tbuckley/cabot-search huggingface dataset:
LBA7 Nivolumab (NIVO) plus chemotherapy (Chemo) or ipilimumab (IPI) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): CheckMate 649 study
Authors: Y.Y. Janjigian, J.A. Ajani, M. Moehler, M. Garrido, C. Gallardo, L. Shen, K. Yamaguchi, L. Wyrwicz, T. Skoczylas, A. Bragagnoli, T. Liu, M. Tehfe, E. Elimova, M. Li, V. Poulart, M. Lei, K. Kondo, K. Shitara
Journal: Annals of Oncology (2021)
LBA32 Principal results of the EORTC-1508 trial: A phase II randomised, multicentre study of bevacizumab vs atezolizumab and bevacizumab with acetylsalicylic acid or placebo in recurrent platinum-resistant ovarian, fallopian tube or primary peritoneal adenocarcinoma
Authors: S. Banerjee, P.B. Ottevanger, A. Sarivalasis, R. Le Scodan, A. Montes, J.R. Kroep, M. Romeo Marin, A. Casado Herraez, M. Auvray-Kuentz, A.M. Westermann, B. Lucas, D. Dangaj, F. Herrera, A. Wolfer, C. Coens, M.B. Vanlancker, L. Kandalaft, G. Coukos
Journal: Annals of Oncology (2021)
Intradermal-delivered DNA vaccine induces durable immunity mediating a reduction in viral load in a rhesus macaque SARS-CoV-2 challenge model
Authors: Ami Patel, Jewell N. Walters, Emma L. Reuschel, Katherine Schultheis, Elizabeth Parzych, Ebony N. Gary, Igor Maricic, Mansi Purwar, Zeena Eblimit, Susanne N. Walker, Diana Guimet, Pratik Bhojnagarwala, Opeyemi S. Adeniji, Arthur Doan, Ziyang Xu, Dustin Elwood, Sophia M. Reeder, Laurent Pessaint, Kevin Y. Kim, Anthony Cook, Neethu Chokkalingam, Brad Finneyfrock, Edgar Tello-Ruiz, Alan Dodson, Jihae Choi, Alison Generotti, John Harrison, Nicholas J. Tursi, Viviane M. Andrade, Yaya Dia, Faraz I. Zaidi, Hanne Andersen, Mohamed Abdel-Mohsen, Mark G. Lewis, Kar Muthumani, J. Joseph Kim, Daniel W. Kulp, Laurent M. Humeau, Stephanie J. Ramos, Trevor R.F. Smith, David B. Weiner, Kate E. Broderick
Journal: Cell Reports Medicine (2021)

Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, has had a dramatic global impact on public health and social and economic infrastructures. Here, we assess the immunogenicity and anamnestic protective efficacy in rhesus macaques of an intradermal (i.d.)-delivered SARS-CoV-2 spike DNA vaccine, INO-4800, currently being evaluated in clinical trials. Vaccination with INO-4800 induced T cell responses and induced spike antigen and RBD binding antibodies with ADCP and ADCD activity. Sera from the animals neutralized both the D614 and G614 SARS-CoV-2 pseudotype viruses. Several months after vaccination, animals were challenged with SARS-CoV-2 resulting in rapid recall of anti-SARS-CoV-2 spike protein T cell and neutralizing antibody responses. These responses were associated with lower viral loads in the lung. These studies support the immune impact of INO-4800 for inducing both humoral and cellular arms of the adaptive immune system, which are likely important for providing durable protection against COVID-19 disease.
Eruptive keratoacanthomas associated with dupilumab therapy
Authors: D. Gleeson, S. Cliff, M. Das
Journal: British Journal of Dermatology (2021)

We would like to present the case of eruptive keratoacanthomas associated with dupilumab therapy, which occurred in an 85-year-old woman receiving biologic therapy for the treatment of atopic dermatitis. With the increasing prevalence of Dupilumab usage, this is an important potential complication of which clinicians should be aware.
Increased risk for <scp>COVID</scp>‐19 breakthrough infection in fully vaccinated patients with substance use disorders in the United States between December 2020 and August 2021
Authors: Lindsey Wang, QuanQiu Wang, Pamela B. Davis, Nora D. Volkow, Rong Xu
Journal: World Psychiatry (2021)

Individuals with substance use disorders (SUDs) are at increased risk for COVID‐19 infection and for adverse outcomes of the infection. Though vaccines are highly effective against COVID‐19, their effectiveness in individuals with SUDs might be curtailed by compromised immune status and a greater likelihood of exposures, added to the waning vaccine immunity and the new SARS‐CoV‐2 variants. In a population‐based cohort study, we assessed the risk, time trends, outcomes and disparities of COVID‐19 breakthrough infection in fully vaccinated SUD patients starting 14 days after completion of vaccination. The study included 579,372 individuals (30,183 with a diagnosis of SUD and 549,189 without such a diagnosis) who were fully vaccinated between December 2020 and August 2021, and had not contracted COVID‐19 infection prior to vaccination. We used the TriNetX Analytics network platform to access de‐identified electronic health records from 63 health care organizations in the US. Among SUD patients, the risk for breakthrough infection ranged from 6.8% for tobacco use disorder to 7.8% for cannabis use disorder, all significantly higher than the 3.6% in non‐SUD population (p&lt;0.001). Breakthrough infection risk remained significantly higher after controlling for demographics (age, gender, ethnicity) and vaccine types for all SUD subtypes, except for tobacco use disorder, and was highest for cocaine and cannabis use disorders (hazard ratio, HR=2.06, 95% CI: 1.30‐3.25 for cocaine; HR=1.92, 95% CI: 1.39‐2.66 for cannabis). When we matched SUD and non‐SUD individuals for lifetime comorbidities and adverse socioeconomic determinants of health, the risk for breakthrough infection no longer differed between these populations, except for patients with cannabis use disorder, who remained at increased risk (HR=1.55, 95% CI: 1.22‐1.99). The risk for breakthrough infection was higher in SUD patients who received the Pfizer than the Moderna vaccine (HR=1.49, 95% CI: 1.31‐1.69). In the vaccinated SUD population, the risk for hospitalization was 22.5% for the breakthrough cohort and 1.6% for the non‐breakthrough cohort (risk ratio, RR=14.4, 95% CI: 10.19‐20.42), while the risk for death was 1.7% and 0.5% respectively (RR=3.5, 95% CI: 1.74‐7.05). No significant age, gender and ethnic disparities for breakthrough infection were observed in vaccinated SUD patients. These data suggest that fully vaccinated SUD individuals are at higher risk for breakthrough COVID‐19 infection, and this is largely due to their higher prevalence of comorbidities and adverse socioeconomic determinants of health compared with non‐SUD individuals. The high frequency of comorbidities in SUD patients is also likely to contribute to their high rates of hospitalization and death following breakthrough infection.
339TiP SOLTI-1502 ARIANNA: Targeting PAM50 HER2-enriched intrinsic subtype with enzalutamide in hormone receptor-positive/HER2-negative metastatic breast cancer
Authors: L. Manso, S. Pernas, M. Margelí, S. Blanch, B. Adamo, F.J. Salvador Bofill, D. Moreno, X. González, T. Pascual, J.M. Ferrero-Cafiero, C.M. Perou, A. Prat, M. Oliveira
Journal: Annals of Oncology (2021)
Burden of liver disease progression in hospitalized patients with type 2 diabetes mellitus
Authors: Vincent Mallet, Lucia Parlati, Alessandro Martinino, Juan Pablo Scarano Pereira, Carmen Navas Jimenez, Mehdi Sakka, Samir Bouam, Aurelia Retbi, Donika Krasteva, Jean-François Meritet, Michaël Schwarzinger, Dominique Thabut, Pierre Rufat, Dominique Bonnefont-Rousselot, Philippe Sogni, Stanislas Pol, Emmanuel Tsochatzis, Hélène Fontaine, Marion Corouge, Anaïs Vallet Pichard, Clémence Hollande, Benoit Terris, Etienne Larger, Jérome Bertherat, Vlad Ratziu, Agnès Hartemann
Journal: Journal of Hepatology (2021)
Soft X‐Ray Stimulated Lanthanide@MOF Nanoprobe for Amplifying Deep Tissue Synergistic Photodynamic and Antitumor Immunotherapy
Authors: Xiaoting Zhao, Youbin Li, Linman Du, Zhiming Deng, Mingyang Jiang, Songjun Zeng
Journal: Advanced Healthcare Materials (2021)

Combining photodynamic therapy (PDT) and immunotherapy has shown profound impact for synergistic treatment of malignant tumors. However, the shallow penetration depth of the traditional visible light activated PDT, immunosuppressive tumor microenvironment (TME), and poor immunogenicity of deep-seated solid tumors have significantly impeded the therapeutic efficiency. Herein, a soft X-ray activated nanoprobe is rationally engineered via integrating porphyrin Zr-based metal-organic framework with lanthanide NaYF4 :Gd,Tb@NaYF4 scintillator nanoparticles (SNPs) by a new in situ growth strategy for synergistic PDT and immunotherapy of tumor. The nanoprobe possesses remarkably enhanced reactive oxygen species (ROS) generation triggered by soft X-ray via further covalently grafting rose bengal on the nanoprobe, even at tissue depths of 3 cm. Moreover, the soft X-ray induced ROS can act as potential immunogenic cell death (ICD) trigger, subsequently leading to the activation of the adaptive antitumor immune-response. Significantly, the boosted ROS generation can further modulate the immunosuppressive TME. This work provides new strategy of designing antitumor nanoprobes for soft X-ray triggered deep-tissue PDT and immune response, breaking the depth barriers suffered by the traditional photoactivated PDT or ICD using visible and near infrared light.
The menin-MLL1 interaction is a molecular dependency in <i>NUP98</i>-rearranged AML
Authors: Emily B. Heikamp, Jill A. Henrich, Florian Perner, Eric M. Wong, Charles Hatton, Yanhe Wen, Sonali P. Barwe, Anilkumar Gopalakrishnapillai, Haiming Xu, Hannah J. Uckelmann, Sumiko Takao, Yaniv Kazansky, Yana Pikman, Gerard M. McGeehan, Edward A. Kolb, Alex Kentsis, Scott A. Armstrong
Journal: Blood (2021)

Translocations involving the NUP98 gene produce NUP98-fusion proteins and are associated with a poor prognosis in acute myeloid leukemia (AML). MLL1 is a molecular dependency in NUP98-fusion leukemia, and therefore we investigated the efficacy of therapeutic blockade of the menin-MLL1 interaction in NUP98-fusion leukemia models. Using mouse leukemia cell lines driven by NUP98-HOXA9 and NUP98-JARID1A fusion oncoproteins, we demonstrate that NUP98-fusion-driven leukemia is sensitive to the menin-MLL1 inhibitor VTP50469, with an IC50 similar to what we have previously reported for MLL-rearranged and NPM1c leukemia cells. Menin-MLL1 inhibition upregulates markers of differentiation such as CD11b and downregulates expression of proleukemogenic transcription factors such as Meis1 in NUP98-fusion-transformed leukemia cells. We demonstrate that MLL1 and the NUP98 fusion protein itself are evicted from chromatin at a critical set of genes that are essential for the maintenance of the malignant phenotype. In addition to these in vitro studies, we established patient-derived xenograft (PDX) models of NUP98-fusion-driven AML to test the in vivo efficacy of menin-MLL1 inhibition. Treatment with VTP50469 significantly prolongs survival of mice engrafted with NUP98-NSD1 and NUP98-JARID1A leukemias. Gene expression analysis revealed that menin-MLL1 inhibition simultaneously suppresses a proleukemogenic gene expression program, including downregulation of the HOXa cluster, and upregulates tissue-specific markers of differentiation. These preclinical results suggest that menin-MLL1 inhibition may represent a rational, targeted therapy for patients with NUP98-rearranged leukemias.
77P Identification of prognostic and predictive immunological biomarkers in stage I and III non-small cell lung cancer (NSCLC) patients: A prospective exploratory study
Authors: R. Vaes, K. Reynders, J. Sprooten, K. Nevola, A. Garg, M. Lambrecht, L.E.L. Hendriks, M. Rucevic, D. De Ruysscher
Journal: Annals of Oncology (2021)
Three-dimensional-engineered bioprinted in vitro human neural stem cell self-assembling culture model constructs of Alzheimer's disease
Authors: Yi Zhang, Haiyan Chen, Xiaoyan Long, Tao Xu
Journal: Bioactive Materials (2021)

The pathogenic cascade of Alzheimer's disease (AD) characterized by amyloid-β protein accumulation is still poorly understood, partially owing to the limitations of relevant models without in vivo neural tissue microenvironment to recapitulate cell-cell interactions. To better mimic neural tissue microenvironment, three-dimensional (3D) core-shell AD model constructs containing human neural progenitor cells (NSCs) with 2% matrigel as core bioink and 2% alginate as shell bioink have been bioprinted by a co-axial bioprinter, with a suitable shell thickness for nutrient exchange and barrier-free cell interaction cores. These constructs exhibit cell self-clustering and -assembling properties and engineered reproducibility with long-term cell viability and self-renewal, and a higher differentiation level compared to 2D and 3D MIX models. The different effects of 3D bioprinted, 2D, and MIX microenvironments on the growth of NSCs are mainly related to biosynthesis of amino acids and glyoxylate and dicarboxylate metabolism on day 2 and ribosome, biosynthesis of amino acids and proteasome on day 14. Particularly, the model constructs demonstrated Aβ aggregation and higher expression of Aβ and tau isoform genes compared to 2D and MIX controls. AD model constructs will provide a promising strategy to facilitate the development of a 3D in vitro AD model for neurodegeneration research.
Recommendations for the use of the acetaminophen hepatotoxicity model for mechanistic studies and how to avoid common pitfalls
Authors: Hartmut Jaeschke, Olamide B. Adelusi, Jephte Y. Akakpo, Nga T. Nguyen, Giselle Sanchez-Guerrero, David S. Umbaugh, Wen-Xing Ding, Anup Ramachandran
Journal: Acta Pharmaceutica Sinica B (2021)

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, which is safe at therapeutic doses but can cause severe liver injury and even liver failure after overdoses. The mouse model of APAP hepatotoxicity recapitulates closely the human pathophysiology. As a result, this clinically relevant model is frequently used to study mechanisms of drug-induced liver injury and even more so to test potential therapeutic interventions. However, the complexity of the model requires a thorough understanding of the pathophysiology to obtain valid results and mechanistic information that is translatable to the clinic. However, many studies using this model are flawed, which jeopardizes the scientific and clinical relevance. The purpose of this review is to provide a framework of the model where mechanistically sound and clinically relevant data can be obtained. The discussion provides insight into the injury mechanisms and how to study it including the critical roles of drug metabolism, mitochondrial dysfunction, necrotic cell death, autophagy and the sterile inflammatory response. In addition, the most frequently made mistakes when using this model are discussed. Thus, considering these recommendations when studying APAP hepatotoxicity will facilitate the discovery of more clinically relevant interventions.
140P Benefit of adjuvant chemotherapy in luminal A-like early breast cancer in women aged 40 years or younger: Results of a national multi-institutional study
Authors: O. Dufour, G. Houvenaeghel, J-M. Classe, M. Cohen, C. Faure, C. Mazouni, M-P. Chauvet, E. Jouve, E. Darai, A-S. Azuar, P. Guimbergues, A. Gonçalves, A. De Nonneville
Journal: Annals of Oncology (2021)
Large‐scale provocation studies identify maladaptive responses to ubiquitous aeroallergens as a correlate of severe allergic rhinoconjunctivitis and asthma
Authors: Alisha M. Smith, Robert M. Ramirez, Nathan Harper, Fabio Jimenez, Anne P. Branum, Justin A. Meunier, Lavanya Pandranki, Andrew Carrillo, Caitlyn Winter, Lauryn Winter, Cynthia G. Rather, Daniel A. Ramirez, Charles P. Andrews, Marcos I. Restrepo, Diego J. Maselli, Jacqueline A. Pugh, Robert A. Clark, Grace C. Lee, Alvaro G. Moreira, Muthu Saravanan Manoharan, Jason F. Okulicz, Robert L. Jacobs, Sunil K. Ahuja
Journal: Allergy (2021)

Allergic asthma (AA) and allergic rhinoconjunctivitis (ARC) are common comorbid environmentally triggered diseases. We hypothesized that severe AA/ARC reflects a maladaptive or unrestrained response to ubiquitous aeroallergens.We performed provocation studies wherein six separate cohorts of persons (total n = 217) with ARC, with or without AA, were challenged once or more with fixed concentrations of seasonal or perennial aeroallergens in an aeroallergen challenge chamber (ACC).Aeroallergen challenges elicited fully or partially restrained vs. unrestrained evoked symptom responsiveness, corresponding to the resilient and adaptive vs. maladaptive AA/ARC phenotypes, respectively. The maladaptive phenotype was evoked more commonly during challenge with a non-endemic versus endemic seasonal aeroallergen. In an AA cohort, symptom responses evoked after house dust mite (HDM) challenges vs. recorded in the natural environment were more accurate and precise predictors of asthma severity and control, lung function (FEV1), and mechanistic correlates of maladaptation. Correlates included elevated levels of peripheral blood CD4+ and CD8+ T-cells, eosinophils, and T-cell activation, as well as gene expression proxies for ineffectual epithelial injury/repair responses. Evoked symptom severity after HDM challenge appeared to be more closely related to levels of CD4+ and CD8+ T-cells than eosinophils, neutrophils, or HDM-specific IgE.Provocation studies support the concept that resilience, adaptation, and maladaptation to environmental disease triggers calibrate AA/ARC severity. Despite the ubiquity of aeroallergens, in response to these disease triggers in controlled settings (ie, ACC), most atopic persons manifest the resilient or adaptive phenotype. Thus, ARC/AA disease progression may reflect the failure to preserve the resilient or adaptive phenotype. The triangulation of CD8+ T-cell activation, airway epithelial injury/repair processes and maladaptation in mediating AA disease severity needs more investigation.
Maintenance or Discontinuation of Antidepressants in Primary Care
Authors: Gemma Lewis, Louise Marston, Larisa Duffy, Nick Freemantle, Simon Gilbody, Rachael Hunter, Tony Kendrick, David Kessler, Dee Mangin, Michael King, Paul Lanham, Michael Moore, Irwin Nazareth, Nicola Wiles, Faye Bacon, Molly Bird, Sally Brabyn, Alison Burns, Caroline S. Clarke, Anna Hunt, Jodi Pervin, Glyn Lewis
Journal: New England Journal of Medicine (2021)

Patients with depression who are treated in primary care practices may receive antidepressants for prolonged periods. Data are limited on the effects of maintaining or discontinuing antidepressant therapy in this setting.We conducted a randomized, double-blind trial involving adults who were being treated in 150 general practices in the United Kingdom. All the patients had a history of at least two depressive episodes or had been taking antidepressants for 2 years or longer and felt well enough to consider stopping antidepressants. Patients who had received citalopram, fluoxetine, sertraline, or mirtazapine were randomly assigned in a 1:1 ratio to maintain their current antidepressant therapy (maintenance group) or to taper and discontinue such therapy with the use of matching placebo (discontinuation group). The primary outcome was the first relapse of depression during the 52-week trial period, as evaluated in a time-to-event analysis. Secondary outcomes were depressive and anxiety symptoms, physical and withdrawal symptoms, quality of life, time to stopping an antidepressant or placebo, and global mood ratings.A total of 1466 patients underwent screening. Of these patients, 478 were enrolled in the trial (238 in the maintenance group and 240 in the discontinuation group). The average age of the patients was 54 years; 73% were women. Adherence to the trial assignment was 70% in the maintenance group and 52% in the discontinuation group. By 52 weeks, relapse occurred in 92 of 238 patients (39%) in the maintenance group and in 135 of 240 (56%) in the discontinuation group (hazard ratio, 2.06; 95% confidence interval, 1.56 to 2.70; P<0.001). Secondary outcomes were generally in the same direction as the primary outcome. Patients in the discontinuation group had more symptoms of depression, anxiety, and withdrawal than those in the maintenance group.Among patients in primary care practices who felt well enough to discontinue antidepressant therapy, those who were assigned to stop their medication had a higher risk of relapse of depression by 52 weeks than those who were assigned to maintain their current therapy. (Funded by the National Institute for Health Research; ANTLER ISRCTN number, ISRCTN15969819.).
Novel therapeutic targets for cholestatic and fatty liver disease
Authors: Michael Trauner, Claudia Daniela Fuchs
Journal: Gut (2021)

Cholestatic and non-alcoholic fatty liver disease (NAFLD) share several key pathophysiological mechanisms which can be targeted by novel therapeutic concepts that are currently developed for both areas. Nuclear receptors (NRs) are ligand-activated transcriptional regulators of key metabolic processes including hepatic lipid and glucose metabolism, energy expenditure and bile acid (BA) homoeostasis, as well as inflammation, fibrosis and cellular proliferation. Dysregulation of these processes contributes to the pathogenesis and progression of cholestatic as well as fatty liver disease, placing NRs at the forefront of novel therapeutic approaches. This includes BA and fatty acid activated NRs such as farnesoid-X receptor (FXR) and peroxisome proliferator-activated receptors, respectively, for which high affinity therapeutic ligands targeting specific or multiple isoforms have been developed. Moreover, novel liver-specific ligands for thyroid hormone receptor beta 1 complete the spectrum of currently available NR-targeted drugs. Apart from FXR ligands, BA signalling can be targeted by mimetics of FXR-activated fibroblast growth factor 19, modulation of their enterohepatic circulation through uptake inhibitors in hepatocytes and enterocytes, as well as novel BA derivatives undergoing cholehepatic shunting (instead of enterohepatic circulation). Other therapeutic approaches more directly target inflammation and/or fibrosis as critical events of disease progression. Combination strategies synergistically targeting metabolic disturbances, inflammation and fibrosis may be ultimately necessary for successful treatment of these complex and multifactorial disorders.