tbuckley/cabot-search huggingface dataset:
Expanding the Reach of Precision Oncology by Drugging All <i>KRAS</i> Mutants
Authors: Marco H. Hofmann, Daniel Gerlach, Sandra Misale, Mark Petronczki, Norbert Kraut
Journal: Cancer Discovery (2022)

KRAS is the most frequently mutated oncogene, harboring mutations in approximately one in seven cancers. Allele-specific KRASG12C inhibitors are currently changing the treatment paradigm for patients with KRASG12C-mutated non-small cell lung cancer and colorectal cancer. The success of addressing a previously elusive KRAS allele has fueled drug discovery efforts for all KRAS mutants. Pan-KRAS drugs have the potential to address broad patient populations, including KRASG12D-, KRASG12V-, KRASG13D-, KRASG12R-, and KRASG12A-mutant or KRAS wild-type-amplified cancers, as well as cancers with acquired resistance to KRASG12C inhibitors. Here, we review actively pursued allele-specific and pan-KRAS inhibition strategies and their potential utility. Mutant-selective KRASG12C inhibitors target a fraction (approximately 13.6%) of all KRAS-driven cancers. A broad arsenal of KRAS drugs is needed to comprehensively conquer KRAS-driven cancers. Conceptually, we foresee two future classes of KRAS medicines: mutant-selective KRAS drugs targeting individual variant alleles and pan-KRAS therapeutics targeting a broad range of KRAS alterations.
Abstract EP31: Use Of Low-density Lipoprotein Cholesterol Raising Medication Among United States Adults, 2013 Through 2018
Authors: Alexander Zheutlin, Alexander Chaitoff, Joshua Niforatos
Journal: Circulation (2022)

Introduction: Low-density lipoprotein cholesterol (LDL-C) reduction is a cornerstone to atherosclerotic disease (ASCSVD) prevention. Iatrogenic LDL-C elevation may counteract measures to address ASCVD risk by LDL-C lowering. Methods: Participant data from the National Health and Nutrition Examination Survey (NHANES) between 2013-2018 was pooled to determine the use of medication that raised LDL-C as an adverse effect as determined by literature review. Logistic regression was used to determine the association between the use of LDL-C raising medication and ASCVD with adjustment for demographic, socioeconomic, and health-related variables. Results: Among NHANES participants with medication data availability (weighted n = 238,995,360), 4.9% were taking LDL-C raising medication. Among adults with ACSVD, 5.5% were taking LDL-C raising medication, compared to 4.7% of participants without ASCVD. LDL-C raising medication were more common among participants with an annual income &lt;$20,000, diagnosed with hypertension, taking an antihypertensive medication, greater BMI, and greater medication count. The unadjusted odds-ratio (OR) of the use of LDL-C raising medication with ASCVD was 1.18 (95% CI 0.97,1.44). Following adjustment for demographic, socioeconomic, and health-related variables the OR was further attenuated (OR 1.08 95% CI 0.82, 1.43). Discussion: In this analysis of NHANES, LDL-C raising medication was not associated with presence of ASCVD. However, the use of LDL-C raising medication was prevalent among nearly 5% of U.S. adults and greater monitoring of adverse medication effects may represent an avenue to improve LDL-C reduction
Phase 3 Safety and Efficacy of AZD1222 (ChAdOx1 nCoV-19) Covid-19 Vaccine
Authors: Ann R Falsey, Magdalena E Sobieszczyk, Ian Hirsch, Stephanie Sproule, Merlin L Robb, Lawrence Corey, Kathleen M Neuzil, William Hahn, Julie Hunt, Mark J Mulligan, Charlene McEvoy, Edwin DeJesus, Michael Hassman, Susan J Little, Barbara A Pahud, Anna Durbin, Paul Pickrell, Eric S Daar, Larry Bush, Joel Solis, Quito Osuna Carr, Temitope Oyedele, Susan Buchbinder, Jessica Cowden, Sergio L Vargas, Alfredo Guerreros Benavides, Robert Call, Michael C Keefer, Beth D Kirkpatrick, John Pullman, Tina Tong, Margaret Brewinski Isaacs, David Benkeser, Holly E Janes, Martha C Nason, Justin A Green, Elizabeth J Kelly, Jill Maaske, Nancy Mueller, Kathryn Shoemaker, Therese Takas, Richard P Marshall, Menelas N Pangalos, Tonya Villafana, Antonio Gonzalez-Lopez
Journal: New England Journal of Medicine (2021)

BackgroundThe safety and efficacy of the AZD1222 (ChAdOx1 nCoV-19) vaccine in a large, diverse population at increased risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the United States, Chile, and Peru has not been known.MethodsIn this ongoing, double-blind, randomized, placebo-controlled, phase 3 clinical trial, we investigated the safety, vaccine efficacy, and immunogenicity of two doses of AZD1222 as compared with placebo in preventing the onset of symptomatic and severe coronavirus disease 2019 (Covid-19) 15 days or more after the second dose in adults, including older adults, in the United States, Chile, and Peru.Download a PDF of the Research Summary.ResultsA total of 32,451 participants underwent randomization, in a 2:1 ratio, to receive AZD1222 (21,635 participants) or placebo (10,816 participants). AZD1222 was safe, with low incidences of serious and medically attended adverse events and adverse events of special interest; the incidences were similar to those observed in the placebo group. Solicited local and systemic reactions were generally mild or moderate in both groups. Overall estimated vaccine efficacy was 74.0% (95% confidence interval [CI], 65.3 to 80.5; P<0.001) and estimated vaccine efficacy was 83.5% (95% CI, 54.2 to 94.1) in participants 65 years of age or older. High vaccine efficacy was consistent across a range of demographic subgroups. In the fully vaccinated analysis subgroup, no severe or critical symptomatic Covid-19 cases were observed among the 17,662 participants in the AZD1222 group; 8 cases were noted among the 8550 participants in the placebo group (<0.1%). The estimated vaccine efficacy for preventing SARS-CoV-2 infection (nucleocapsid antibody seroconversion) was 64.3% (95% CI, 56.1 to 71.0; P<0.001). SARS-CoV-2 spike protein binding and neutralizing antibodies increased after the first dose and increased further when measured 28 days after the second dose.ConclusionsAZD1222 was safe and efficacious in preventing symptomatic and severe Covid-19 across diverse populations that included older adults. (Funded by AstraZeneca and others; ClinicalTrials.gov number, NCT04516746.) Quick Take AZD1222 Covid-19 Vaccine Safety and Efficacy 1m 49s
Orbital Granulomatous Inflammation Mimicking Malignancy on 68Ga-FAPI PET/CT
Authors: Yong Wang, Xiao Yang, Min Tian, Hongbin Lv, Huipan Liu
Journal: Clinical Nuclear Medicine (2022)

A 31-year-old man presented with a left orbital mass for 3 months traumatic enucleation of the left eye. On 68Ga-FAPI PET/CT images, the lesion presented as a soft tissue mass with irregular shape, filling the left orbital cavity and showing intense FAPI uptake. Based on imaging findings, a malignancy was suspected. However, the orbital mass was diagnosed as granulomatous inflammation by pathological biopsy.
A Humanized Animal Model Predicts Clonal Evolution and Therapeutic Vulnerabilities in Myeloproliferative Neoplasms
Authors: Hamza Celik, Ethan Krug, Christine R. Zhang, Wentao Han, Nancy Issa, Won Kyun Koh, Hassan Bjeije, Ostap Kukhar, Maggie Allen, Tiandao Li, Daniel A.C. Fisher, Jared S. Fowles, Terrence N. Wong, Matthew C. Stubbs, Holly K. Koblish, Stephen T. Oh, Grant A. Challen
Journal: Cancer Discovery (2021)

Myeloproliferative neoplasms (MPN) are chronic blood diseases with significant morbidity and mortality. Although sequencing studies have elucidated the genetic mutations that drive these diseases, MPNs remain largely incurable with a significant proportion of patients progressing to rapidly fatal secondary acute myeloid leukemia (sAML). Therapeutic discovery has been hampered by the inability of genetically engineered mouse models to generate key human pathologies such as bone marrow fibrosis. To circumvent these limitations, here we present a humanized animal model of myelofibrosis (MF) patient-derived xenografts (PDX). These PDXs robustly engrafted patient cells that recapitulated the patient's genetic hierarchy and pathologies such as reticulin fibrosis and propagation of MPN-initiating stem cells. The model can select for engraftment of rare leukemic subclones to identify patients with MF at risk for sAML transformation and can be used as a platform for genetic target validation and therapeutic discovery. We present a novel but generalizable model to study human MPN biology. Although the genetic events driving MPNs are well defined, therapeutic discovery has been hampered by the inability of murine models to replicate key patient pathologies. Here, we present a PDX system to model human myelofibrosis that reproduces human pathologies and is amenable to genetic and pharmacologic manipulation. This article is highlighted in the In This Issue feature, p. 2945.
Will GWAS eventually allow the identification of genomic biomarkers for COVID-19 severity and mortality?
Authors: Vito Luigi Colona, Michela Biancolella, Antonio Novelli, Giuseppe Novelli
Journal: Journal of Clinical Investigation (2021)

GWAS involve testing genetic variants across the genomes of many individuals to identify genotype-phenotype associations. GWAS have enabled the identification of numerous genomic biomarkers in various complex human diseases, including infectious ones. However, few of these studies are relevant for clinical practice or at the bedside. In this issue of the JCI, Nakanishi et al. characterized the clinical implications of a major genetic risk factor for COVID-19 severity and its age-dependent effect, using individual-level data in a large international multicenter consortium. This study indicates that a common COVID-19 genetic risk factor (rs10490770) associates with increased risks of morbidity and mortality, suggesting potential implications for future clinical risk management. How can the genomic biomarkers identified by GWAS be associated with the clinical outcomes of an infectious disease? In this Commentary, we evaluate the advantages and limitations of this approach.
Rilzabrutinib, an Oral BTK Inhibitor, in Immune Thrombocytopenia
Authors: David J. Kuter, Merlin Efraim, Jiri Mayer, Marek Trněný, Vickie McDonald, Robert Bird, Thomas Regenbogen, Mamta Garg, Zane Kaplan, Nikolay Tzvetkov, Philip Y. Choi, A.J. Gerard Jansen, Milan Kostal, Ross Baker, Jaromir Gumulec, Eun-Ju Lee, Ilona Cunningham, Isaac Goncalves, Margaret Warner, Ralph Boccia, Terry Gernsheimer, Waleed Ghanima, Olga Bandman, Regan Burns, Ann Neale, Dolca Thomas, Puneet Arora, Beiyao Zheng, Nichola Cooper
Journal: New England Journal of Medicine (2022)

Rilzabrutinib, an oral, reversible covalent inhibitor of Bruton's tyrosine kinase, may increase platelet counts in patients with immune thrombocytopenia by means of dual mechanisms of action: decreased macrophage (Fcγ receptor)–mediated platelet destruction and reduced production of pathogenic autoantibodies.
Unfavourable intrauterine environment contributes to abnormal gut microbiome and metabolome in twins
Authors: Jing Yang, Lingling Hou, Jinfeng Wang, Liwen Xiao, Jinyang Zhang, Nanlin Yin, Su Yao, Kun Cheng, Wen Zhang, Zhonghua Shi, Jing Wang, Hai Jiang, Nana Huang, Yanxia You, Mingmei Lin, Ruiyan Shang, Yuan Wei, Yangyu Zhao, Fangqing Zhao
Journal: Gut (2022)

Objective Fetal growth restriction (FGR) is a devastating pregnancy complication that increases the risk of perinatal mortality and morbidity. This study aims to determine the combined and relative effects of genetic and intrauterine environments on neonatal microbial communities and to explore selective FGR-induced gut microbiota disruption, metabolic profile disturbances and possible outcomes. Design We profiled and compared the gut microbial colonisation of 150 pairs of twin neonates who were classified into four groups based on their chorionicity and discordance of fetal birth weight. Gut microbiota dysbiosis and faecal metabolic alterations were determined by 16S ribosomal RNA and metagenomic sequencing and metabolomics, and the long-term effects were explored by surveys of physical and neurocognitive development conducted after 2~3 years of follow-up. Results Adverse intrauterine environmental factors related to selective FGR dominate genetics in their effects of elevating bacterial diversity and altering the composition of early-life gut microbiota, and this effect is positively related to the severity of selective FGR in twins. The influence of genetic factors on gut microbes diminishes in the context of selective FGR. Gut microbiota dysbiosis in twin neonates with selective FGR and faecal metabolic alterations features decreased abundances of Enterococcus and Acinetobacter and downregulated methionine and cysteine levels. Correlation analysis indicates that the faecal cysteine level in early life is positively correlated with the physical and neurocognitive development of infants. Conclusion Dysbiotic microbiota profiles and pronounced metabolic alterations are associated with selective FGR affected by adverse intrauterine environments, emphasising the possible effects of dysbiosis on long-term neurobehavioural development.
Myosin modulators: emerging approaches for the treatment of cardiomyopathies and heart failure
Authors: Sharlene M. Day, Jil C. Tardiff, E. Michael Ostap
Journal: Journal of Clinical Investigation (2022)

Myosin modulators are a novel class of pharmaceutical agents that are being developed to treat patients with a range of cardiomyopathies. The therapeutic goal of these drugs is to target cardiac myosins directly to modulate contractility and cardiac power output to alleviate symptoms that lead to heart failure and arrhythmias, without altering calcium signaling. In this Review, we discuss two classes of drugs that have been developed to either activate (omecamtiv mecarbil) or inhibit (mavacamten) cardiac contractility by binding to β-cardiac myosin (MYH7). We discuss progress in understanding the mechanisms by which the drugs alter myosin mechanochemistry, and we provide an appraisal of the results from clinical trials of these drugs, with consideration for the importance of disease heterogeneity and genetic etiology for predicting treatment benefit.
18F-FDG PET/CT Imaging in Sarcomatoid Hepatocellular Carcinoma
Authors: Ting Yang, Min-Hong Zou, Qiong Zou, Ju Jiao, Yong Zhang
Journal: Clinical Nuclear Medicine (2022)

Abstract Sarcomatoid hepatocellular carcinoma is a rare subtype of hepatocellular carcinoma. We present a 53-year-old man with a hepatic IV/VIII segment neoplasm whose tumor markers were all in the reference range. The neoplasm presented intense uptake of 18 F-FDG and was confirmed as sarcomatoid hepatocellular carcinoma by immunohistochemistry. After 6 cycles of PD-1 treatment, no recurrence or metastasis was found by follow-up CT over 2 years. Thus, we reported a case of sarcomatoid hepatocellular carcinoma with complete remission to PD-1 treatment and provided some help for the diagnosis and treatment of sarcomatoid hepatocellular carcinoma.
Abstract 11765: Admission to Hospital with Acute Gout is Associated with a Short Term Increased Risk of Major Adverse Cardiovascular Events: A Longitudinal, Population-Level Linked Health Data Study in Western Australia
Authors: Derrick Lopez, Johannes NOssent, Raymond Warren, David Preen, Charles Inderjeeth, Kevin Murray, girish dwivedi, Helen I Keen
Journal: Circulation (2021)

Introduction: Cardiovascular disease is the largest contributor to the increased mortality seen in gout. Acute inflammation, which is characteristic of gout, may have a mechanistic role in Major Adverse Cardiovascular Events (MACE). Hypothesis: TA temporal relationship exists between admissions to hospital with acute gout, and major adverse cardiovascular events, in a large population based administrative health data set using the self-controlled case series study design Methods: Data were extracted from the Hospital Morbidity Data Collection (from 1970) and Death Registrations (from 1969) of the Western Australian Rheumatic Disease Epidemiology Registry. Participants were patients admitted to hospital with first-ever acute gout (ICD-9: 274; ICD-10: M10) between 1990 and 2010 and had an admission or death due to MACE (ICD-9: 410, 411.1, 428, 430-438; ICD-10: I20-I25, I45-I46, I50, I60-169) during the at risk periods (1-10, 11-20 and 21-30 days after acute gout admission) and control period (365 days prior to admissions and 31-365 days after acute gout admission). We used a self-controlled case-series design (within person design which controls for time-constant patient-specific confounding) and performed a conditional fixed-effects Poisson regression to compare the risk of MACE in the at-risk periods to the control periods. Results: We identified 835 patients (average age=75.1 years, SD=12.1; 67.4% male) with first-ever acute gout admission and a documented MACE in the control or at-risk periods. An increased risk of MACE was observed in the 1-10 days (Incidence rate ratio [IRR]=3.07, 95%CI: 2.19-4.31), 11-20 days (IRR=2.81, 95%CI: 1.97-4.00), 21-30 days (IRR=1.93, 95%CI: 1.27-2.95) compared to the control period. Conclusion: Our self-controlled case series study shows an increased risk of MACE in the first 30 days following a first-ever gout admission and suggests a temporal association between acute inflammation and MACE.
Adamantinoma-Like Ewing Sarcoma of the Mandible Evaluated on 18F-FDG PET/CT
Authors: Sean J. Huls, Stephen M. Broski, Ray Ruifeng Guo, Larry A. Binkovitz
Journal: Clinical Nuclear Medicine (2022)

Abstract Ewing sarcoma is the second most common primary bone tumor in children. Typical Ewing sarcoma most frequently occurs in long bones and within the pelvis. ALES (adamantinoma-like Ewing sarcoma) is a rare subtype of Ewing sarcoma that is characterized by epithelial differentiation in addition to small round blue cells. Unlike typical Ewing sarcoma, ALES has been described in several cases in the head and neck. Herein, we describe a case of a 9-year-old boy with ALES of the mandible evaluated on 18 F-FDG PET/CT with correlative MRI scans.
Indoor Air Pollution and Susceptibility to Tuberculosis Infection in Urban Vietnamese Children
Authors: Robert J. Blount, Ha Phan, Trang Trinh, Hai Dang, Cindy Merrifield, Michael Zavala, Joseph Zabner, Alejandro P. Comellas, Emma M. Stapleton, Mark R. Segal, John Balmes, Nguyen Viet Nhung, Payam Nahid
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: The Southeast Asian tuberculosis burden is high, and it remains unclear if urban indoor air pollution in this setting is exacerbating the epidemic. Objectives: To determine the associations of latent tuberculosis with common urban indoor air pollution sources (secondhand smoke, indoor motorcycle emissions, and cooking) in Southeast Asia. Methods: We enrolled child household contacts of patients with microbiologically confirmed active tuberculosis in Vietnam, from July 2017 to December 2019. We tested children for latent tuberculosis and evaluated air pollution exposures with questionnaires and personal aerosol sampling. We tested hypotheses using generalized estimating equations. Measurements and Main Results: We enrolled 72 patients with tuberculosis (27% with cavitary disease) and 109 of their child household contacts. Latent tuberculosis was diagnosed in 58 (53%) household contacts at baseline visit. Children experienced a 2.56-fold increased odds of latent tuberculosis for each additional household member who smoked (95% confidence interval, 1.27-5.16). Odds were highest among children exposed to indoor smokers and children <5 years old exposed to household smokers. Each residential floor above street-level pollution decreased the odds of latent tuberculosis by 36% (adjusted odds ratio, 0.64; 95% confidence interval, 0.42-0.96). Motorcycles parked inside children's homes and cooking with liquid petroleum gas compared with electricity increased the odds of latent tuberculosis, whereas kitchen ventilation decreased the effect, but these findings were not statistically significant. Conclusions: Common urban indoor air pollution sources were associated with increased odds of latent tuberculosis infection in child household contacts of patients with active tuberculosis.
ESMO Scale for Clinical Actionability of Molecular Targets Driving Targeted Treatment in Patients with Cholangiocarcinoma
Authors: Helena Verdaguer, Tamara Saurí, Daniel Alejandro Acosta, Magdalena Guardiola, Alexandre Sierra, Jorge Hernando, Paulo Nuciforo, Josep M. Miquel, Cristina Molero, Sandra Peiró, Queralt Serra-Camprubí, Guillermo Villacampa, Susana Aguilar, Ana Vivancos, Josep Tabernero, Rodrigo Dienstmann, Teresa Macarulla
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Treatment options for advanced cholangiocarcinoma are limited and prognosis is poor. Cholangiocarcinomas are highly heterogeneous at the molecular level, with divergent patterns between intrahepatic and extrahepatic forms, intrahepatic being particularly rich in actionable alterations. We compared survival in patients with advanced cholangiocarcinoma harboring alterations matched to targeted drugs, with patients harboring nonactionable alterations. Experimental Design: Patients with cholangiocarcinoma treated between 2011 and 2020 at one institution, with available molecular analyses, were retrospectively reviewed. Genomic alteration actionability was classified according to the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) and correlated with efficacy endpoints. Results: Of 327 patients included, 78.9% had intrahepatic cholangiocarcinoma, 97.9% had received chemotherapy for metastatic disease. Actionable molecular alterations per ESCAT were identified in 184 patients (56.3%), including IDH1 mutations and FGFR2 fusions (23.1% and 8.0% of patients with intrahepatic cholangiocarcinoma, respectively). Median overall survival in 50 patients with ESCAT I-IV alterations who received matched therapy (48 with intrahepatic cholangiocarcinoma) was 22.6 months [95% confidence interval (CI), 20.1–32.8], compared with 14.3 months (95% CI 11.9–18.1) in 130 patients without actionable ESCAT alterations (HR, 0.58; 95% CI, 0.40–0.85; P = 0.005). Among patients receiving matched targeted therapy, median progression-free survival was longer for patients with alterations classified as ESCAT I-II compared with ESCAT III-IV (5.0 vs. 1.9 months; HR, 0.36; 95% CI, 0.15–0.87; P = 0.02). Conclusions: ESCAT represents a tool to guide clinicians in fine-tuning use of molecular profiling data to choose matched targeted therapies. Our data demonstrate that targeted treatment administered per alteration actionability according to ESCAT is associated with improved survival in cholangiocarcinoma, particularly in ESCAT I-II intrahepatic cholangiocarcinoma.
Optimising the deployment of vector control tools against malaria: a data-informed modelling study
Authors: Ellie Sherrard-Smith, Peter Winskill, Arran Hamlet, Corine Ngufor, Raphael N'Guessan, Moussa W Guelbeogo, Antoine Sanou, Rebecca K Nash, Alexander Hill, Emma L Russell, Mark Woodbridge, Patrick K Tungu, Mara D Kont, Tom Mclean, Christen Fornadel, Jason H Richardson, Martin J Donnelly, Sarah G Staedke, Samuel Gonahasa, Natacha Protopopoff, Mark Rowland, Thomas S Churcher
Journal: The Lancet Planetary Health (2022)