tbuckley/cabot-search huggingface dataset:
Breaking through the barrier: Modelling and exploiting the physical microenvironment to enhance drug transport and efficacy
Authors: Magdalena Z. Gładysz, Maja Stevanoska, Małgorzata K. Włodarczyk-Biegun, Anika Nagelkerke
Journal: Advanced Drug Delivery Reviews (2022)

Pharmaceutical compounds are the main pillar in the treatment of various illnesses. To administer these drugs in the therapeutic setting, multiple routes of administration have been defined, including ingestion, inhalation, and injection. After administration, drugs need to find their way to the intended target for high effectiveness, and this penetration is greatly dependent on obstacles the drugs encounter along their path. Key hurdles include the physical barriers that are present within the body and knowledge of those is indispensable for progress in the development of drugs with increased therapeutic efficacy. In this review, we examine several important physical barriers, such as the blood-brain barrier, the gut-mucosal barrier, and the extracellular matrix barrier, and evaluate their influence on drug transport and efficacy. We explore various in vitro model systems that aid in understanding how parameters within the barrier model affect drug transfer and therapeutic effect. We conclude that physical barriers in the body restrict the quantity of drugs that can pass through, mainly as a consequence of the barrier architecture. In addition, the specific physical properties of the tissue can trigger intracellular changes, altering cell behavior in response to drugs. Though the barriers negatively influence drug distribution, physical stimulation of the surrounding environment may also be exploited as a mechanism to control drug release. This drug delivery approach is explored in this review as a potential alternative to the conventional ways of delivering therapeutics.
Circulating HBV RNA: From biology to clinical applications
Authors: Rui Deng, Shi Liu, Sheng Shen, Haitao Guo, Jian Sun
Journal: Hepatology (2022)

Chronic HBV infection can hardly be cured due to the persistence of an intrahepatic pool of viral covalently closed circular DNA (cccDNA) transcription template, which is refractory to current antivirals. The direct analyses of cccDNA quantity and transcriptional activity require an invasive biopsy. Recently, circulating HBV RNA has been identified as a promising noninvasive surrogate marker of cccDNA and can be used for monitoring disease progression and predicting prognosis of patients with chronic HBV infection. To better understand this surrogate biomarker of cccDNA, we reviewed the current knowledge about the molecular characteristics and potential clinical applications of circulating HBV RNA. Specifically, we summarized the reported species and existing forms of circulating HBV RNA and discussed their biogenesis and the capacity of de novo infection by RNA virions. Moreover, we described the potential applications of circulating HBV RNA in different clinical scenarios, such as classifying the phases of chronic HBV infection, analyzing sustained on-treatment and off-treatment outcomes of treated patients, as well as predicting HCC development. Perspectives on future research of circulating HBV RNA were also proposed in this review.
The burden of rare protein-truncating genetic variants on human lifespan
Authors: Jimmy Z. Liu, Chia-Yen Chen, Ellen A. Tsai, Christopher D. Whelan, David Sexton, Sally John, Heiko Runz
Journal: Nature Aging (2022)

Abstract Genetic predisposition has been shown to contribute substantially to the age at which we die. Genome-wide association studies (GWASs) have linked more than 20 loci to phenotypes related to human lifespan 1 . However, little is known about how lifespan is impacted by gene loss of function. Through whole-exome sequencing of 352,338 UK Biobank participants of European ancestry, we assessed the relevance of protein-truncating variant (PTV) gene burden on individual and parental survival. We identified four exome-wide significant ( P &lt; 4.2 × 10 −7 ) human lifespan genes, BRCA1 , BRCA2 , ATM and TET2 . Gene and gene-set, PTV-burden, phenome-wide association studies support known roles of these genes in cancer to impact lifespan at the population level. The TET2 PTV burden was associated with a lifespan through somatic mutation events presumably due to clonal hematopoiesis. The overlap between PTV burden and common variant-based lifespan GWASs was modest, underscoring the value of exome sequencing in well-powered biobank cohorts to complement GWASs for identifying genes underlying complex traits.
Fulminant Myocarditis Following SARS-CoV-2 Infection
Authors: Saurabh Rajpal, Rami Kahwash, Matthew S. Tong, Kelly Paschke, Anjali A. Satoskar, Beth Foreman, Larry A. Allen, Nicole M. Bhave, Ty J. Gluckman, Valentin Fuster
Journal: Journal of the American College of Cardiology (2022)
RISK STRATIFICATION BY CORONARY ARTERY CALCIFICATION IN PATIENTS WITH LDL&gt;190 MG/DL
Authors: Francesco Castagna, Jeremy Miles, Ephraim Leiderman, Javier Arce, Patrick Neshiwat, Paul Ippolito, Aldo Schenone, Lili Zhang, Carlos Jose Rodriguez, Jeffrey Levsky, Mario J. Garcia, Leandro Slipczuk
Journal: Journal of the American College of Cardiology (2022)
Infigratinib in Patients with Recurrent Gliomas and <i>FGFR</i> Alterations: A Multicenter Phase II Study
Authors: Andrew B. Lassman, Juan Manuel Sepúlveda-Sánchez, Timothy F. Cloughesy, Miguel J. Gil-Gil, Vinay K. Puduvalli, Jeffrey J. Raizer, Filip Y.F. De Vos, Patrick Y. Wen, Nicholas A. Butowski, Paul M.J. Clement, Morris D. Groves, Cristóbal Belda-Iniesta, Pierre Giglio, Harris S. Soifer, Steven Rowsey, Cindy Xu, Francesca Avogadri, Ge Wei, Susan Moran, Patrick Roth
Journal: Clinical Cancer Research (2022)

FGFR genomic alterations (amplification, mutations, and/or fusions) occur in ∼8% of gliomas, particularly FGFR1 and FGFR3. We conducted a multicenter open-label, single-arm, phase II study of a selective FGFR1-3 inhibitor, infigratinib (BGJ398), in patients with FGFR-altered recurrent gliomas.Adults with recurrent/progressive gliomas harboring FGFR alterations received oral infigratinib 125 mg on days 1 to 21 of 28-day cycles. The primary endpoint was investigator-assessed 6-month progression-free survival (PFS) rate by Response Assessment in Neuro-Oncology criteria. Comprehensive genomic profiling was performed on available pretreatment archival tissue to explore additional molecular correlations with efficacy.Among 26 patients, the 6-month PFS rate was 16.0% [95% confidence interval (CI), 5.0-32.5], median PFS was 1.7 months (95% CI, 1.1-2.8), and objective response rate was 3.8%. However, 4 patients had durable disease control lasting longer than 1 year. Among these, 3 had tumors harboring activating point mutations at analogous positions of FGFR1 (K656E; n = 2) or FGFR3 (K650E; n = 1) in pretreatment tissue; an FGFR3-TACC3 fusion was detected in the other. Hyperphosphatemia was the most frequently reported treatment-related adverse event (all-grade, 76.9%; grade 3, 3.8%) and is a known on-target toxicity of FGFR inhibitors.FGFR inhibitor monotherapy with infigratinib had limited efficacy in a population of patients with recurrent gliomas and different FGFR genetic alterations, but durable disease control lasting more than 1 year was observed in patients with tumors harboring FGFR1 or FGFR3 point mutations or FGFR3-TACC3 fusions. A follow-up study with refined biomarker inclusion criteria and centralized FGFR testing is warranted.
Case 7-2022: A 65-Year-Old Woman with Depression, Recurrent Falls, and Inability to Care for Herself
Authors: Deborah A. Forst, Judith A. Restrepo, R. Gilberto Gonzalez, Pamela S. Jones, Michael S. Marshall
Journal: New England Journal of Medicine (2022)

A 65-year-old woman was admitted with depression, recurrent falls, and difficulty caring for herself. She reported weakness on the left side and had a monoplegic gait, but results of strength testing were normal. She was treated for functional neurologic disorder but then had progressive neurologic decline. A diagnostic test was performed.
Abstract P4-12-05: Benefit of multidisciplinary consultation at initiation of oral antineoplastic agents in metastatic breast cancer patients
Authors: Adeline Morel, Margaux Jacobs, Angelique Da Silva, Djelila Allouache, Ioana Hrab, Carine Segura, Maud Villemin, Clémence Boscher, Alison Johnson, Charlotte Ceintre, Rose-Marie Charles, François Lahaye, Justine Lequesne, Fabienne Divanon, Christelle Levy, Georges Emile
Journal: Cancer Research (2022)

Abstract INTRODUCTION: The management of cancer patients changed in the recent years with increased in the number of oral antineoplastic agents (OANA) prescriptions. Recent guidelines encouraged improvement of information and patient education, and the coordination between health care professionals to secure and optimize the management of these drugs. To cope with current recommendations, a multidisciplinary consultation (MDC) for initiation of OANA was initiated at François Baclesse comprehensive cancer center in Caen, France. OBJECTIVE: The aim of this study was to evaluate the benefit of the MDC before the initiation OANA in patients with metastatic breast cancer. MDC consisted of a medical oncologist, hospital pharmacist, and oncology nurse consultations. Primary endpoint was the rate of hospitalizations. Secondary endpoints were treatment discontinuation and of adverse events rate. MATERIALS AND METHODS: We conducted a retrospective single center study comparing patients receiving MDC to the population with a single medical visit. RESULTS: A total of 482 patients were included in this study between January 2017 and December 2019 (329 patients had only a consultation with a medical oncologist before initiation of OANA and 153 had the MDC). A statistically significant decrease in the rate of hospitalizations for toxicity was found in the group of patients with MDC 3.9% (n=6) vs 18.5% (n = 61) in the group without MDC (p &amp;lt; 0.001). A significant decrease in treatment interruption rate for toxicity was found in the group of patients with MDC 11% (n = 16) vs 26% (n=86) (p &amp;lt; 0.001). Adverse events rate was not statistically significant between the two groups CONCLUSION: A statistically significant decrease in hospitalizations and rate of treatment interruption for toxicity was observed after initiation of MDC in patients with a metastatic breast cancer treated with an OANA. This process should be generalized for a better security in the management of the OANA. Citation Format: Adeline Morel, Margaux Jacobs, Angelique Da Silva, Djelila Allouache, Ioana Hrab, Carine Segura, Maud Villemin, Clémence Boscher, Alison Johnson, Charlotte Ceintre, Rose-Marie Charles, François Lahaye, Justine Lequesne, Fabienne Divanon, Christelle Levy, Georges Emile. Benefit of multidisciplinary consultation at initiation of oral antineoplastic agents in metastatic breast cancer patients [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 P4-12-05.
Oral desensitization therapy for peanut allergy induces dynamic changes in peanut‐specific immune responses
Authors: Veronique Bajzik, Hannah A. DeBerg, Nahir Garabatos, Blake J. Rust, Kimberly K. Obrien, Quynh‐Anh Nguyen, Colin O’Rourke, Alex Smith, Alex H. Walker, Charlie Quinn, Vivian H. Gersuk, Mary Farrington, David Jeong, Brian P. Vickery, Daniel C. Adelman, Erik Wambre
Journal: Allergy (2022)

The PALISADE study, an international, phase 3 trial of peanut oral immunotherapy (POIT) with AR101, resulted in desensitization in children and adolescents who were highly allergic to peanut. An improved understanding of the immune mechanism induced in response to food allergen immunotherapy would enable more informed and effective therapeutic strategies. Our main purpose was to examine the immunological changes in blood samples from a subset of peanut-allergic individuals undergoing oral desensitization immunotherapy with AR101.
Targeting platelet-derived CXCL12 impedes arterial thrombosis
Authors: Julian Leberzammer, Stijn M. Agten, Xavier Blanchet, Rundan Duan, Hans Ippel, Remco T. A. Megens, Christian Schulz, Maria Aslani, Johan Duchene, Yvonne Döring, Natalie J. Jooss, Pengyu Zhang, Richard Brandl, Konstantin Stark, Wolfgang Siess, Kerstin Jurk, Johan W. M. Heemskerk, Tilman M. Hackeng, Kevin H. Mayo, Christian Weber, Philipp von Hundelshausen
Journal: Blood (2022)

Abstract The prevention and treatment of arterial thrombosis continue to be clinically challenging, and understanding the relevant molecular mechanisms in detail may facilitate the quest to identify novel targets and therapeutic approaches that improve protection from ischemic and bleeding events. The chemokine CXCL12 augments collagen-induced platelet aggregation by activating its receptor CXCR4. Here we show that inhibition of CXCR4 attenuates platelet aggregation induced by collagen or human plaque homogenate under static and arterial flow conditions by antagonizing the action of platelet-secreted CXCL12. We further show that platelet-specific CXCL12 deficiency in mice limits arterial thrombosis by affecting thrombus growth and stability without increasing tail bleeding time. Accordingly, neointimal lesion formation after carotid artery injury was attenuated in these mice. Mechanistically, CXCL12 activated via CXCR4 a signaling cascade involving Bruton’s tyrosine kinase (Btk) that led to integrin αIIbβ3 activation, platelet aggregation, and granule release. The heterodimeric interaction between CXCL12 and CCL5 can inhibit CXCL12-mediated effects as mimicked by CCL5-derived peptides such as [VREY]4. An improved variant of this peptide, i[VREY]4, binds to CXCL12 in a complex with CXCR4 on the surface of activated platelets, thereby inhibiting Btk activation and preventing platelet CXCL12-dependent arterial thrombosis. In contrast to standard antiplatelet therapies such as aspirin or P2Y12 inhibition, i[VREY]4 reduced CXCL12-induced platelet aggregation and yet did not prolong in vitro bleeding time. We provide evidence that platelet-derived CXCL12 is involved in arterial thrombosis and can be specifically targeted by peptides that harbor potential therapeutic value against atherothrombosis.
SOCIAL AND CLINICAL PREDICTORS OF 30-DAY READMISSION AFTER HOSPITALIZATION FOR ACUTE DECOMPENSATED HEART FAILURE WITH BIPOLAR DISORDER: INSIGHT FROM THE NATIONAL READMISSIONS DATABASE
Authors: Ramtej Atluri, Sreeram Yalamanchili, Satyam Krishan, Mouna Kodali, Omar Khdeir, Bharosa Sharma
Journal: Journal of the American College of Cardiology (2022)
HYPERTENSIVE PATIENTS WITH ANGINA AND NONOBSTRUCTIVE CORONARY ARTERY DISEASE ARE CHARACTERIZED BY INCREASED SYMPATHETIC NERVOUS SYSTEM ACTIVATION
Authors: Athanasios Sakalidis, Kyriakos Dimitriadis, Stergios Soulaidopoulos, Eirini Dri, Konstantinos A. Aznaouridis, Eleni Manta, Konstantinos Konstantinou, Konstantinos Tsioufis
Journal: Journal of the American College of Cardiology (2022)
Abstract ES7-2: Emergent pharmacologic interventions for prevention: Non endocrine treatments
Authors: BM Heckman-Stoddard
Journal: Cancer Research (2022)

Abstract Many agents have been examined in preclinical and early phase clinical trials for their potential to reduce the risk of breast cancer in additional to the traditional endocrine agents that have been shown in large, randomized phase III clinical trials to reduce the risk of hormone-receptor positive breast cancer. The focus on non-endocrine agents has included commonly used drugs such as statins, non-steroidal anti-inflammatory agents (NSAIDs), and metformin. There were also many trials that have examined nutraceutical agents such as soy and omega-3-fatty acids. In addition, there is interest in target agents such as rexinoids, Her-2 targeted agents, and PARP inhibitors because of their potential to inhibit hormone-receptor negative breast cancer. Finally, there is significant interest in developing immunoprevention strategies for breast cancer risk reduction. There is a renewed focus on examining lower doses, intermittent dosing strategies, and local delivery to maximize the benefit and reduce the toxicity. Results of preclinical and clinical studies will be presented and discussed as well as ongoing clinical trials that will further inform work in this area. Citation Format: BM Heckman-Stoddard. Emergent pharmacologic interventions for prevention: Non endocrine treatments [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 ES7-2.
Global Population Genomics of Two Subspecies of<i>Cryptosporidium hominis</i>during 500 Years of Evolution
Authors: Swapnil Tichkule, Simone M. Cacciò, Guy Robinson, Rachel M. Chalmers, Ivo Mueller, Samantha J. Emery-Corbin, Daniel Eibach, Kevin M. Tyler, Cock van Oosterhout, Aaron R. Jex
Journal: Molecular Biology and Evolution (2022)

Cryptosporidiosis is a major global health problem and a primary cause of diarrhea, particularly in young children in low- and middle-income countries (LMICs). The zoonotic Cryptosporidium parvum and anthroponotic Cryptosporidium hominis cause most human infections. Here, we present a comprehensive whole-genome study of C. hominis, comprising 114 isolates from 16 countries within five continents. We detect two lineages with distinct biology and demography, which diverged circa 500 years ago. We consider these lineages two subspecies and propose the names C. hominis hominis and C. hominis aquapotentis (gp60 subtype IbA10G2). In our study, C. h. hominis is almost exclusively represented by isolates from LMICs in Africa and Asia and appears to have undergone recent population contraction. In contrast, C. h. aquapotentis was found in high-income countries, mainly in Europe, North America, and Oceania, and appears to be expanding. Notably, C. h. aquapotentis is associated with high rates of direct human-to-human transmission, which may explain its success in countries with well-developed environmental sanitation infrastructure. Intriguingly, we detected genomic regions of introgression following secondary contact between the subspecies. This resulted in high diversity and divergence in genomic islands of putative virulence genes, including muc5 (CHUDEA2_430) and a hypothetical protein (CHUDEA6_5270). This diversity is maintained by balancing selection, suggesting a co-evolutionary arms race with the host. Finally, we find that recent gene flow from C. h. aquapotentis to C. h. hominis, likely associated with increased human migration, maybe driving the evolution of more virulent C. hominis variants.
RESTING MYOCARDIAL BLOOD FLOW IS INVERSELY RELATED TO AMYLOID BURDEN IN LIGHT CHAIN CARDIAC AMYLOIDOSIS
Authors: Ethan Katznelson, Michael Jerosch-Herold, Sarah Cuddy, Olivier Clerc, Alexandra Taylor, Marie F. Kijewski, Frederick L. Ruberg, Marcelo F. Di Carli, Ronglih Liao, Rodney H. Falk, Raymond Y. Kwong, Sharmila Dorbala
Journal: Journal of the American College of Cardiology (2022)
Risks for Anaphylaxis With Intravenous Iron Formulations
Authors: Chintan V. Dave, Gary M. Brittenham, Jeffrey L. Carson, Soko Setoguchi
Journal: Annals of Internal Medicine (2022)

The risks for anaphylaxis among intravenous (IV) iron products currently in use have not been assessed.To compare risks for anaphylaxis among 5 IV iron products that are used frequently.Retrospective cohort study using a target trial emulation framework.Medicare fee-for-service data with Part D coverage between July 2013 and December 2018.Older adults receiving their first administration of IV iron.The primary outcome was the occurrence of anaphylaxis within 1 day of IV iron administration, ascertained using a validated case definition. Analysis was adjusted for 40 baseline covariates using inverse probability of treatment weighting. The adjusted incidence rates (IRs) for anaphylaxis per 10 000 first administrations and odds ratios (ORs) were computed.The adjusted IRs for anaphylaxis per 10 000 first administrations were 9.8 cases (95% CI, 6.2 to 15.3 cases) for iron dextran, 4.0 cases (CI, 2.5 to 6.6 cases) for ferumoxytol, 1.5 cases (CI, 0.3 to 6.6 cases) for ferric gluconate, 1.2 cases (CI, 0.6 to 2.5 cases) for iron sucrose, and 0.8 cases (CI, 0.3 to 2.6 cases) for ferric carboxymaltose. Using iron sucrose as the referent category, the adjusted ORs for anaphylaxis were 8.3 (CI, 3.5 to 19.8) for iron dextran and 3.4 (CI, 1.4 to 8.3) for ferumoxytol. When cohort entry was restricted to the period after withdrawal of high-molecular-weight iron dextran from the U.S. market in 2014, the risk for anaphylaxis associated with low-molecular-weight iron dextran (OR, 8.4 [CI, 2.8 to 24.7]) did not change appreciably. Anaphylactic reactions requiring hospitalizations were observed only among patients using iron dextran or ferumoxytol.Generalizability to non-Medicare populations.The rates of anaphylaxis were very low with all IV iron products but were 3- to 8-fold greater for iron dextran and ferumoxytol than for iron sucrose.None.
QIM22-190: Virtual Patient Navigation: A Revised Navigation Strategy Proves Successful at Completing CRC Screening in Vulnerable Populations
Authors: William Alex Carson, Delecia Robinson, Lisa Scott, Tracie Lewis, Becky Eaddy, Annie Thibault, Frank Berger
Journal: Journal of the National Comprehensive Cancer Network (2022)

"QIM22-190: Virtual Patient Navigation: A Revised Navigation Strategy Proves Successful at Completing CRC Screening in Vulnerable Populations" published on 31 Mar 2022 by National Comprehensive Cancer Network.
SUCCESSFUL MULTIMODALITY INVESTIGATION OF REFRACTORY PLATYPNEA ORTHODEOXIA NECESSITATING REDO PERCUTANEOUS PATENT FORAMEN OVALE CLOSURE
Authors: Gursharan Singh Samra, Ali J. Noory, Kushani Gajjar, David Lasorda, Anita Umayal Radhakrishnan
Journal: Journal of the American College of Cardiology (2022)
Reply to Yu Wei, Yao Zhu, and Dingwei Ye's Letter to the Editor re: Fabio Turco, Andrew Armstrong, Gerhardt Attard, et al. What Experts Think About Prostate Cancer Management During the COVID-19 Pandemic: Report from the Advanced Prostate Cancer Consensus Conference 2021. Eur Urol. 2022;82:6–11
Authors: F. Turco, M. Smith, A. Omlin, S. Gillessen
Journal: European Urology (2022)