tbuckley/cabot-search huggingface dataset:
Discovery of N-benzyl hydroxypyridone carboxamides as a novel and potent antiviral chemotype against human cytomegalovirus (HCMV)
Authors: Sameera Senaweera, Tiffany C. Edwards, Jayakanth Kankanala, Yan Wang, Rajkumar Lalji Sahani, Jiashu Xie, Robert J. Geraghty, Zhengqiang Wang
Journal: Acta Pharmaceutica Sinica B (2021)

Current drugs for treating human cytomegalovirus (HCMV) infections are limited by resistance and treatment-associated toxicities. In developing mechanistically novel HCMV antivirals, we discovered an N-benzyl hydroxypyridone carboxamide antiviral hit (8a) inhibiting HCMV in submicromolar range. We describe herein the structure-activity relationship (SAR) for 8a, and the characterization of potent analogs for cytotoxicity/cytostatic property, the preliminary mechanism of action, and the absorption, distribution, metabolism and excretion (ADME) properties. The SAR revealed a few pharmacophore features conferring optimal antiviral profile, including the 5-OH, the N-1 benzyl, at least one -CH2- in the linker, and a di-halogen substituted phenyl ring in the amide moiety. In the end, we identified numerous analogs with sub-micromolar antiviral potency and good selectivity index. The preliminary mechanism of action characterization used a pUL89-C biochemical endonuclease assay, a virus entry assay, a time-of-addition assay, and a compound withdrawal assay. ADME profiling measuring aqueous solubility, plasma and liver microsomal stability, and parallel artificial membrane permeability assay (PAMPA) permeability demonstrated largely favorable drug-like properties. Together, these studies validate the N-benzyl hydroxypyridone carboxamide as a viable chemotype for potent and mechanistically distinct antivirals against HCMV.
MYXOMA HIDING BEHIND THROMBUS: A RARE CASE OF LEFT ATRIAL APPENDAGE MYXOMA MIMICKING THROMBUS!!! SOME DIFFERENTIAL FEATURES ON IMAGING
Authors: Anand Subramanian, Sanjeev Nair, Daniel Jipescu, Aman Patel, Senthil Thambidorai, Ahsan Khan, Satish Chandraprakasam
Journal: Journal of the American College of Cardiology (2020)
26900 A phase 2b trial evaluating the efficacy of delgocitinib cream for the treatment of chronic hand eczema (CHE) using and validating the Hand Eczema Severity Index (HECSI)
Authors: Per Soerensen, Per Soerensen, Philip Griffiths, Thor Schüett Svane Nielsen, Lotte Seiding Larsen, Katarina Resen, Tove Agner Prof
Journal: Journal of the American Academy of Dermatology (2021)
Association of Preoperative Clinical, Laboratory, Imaging, and Pathologic Data With Clinically Beneficial Pathology Among Routine Splenectomy Specimens
Authors: Lee Erez, Ginette Schiby, Imri Amiel, Shachar Naor, Naama Keren, Danny Rosin, Iris Barshack, Jonathan Canaani
Journal: JAMA Network Open (2021)

Previous studies have shown that uniform pathologic review of all splenectomy surgical specimens reveals new clinically actionable diagnoses only in a minority of cases.To examine whether the aggregate of clinical, laboratory, imaging, and pathologic preoperative data is associated with a clinically beneficial pathologic study for routine splenectomy surgical specimens.This single-center retrospective cohort study included all patients who underwent splenectomy from January 1, 2013, through December 31, 2018, at a single center. Clinical, imaging, and pathologic data were extracted from the institution's electronic medical records system. Data analysis was conducted from June to November 2020.Undergoing splenectomy for trauma or diagnostic or therapeutic indications.Spleen pathology study resulting in a new medical diagnosis or change in medical management.Overall, 90 patients (53 [59%] men) with a median (range) age of 59 (19-90) years underwent splenectomy for therapeutic purposes in 41 patients (45%), trauma in 24 patients (27%), diagnostic purposes in 15 patients (17%), and combined therapeutic and diagnostic purposes in 9 patients (10%). In 14 patients (15%) a new malignant neoplasm was found, and in 8 patients (9%), a new nonneoplastic medical condition was diagnosed. A new pathologic diagnosis resulted in change in medical management in 16 patients (18%). In patients without a prior diagnosis of cancer, 41 of 56 pathology biopsies (73%) were found to be normal whereas in 7 biopsies (13%), a new diagnosis of a hematologic malignant neoplasm was revealed (P < .001). Patients with clinical splenomegaly were significantly more likely to have a new pathologic diagnosis of cancer compared with patients without splenomegaly (15 of 26 [58%] vs 4 of 64 [7%]; P < .001). In 39 of 43 patients (91%) with normal presurgery imaging studies, normal spleen pathology was revealed, whereas in 14 of 17 patients (82%) with abnormal imaging studies, a new hematological malignant neoplasm was diagnosed following pathologic review of the spleen specimen (P < .001). Patients with gross abnormalities on macroscopic examination had a significantly increased likelihood of a hematological cancer diagnosis (17 of 40 [43%]) and a solid cancer diagnosis (4 [10%]) compared with patients with grossly normal specimens (4 of 49 [8%]; P < .001).In this cohort study, routine pathologic review of spleen specimens was clinically beneficial in patients with splenomegaly, abnormal imaging results, a prior diagnosis of cancer, and with grossly abnormal spleens.
Profile of humoral and cellular immune responses to single doses of BNT162b2 or ChAdOx1 nCoV-19 vaccines in residents and staff within residential care homes (VIVALDI): an observational study
Authors: Gokhan Tut, Tara Lancaster, Maria Krutikov, Panagiota Sylla, David Bone, Nayandeep Kaur, Eliska Spalkova, Christopher Bentley, Umayr Amin, Azar T Jadir, Samuel Hulme, Megan S Butler, Morenike Ayodele, Rachel Bruton, Madhumita Shrotri, Borscha Azmi, Chris Fuller, Aidan Irwin-Singer, Andrew Hayward, Andrew Copas, Laura Shallcross, Paul Moss
Journal: The Lancet Healthy Longevity (2021)
Advances and highlights in asthma in 2021
Authors: Ioana Agache, Ibon Eguiluz‐Gracia, Catalina Cojanu, Alexandru Laculiceanu, Stefano del Giacco, Magdalena Zemelka‐Wiacek, Anna Kosowska, Cezmi A. Akdis, Marek Jutel
Journal: Allergy (2021)

Last year brought a significant advance in asthma management, unyielding to the pressure of the pandemics. Novel key findings in asthma pathogenesis focus on the resident cell compartment, epigenetics and the innate immune system. The precision immunology unbiased approach was supplemented with novel tools and greatly facilitated by the use of artificial intelligence. Several randomised clinical trials and good quality real-world evidence shed new light on asthma treatment and supported the revision of several asthma guidelines (GINA, Expert Panel Report 3, ERS/ATS guidelines on severe asthma) and the conception of new ones (EAACI Guidelines for the use of biologicals in severe asthma). Integrating asthma management within the broader context of Planetary Health has been put forward. In this review, recently published articles and clinical trials are summarised and discussed with the goal to provide clinicians and researchers with a concise update on asthma research from a translational perspective.
Synthetic Mimics of Antimicrobial Peptides for the Targeted Therapy of Multidrug‐Resistant Bacterial Infection
Authors: Chenyu Gong, Junjie Sun, Yan Xiao, Xue Qu, Meidong Lang
Journal: Advanced Healthcare Materials (2021)

Abstract Antibacterial materials are highly demanded in treatment of bacterial infection, especially severe ones with multidrug‐resistance. Herein, pH‐responsive polypeptide, i.e., poly‐L‐lysine modified by 1‐(propylthio)acetic acid‐3‐octylimidazolium and citraconic anhydride (PLL‐POIM‐CA), is synthesized by post‐polymerization modification of poly‐L‐lysine (PLL) with 1‐(propylthio)acetic acid‐3‐octylimidazolium (POIM) and citraconic anhydride (CA). It is observed that PLL‐POIM‐CA is stable under normal physiological condition, while CA cleaves rapidly at weakly acidic environment like bacterial infectious sites. The hydrolyzed PLL‐POIM‐CA exhibits excellent broad‐spectrum antibacterial activities against Gram‐negative bacteria of Escherichia coli and Gram‐positive bacteria of Staphylococcus aureus and methicillin‐resistant Staphylococcus aureus (MRSA). In particular, the minimum inhibitory concentration (MIC) against multidrug‐resistant bacteria like MRSA is as low as 7.8 µg mL −1 . Moreover, PLL‐POIM‐CA exhibits good biocompatibility with mouse fibroblast cells (L929) in vitro and improved hemocompatibility with an HC 50 exceeding 5000 µg mL −1 . Therefore, PLL‐POIM‐CA displays an excellent bacteria versus cells selectivity (HC 50 /MIC) over 534, which is 53 times higher than natural antimicrobial peptide of indolicidin. It is further demonstrated in vivo that the antimicrobial polypeptide effectively accelerates MRSA‐infected wound healing by relieving local inflammatory response. Therefore, this targeted antimicrobial polypeptide has broad application prospects for the treatment of multidrug‐resistant bacterial infection.
Efficacy and safety of PD-1/PD-L1 antibody combined with chemotherapy as second-line or third-line treatment for metastatic small cell lung cancer.
Authors: Jun Wang, Beibei Yin, Yaping Guan, Dongfeng Feng
Journal: Journal of Clinical Oncology (2021)

e20574 Background: For a small subset of patients, immune checkpoint blockade heralds a promising strategy for achieving disease control in small cell lung cancer (SCLC). Nivolumab or pembrolizumab monotherapy has been granted accelerated approval for treatment of patients with extensive-stage SCLC with disease progression after platinum-based chemotherapy and at least one other line of therapy. Moreover, Based on IMpower133 and CASPIAN data, addition of PD-L1 antibody such as atezolizumab or durvalumab to first-line platinum-based chemotherapy prolongs overall survival over chemotherapy alone. However, it remains exclusive that whether PD-1/PD-L1 antibody combined with chemotherapy is effective against extensive-stage SCLC when progressed on previous chemotherapy. Methods: We reviewed patients with extensive-stage SCLC who have failed in first-line or beyond chemotherapy and received PD-1/PD-L1 antibodies with chemotherapy in a single institute. The efficacy and safety were evaluated. The primary end point was the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1. Results: A total of 11 patients were included in this retrospective cohort study. The median age was 46 years (range from 29 to 62). Seven patients were male. Four were current or former smokers. Six received two prior therapies. Nine had previously received radiation therapy. PD-1 and PD-L1 inhibitors were administrated in 5 and 6 patients, respectively. No patient had a complete response. 2 patients had a partial response, and the objective response rate was 18.2%. 5 patients were evaluated as stable disease with a disease control rate of 63.6%. The median overall survival and progression-free survival was 3.0 months and 2.3 months, respectively. A patient with partial response had a long duration of response of 5.2 months. The most common grade 3 or 4 treatment-related were neutropenia, anemia, and decreased neutrophil count. Most immune-related adverse events were grade 1 or 2, with rash, pruritus and hypothyroidism being the most common, and 1 patient had grade 3 pneumonia. Conclusions: Immunotherapy plus chemotherapy could be beneficial for a subgroup of extensive-stage SCLC patients who have progressed after previous chemotherapy. Further prospective, randomized studies are warranted.
Preformed Ω-profile closure and kiss-and-run mediate endocytosis and diverse endocytic modes in neuroendocrine chromaffin cells
Authors: Wonchul Shin, Lisi Wei, Gianvito Arpino, Lihao Ge, Xiaoli Guo, Chung Yu Chan, Edaeni Hamid, Oleg Shupliakov, Christopher K E Bleck, Ling-Gang Wu
Journal: Neuron (2021)
The Promise of Adjuvant Immunotherapy in Renal-Cell Carcinoma
Authors: Rana R. McKay
Journal: New England Journal of Medicine (2021)

Renal-cell carcinoma is a common cancer in both men and women around the world. Although nephrectomy remains the standard care for patients with locally advanced renal-cell carcinoma, recurrence occurs in up to 50 to 80% of patients, ultimately causing death from the disease. Adjuvant therapy, conceptually developed in the 1960s, is used to improve cure rates and prolong survival after surgical resection. The first studies of adjuvant therapy in renal-cell carcinoma began in the 1980s,1 and since that time, multiple trials have been conducted to test chemotherapy, immunotherapy, and targeted therapy regimens in patients after nephrectomy. Despite numerous worthy attempts, . . .
Two cases of T cell lymphoma following Piggybac-mediated CAR T cell therapy
Authors: Axel Schambach, Michael Morgan, Boris Fehse
Journal: Molecular Therapy (2021)

Recently, Micklethwaite et al. 1 Micklethwaite K.P. Gowrishankar K. Gloss B.S. Li Z. Street J.A. Moezzi L. Mach M.A. Sutrave G. Clancy L.E. Bishop D.C. et al. Investigation of product derived lymphoma following infusion of piggyBac modified CD19 chimeric antigen receptor T-cells. Blood. 2021; (Published online May 11, 2021)https://doi.org/10.1182/blood.2021010858 Crossref Scopus (28) Google Scholar and Bishop et al. 2 Bishop D.C. Clancy L.E. Simms R. Burgess J. Mathew G. Moezzi L. Street, J.A., Sutrave, G., Atkins, E., McGuire, H.M. et al. Development of CAR T-cell lymphoma in two of ten patients effectively treated with piggyBac modified CD19 CAR T-cells. Blood. 2021; (Published online May 19, 2021)https://doi.org/10.1182/blood.2021010813 Crossref Scopus (25) Google Scholar reported results of a phase I first-in-human clinical trial of CD19-directed allogeneic chimeric antigen receptor (CAR)-T cells in 10 patients with relapsed or persistent B cell malignancies after matched-related allogeneic hematopoietic stem cell transplantation (HSCT). CAR-T cells were produced via electroporation with a Piggybac (PB) transposon vector, encoding a CD19 CAR (second generation, with a 4-1BB co-stimulatory domain) driven by a human elongation factor-1 alpha (EF1a) promoter, terminated by an SV40 polyadenylation signal, and flanked by chicken hypersensitivity site 4 (cHS4) β-globin insulator sequences. Clinical responses (five patients with continuous complete remission at median follow-up of 18 months) were promising and comparable to those seen with retroviral CD19-CAR vectors. Surprisingly, two patients developed donor-derived T cell lymphoma. While the exact causes are still under investigation, clinical trials with PB-based CAR-T cells were voluntarily suspended at the investigators' research centers. The authors discuss a number of mechanisms that may have contributed to T cell transformation and have performed work to address potential underlying causes, which we put into perspective here regarding lessons learned in gene therapy trials with integrating retroviral vectors.
Early high antibody titre convalescent plasma for hospitalised COVID-19 patients: DAWn-plasma
Authors: Timothy Devos, Quentin Van Thillo, Veerle Compernolle, Tomé Najdovski, Marta Romano, Nicolas Dauby, Laurent Jadot, Mathias Leys, Evelyne Maillart, Sarah Loof, Lucie Seyler, Martial Moonen, Michel Moutschen, Niels Van Regenmortel, Kevin K. Ariën, Cyril Barbezange, Albrecht Betrains, Mutien Garigliany, Matthias M. Engelen, Iwein Gyselinck, Piet Maes, Alexander Schauwvlieghe, Laurens Liesenborghs, Ann Belmans, Peter Verhamme, Geert Meyfroidt
Journal: European Respiratory Journal (2021)

Background Several randomised clinical trials have studied convalescent plasma for coronavirus disease 2019 (COVID-19) using different protocols, with different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralising antibody titres, at different time-points and severities of illness. Methods In the prospective multicentre DAWn-plasma trial, adult patients hospitalised with COVID-19 were randomised to 4 units of open-label convalescent plasma combined with standard of care (intervention group) or standard of care alone (control group). Plasma from donors with neutralising antibody titres (50% neutralisation titre (NT 50 )) ≥1/320 was the product of choice for the study. Results Between 2 May 2020 and 26 January 2021, 320 patients were randomised to convalescent plasma and 163 patients to the control group according to a 2:1 allocation scheme. A median (interquartile range) volume of 884 (806–906) mL) convalescent plasma was administered and 80.68% of the units came from donors with neutralising antibody titres (NT 50 ) ≥1/320. Median time from onset of symptoms to randomisation was 7 days. The proportion of patients alive and free of mechanical ventilation on day 15 was not different between both groups (convalescent plasma 83.74% (n=267) versus control 84.05% (n=137)) (OR 0.99, 95% CI 0.59–1.66; p=0.9772). The intervention did not change the natural course of antibody titres. The number of serious or severe adverse events was similar in both study arms and transfusion-related side-effects were reported in 19 out of 320 patients in the intervention group (5.94%). Conclusions Transfusion of 4 units of convalescent plasma with high neutralising antibody titres early in hospitalised COVID-19 patients did not result in a significant improvement of clinical status or reduced mortality.
Bell's palsy following vaccination with mRNA (BNT162b2) and inactivated (CoronaVac) SARS-CoV-2 vaccines: a case series and nested case-control study
Authors: Eric Yuk Fai Wan, Celine Sze Ling Chui, Francisco Tsz Tsun Lai, Esther Wai Yin Chan, Xue Li, Vincent Ka Chun Yan, Le Gao, Qiuyan Yu, Ivan Chun Hang Lam, Raccoon Ka Cheong Chun, Benjamin John Cowling, Wing Chi Fong, Alexander Yuk Lun Lau, Vincent Chung Tong Mok, Frank Ling Fung Chan, Cheuk Kwong Lee, Lot Sze Tao Chan, Dawin Lo, Kui Kai Lau, Ivan Fan Ngai Hung, Gabriel Matthew Leung, Ian Chi Kei Wong
Journal: The Lancet Infectious Diseases (2021)
GSK3β as a novel promising target to overcome chemoresistance in pancreatic cancer
Authors: Camilla Pecoraro, Beatrice Faggion, Beatrice Balboni, Daniela Carbone, Godefridus J. Peters, Patrizia Diana, Yehuda G. Assaraf, Elisa Giovannetti
Journal: Drug Resistance Updates (2021)

Pancreatic cancer is an aggressive malignancy with increasing incidence and poor prognosis due to its late diagnosis and intrinsic chemoresistance. Most pancreatic cancer patients present with locally advanced or metastatic disease characterized by inherent resistance to chemotherapy. These features pose a series of therapeutic challenges and new targets are urgently needed. Glycogen synthase kinase 3 beta (GSK3β) is a conserved serine/threonine kinase, which regulates key cellular processes including cell proliferation, DNA repair, cell cycle progression, signaling and metabolic pathways. GSK3β is implicated in non-malignant and malignant diseases including inflammation, neurodegenerative diseases, diabetes and cancer. GSK3β recently emerged among the key factors involved in the onset and progression of pancreatic cancer, as well as in the acquisition of chemoresistance. Intensive research has been conducted on key oncogenic functions of GSK3β and its potential as a druggable target; currently developed GSK3β inhibitors display promising results in preclinical models of distinct tumor types, including pancreatic cancer. Here, we review the latest findings about GSK-3β biology and its role in the development and progression of pancreatic cancer. Moreover, we discuss therapeutic agents targeting GSK3β that could be administered as monotherapy or in combination with other drugs to surmount chemoresistance. Several studies are also defining potential gene signatures to identify patients who might benefit from GSK3β-based therapeutic intervention. This detailed overview emphasizes the urgent need of additional molecular studies on the impact of GSK3β inhibition as well as structural analysis of novel compounds and omics studies of predictive biomarkers.
Torque teno mini virus as a cause of childhood acute promyelocytic leukemia lacking PML/RARA fusion
Authors: Annalisa Astolfi, Riccardo Masetti, Valentina Indio, Salvatore Nicola Bertuccio, Daria Messelodi, Simone Rampelli, Davide Leardini, Matteo Carella, Salvatore Serravalle, Virginia Libri, Jessica Bandini, Stefano Volinia, Marco Candela, Andrea Pession
Journal: Blood (2021)
27468 Bimekizumab short-term and longer-term infection rates in patients with moderate to severe plaque psoriasis: Analysis of pooled data from eight phase 2/3 clinical trials
Authors: Kristian Reich, Yukari Okubo, Kenneth B. Gordon, Andrew Blauvelt, April Armstrong, Dirk De Cuyper, Christopher Cioffi, Luke Peterson, Mark Lebwohl
Journal: Journal of the American Academy of Dermatology (2021)
26607 Proactive management using Cal/BD foam in patients with plaque psoriasis prolongs time with a health-related quality of life improvement, compared with reactive management
Authors: Linda Stein Gold, Ahmad Jalili, Dominique Lons Danic, Nanna Nyholm, Henrik Thoning, Piergiacomo Calzavara-Pinton
Journal: Journal of the American Academy of Dermatology (2021)
Atogepant for the Preventive Treatment of Migraine
Authors: Jessica Ailani, Richard B. Lipton, Peter J. Goadsby, Hua Guo, Rosa Miceli, Lawrence Severt, Michelle Finnegan, Joel M. Trugman
Journal: New England Journal of Medicine (2021)

Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist that is being investigated for the preventive treatment of migraine.In a phase 3, double-blind trial, we randomly assigned adults with 4 to 14 migraine days per month in a 1:1:1:1 ratio to receive a once-daily dose of oral atogepant (10 mg, 30 mg, or 60 mg) or placebo for 12 weeks. The primary end point was the change from baseline in the mean number of migraine days per month across the 12 weeks. Secondary end points included headache days per month, a reduction from baseline of at least 50% in the 3-month average of migraine days per month, quality of life, and scores on the Activity Impairment in Migraine-Diary (AIM-D).A total of 2270 participants were screened, 910 were enrolled, and 873 were included in the efficacy analysis; 214 were assigned to the 10-mg atogepant group, 223 to the 30-mg atogepant group, 222 to the 60-mg atogepant group, and 214 to the placebo group. The mean number of migraine days per month at baseline ranged from 7.5 to 7.9 in the four groups. The changes from baseline across 12 weeks were -3.7 days with 10-mg atogepant, -3.9 days with 30-mg atogepant, -4.2 days with 60-mg atogepant, and -2.5 days with placebo. The mean differences from placebo in the change from baseline were -1.2 days with 10-mg atogepant (95% confidence interval [CI], -1.8 to -0.6), -1.4 days with 30-mg atogepant (95% CI, -1.9 to -0.8), and -1.7 days with 60-mg atogepant (95% CI, -2.3 to -1.2) (P<0.001 for all comparisons with placebo). Results for the secondary end points favored atogepant over placebo with the exceptions of the AIM-D Performance of Daily Activities score and the AIM-D Physical Impairment score for the 10-mg dose. The most common adverse events were constipation (6.9 to 7.7% across atogepant doses) and nausea (4.4 to 6.1% across atogepant doses). Serious adverse events included one case each of asthma and optic neuritis in the 10-mg atogepant group.Oral atogepant once daily was effective in reducing the number of migraine days and headache days over a period of 12 weeks. Adverse events included constipation and nausea. Longer and larger trials are needed to determine the effect and safety of atogepant for migraine prevention. (Funded by Allergan; ADVANCE ClinicalTrials.gov number, NCT03777059.).
Transpancreatic biliary sphincterotomy: justified or overkill?
Authors: Sridhar Sundaram, Nitin Jagtap
Journal: Endoscopy (2021)

See also: Reply to Sundaram and JagtapEndoscopy 2021; 53(09): 986-986DOI: 10.1055/a-1408-3754 See also: Transpancreatic biliary sphincterotomy versus double guidewire in difficult biliary cannulation: a randomized controlled trialEndoscopy 2021; 53(10): 1011-1019DOI: 10.1055/a-1327-2025