoid cultures are grown in a hydrogel that mimics the basement membrane and are bathed in a cocktail of growth factors, vitamins, and compounds that mimic the microenvironment provided by stroma, resulting in the growth of cells in a polarized fashion to recapitulate breast acinar- and duct-like structures. Breast epithelial cells within organoids are able to differentiate into all of the major mammary epithelial lineages, and hence organoids can be used to study several types of epithelial lineages and their relative contributions to tumor development. In addition, breast cancer organoids can be used to expand heterogeneous populations of tumor cells for in vitro assays. For example, genome editing approaches can be used to model mutations associated with breast cancer, and compound screening approaches can facilitate target discovery. In this educational talk, we will review some of these recent advances, consider advantages and disadvantages of this model system, and discuss some practical considerations for bio-banking efforts and downstream applications. Citation Format: JM Rosenbluth. Genome editing in human organoids as new models for discovery [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr WS2-1.
Tumor Intrinsic PD-L1 Promotes DNA Repair in Distinct Cancers and Suppresses PARP Inhibitor–Induced Synthetic Lethality
Authors: Anand V.R. Kornepati, Jacob T. Boyd, Clare E. Murray, Julia Saifetiarova, Bárbara de la Peña Avalos, Cody M. Rogers, Haiyan Bai, Alvaro S. Padron, Yiji Liao, Carlos Ontiveros, Robert S. Svatek, Robert Hromas, Rong Li, Yanfen Hu, Jose R. Conejo-Garcia, Ratna K. Vadlamudi, Weixing Zhao, Eloïse Dray, Patrick Sung, Tyler J. Curiel
Journal: Cancer Research (2022)

BRCA1-mediated homologous recombination is an important DNA repair mechanism that is the target of FDA-approved PARP inhibitors, yet details of BRCA1-mediated functions remain to be fully elucidated. Similarly, immune checkpoint molecules are targets of FDA-approved cancer immunotherapies, but the biological and mechanistic consequences of their application are incompletely understood. We show here that the immune checkpoint molecule PD-L1 regulates homologous recombination in cancer cells by promoting BRCA1 nuclear foci formation and DNA end resection. Genetic depletion of tumor PD-L1 reduced homologous recombination, increased nonhomologous end joining, and elicited synthetic lethality to PARP inhibitors olaparib and talazoparib in vitro in some, but not all, BRCA1 wild-type tumor cells. In vivo, genetic depletion of tumor PD-L1 rendered olaparib-resistant tumors sensitive to olaparib. In contrast, anti-PD-L1 immune checkpoint blockade neither enhanced olaparib synthetic lethality nor improved its efficacy in vitro or in wild-type mice. Tumor PD-L1 did not alter expression of BRCA1 or its cofactor BARD1 but instead coimmunoprecipitated with BARD1 and increased BRCA1 nuclear accumulation. Tumor PD-L1 depletion enhanced tumor CCL5 expression and TANK-binding kinase 1 activation in vitro, similar to known immune-potentiating effects of PARP inhibitors. Collectively, these data define immune-dependent and immune-independent effects of PARP inhibitor treatment and genetic tumor PD-L1 depletion. Moreover, they implicate a tumor cell-intrinsic, immune checkpoint-independent function of PD-L1 in cancer cell BRCA1-mediated DNA damage repair with translational potential, including as a treatment response biomarker.
Abstract P5-06-13: Second-harmonic generation imaging reveals neoadjuvant chemotherapy-induced changes in breast tumor collagen
Authors: Edward Brown, Danielle Desa, Robert M Brown, Edward B Brown, Robert L Hill, Bradley M Turner
Journal: Cancer Research (2022)

Abstract Breast cancer is the most common invasive cancer in women, with most deaths attributed to metastases. Neoadjuvant chemotherapy (NACT) may be prescribed prior to surgical removal of the tumor for subsets of breast cancer patients but can have diverse undesired and off-target effects including increased appearance of the ‘tumor microenvironment of metastasis’ or TMEMs, image-based multicellular signatures which are prognostic of metastasis. In this study we explored whether NACT alters other image-based prognostic/predictive signatures, specifically second-harmonic generation (SHG) directionality, which is indicative of collagen fiber internal structure, as well as the disorganization in collagen fiber alignment. This was performed in paired biopsy/excision samples from 22 patients with HER2 overexpressing invasive ductal carcinoma as well as 22 patients with triple negative breast cancer (TNBC). We found that collagen fiber internal structure, measured using the SHG forward-to-backward-scattered ratio (F/B), is altered in the bulk of the tumor in both tumor types (p = 0.015 and 0.038, respectively), but not the adjacent tumor-stroma interface (p = 0.54 and 0.92, respectively), where F/B is prognostic of metastatic outcome. Overall disorganization in collagen fiber alignment was not significantly changed by NACT in HER2 overexpressing disease (p = 0.41) but was decreased in TNBC (p = 0.0051). These results suggest that NACT alters the collagenous extracellular matrix in diverse ways, with implications for the use of F/B and collagen fiber alignment as prognostic and predictive tools. Citation Format: Edward Brown, Danielle Desa, Robert M Brown, Edward B Brown, Robert L Hill, Bradley M Turner. Second-harmonic generation imaging reveals neoadjuvant chemotherapy-induced changes in breast tumor collagen [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-06-13.
Mosaic theory revised: inflammation and salt play central roles in arterial hypertension
Authors: Felicitas E. Hengel, Jean-Pierre Benitah, Ulrich O. Wenzel
Journal: Cellular and Molecular Immunology (2022)

Abstract The mosaic theory of hypertension was advocated by Irvine Page ~80 years ago and suggested that hypertension resulted from the close interactions of different causes. Increasing evidence indicates that hypertension and hypertensive end-organ damage are not only mediated by the proposed mechanisms that result in hemodynamic injury. Inflammation plays an important role in the pathophysiology and contributes to the deleterious consequences of arterial hypertension. Sodium intake is indispensable for normal body function but can be detrimental when it exceeds dietary requirements. Recent data show that sodium levels also modulate the function of monocytes/macrophages, dendritic cells, and different T-cell subsets. Some of these effects are mediated by changes in the microbiome and metabolome due to high-salt intake. The purpose of this review is to propose a revised and extended version of the mosaic theory by summarizing and integrating recent advances in salt, immunity, and hypertension research. Salt and inflammation are placed in the middle of the mosaic because both factors influence each of the remaining pieces.
In vivo prime editing of a metabolic liver disease in mice
Authors: Desirée Böck, Tanja Rothgangl, Lukas Villiger, Lukas Schmidheini, Mai Matsushita, Nicolas Mathis, Eleonora Ioannidi, Nicole Rimann, Hiu Man Grisch-Chan, Susanne Kreutzer, Zacharias Kontarakis, Manfred Kopf, Beat Thöny, Gerald Schwank
Journal: Science Translational Medicine (2022)

Prime editing is a highly versatile CRISPR-based genome editing technology that works without DNA double-strand break formation. Despite rapid technological advances, in vivo application for the treatment of genetic diseases remains challenging. Here, we developed a size-reduced Sp Cas9 prime editor (PE) lacking the RNaseH domain (PE2 Δ RnH ) and an intein-split construct (PE2 p.1153) for adeno-associated virus–mediated delivery into the liver. Editing efficiencies reached 15% at the Dnmt1 locus and were further elevated to 58% by delivering unsplit PE2 Δ RnH via human adenoviral vector 5 (AdV). To provide proof of concept for correcting a genetic liver disease, we used the AdV approach for repairing the disease-causing Pah enu2 mutation in a mouse model of phenylketonuria (PKU) via prime editing. Average correction efficiencies of 11.1% (up to 17.4%) in neonates led to therapeutic reduction of blood phenylalanine, without inducing detectable off-target mutations or prolonged liver inflammation. Although the current in vivo prime editing approach for PKU has limitations for clinical application due to the requirement of high vector doses (7 × 10 14 vg/kg) and the induction of immune responses to the vector and the PE, further development of the technology may lead to curative therapies for PKU and other genetic liver diseases.
A New Resource in CDC’s Campaign to Reduce Maternal Deaths
Authors: Bridget M. Kuehn
Journal: JAMA (2022)

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 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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
Derivation and validation of a simple multidimensional index incorporating exercise capacity parameters for survival prediction in idiopathic pulmonary fibrosis
Authors: Abhimanyu Chandel, Jean Pastre, Solène Valery, Christopher S King, Steven D Nathan
Journal: Thorax (2022)

Introduction The gender-age-physiology (GAP) index is an easy-to-use baseline mortality prediction model in idiopathic pulmonary fibrosis (IPF). The GAP index does not incorporate exercise capacity parameters such as 6 min walk distance (6MWD) or exertional hypoxia. We evaluated if the addition of 6MWD and exertional hypoxia to the GAP index improves survival prediction in IPF. Methods Patients with IPF were identified at a tertiary care referral centre. Discrimination and calibration of the original GAP index were assessed. The cohort was then randomly divided into a derivation and validation set and performance of the GAP index with the addition of 6MWD and exertional hypoxia was evaluated. A final model was selected based on improvement in discrimination. Application of this model was then evaluated in a geographically distinct external cohort. Results There were 562 patients with IPF identified in the internal cohort. Discrimination of the original GAP index was measured by a C-statistic of 0.676 (95% CI 0.635 to 0.717) and overestimated observed risk. 6MWD and exertional hypoxia were strongly predictive of mortality. The addition of these variables to the GAP index significantly improved model discrimination. A revised index incorporating exercise capacity parameters was constructed and performed well in the internal validation set (C-statistic: 0.752; 95% CI 0.701 to 0.802, difference in C-statistic compared with the refit GAP index: 0.050; 95% CI 0.004 to 0.097) and external validation set (N=108 (C-statistic: 0.780; 95% CI 0.682 to 0.877)). Conclusion A simple point-based baseline-risk prediction model incorporating exercise capacity predictors into the original GAP index may improve prognostication in patients with IPF.
HSR22-152: Healthcare Resource Utilization, Dosing and Time on Treatment in Patients on Pexidartinib Tenosynovial Giant Cell Tumors: Real-World Evidence from a Claims-Based Dataset
Authors: Feng Lin, Jenny Tse, Hangcheng Liu, Keiko Wada, Aimee M. Near, Winghan J. Kwong, Matthew Ingham
Journal: Journal of the National Comprehensive Cancer Network (2022)

"HSR22-152: Healthcare Resource Utilization, Dosing and Time on Treatment in Patients on Pexidartinib Tenosynovial Giant Cell Tumors: Real-World Evidence from a Claims-Based Dataset" published on 31 Mar 2022 by National Comprehensive Cancer Network.
ASSESSMENT OF AORTIC VALVE TISSUE COMPOSITION BY SEMI-AUTOMATED ANALYSIS OF CTA FOR PREDICTING THE NEED FOR PACEMAKER IMPLANTATION IN TAVR PATIENTS
Authors: Billy Chen, Josiah N. Brown, Donghee Han, Heidi Gransar, Sean Hayes, John Friedman, Damini Dey, Raj Makkar, Balaji Tamarappoo, Daniel S. Berman
Journal: Journal of the American College of Cardiology (2022)
CHF FOLLOWING CRT - BIV RIDDLE WITH A TWIDDLE
Authors: Usman Sarwar, Nikky Bardia, Maulikkumar Patel, Siva Chiranjeevi, Nilarun Chowdhuri, Nupur Shah, Christopher Michael Malozzi, Farnoosh Rahimi, Ghulam Mustafa Awan, Amod Amritphale, Bassam A. Omar
Journal: Journal of the American College of Cardiology (2022)