tbuckley/cabot-search huggingface dataset:
627 - A checklist to aid in identifying patients with atopic dermatitis who are candidates for systemic therapy
Authors: Jonathan Silverberg, Matthias Augustin, Lawrence Eichenfield, Peter Lio, Emma Guttman-Yassky, Amber Reck Atwater, Evangeline Pierce, Maria Jose Rueda, Alvin Li, Yolanda Munoz Maldonado, Eric Simpson
Journal: British Journal of Dermatology (2024)

Abstract Introduction The decision to initiate systemic therapy (ST) in patients with atopic dermatitis (AD) is complex, with no criteria that are globally agreed upon. To aid dermatology providers in this decision-making, the “When to Start Systemic Therapy Checklist” was developed. The checklist comprises three components: (A) clinical severity, (B) subjective burden, and (C) lack of treatment response, each with several criteria. Systemic therapy is indicated when at least one criterion in each component is fulfilled. Objectives To corroborate the validity of this checklist, we evaluated the agreement between the decision to initiate ST using the checklist, against the reference, CorEvitas AD Registry patients prescribed a ST. Methods Adults with moderate-to-severe AD from the prospective, longitudinal CorEvitas AD registry were included in this descriptive analysis (July 2020 – August 2023). Patients were included if they were initiating ST at enrollment (ST group) or not initiating ST at enrollment (non-ST group) but had vIGA-AD® ≥3 and Eczema Area Severity Index ≥12. The checklist criteria were compared against registry outcome measures; when a criterion did not match a measure, either a proxy measure was selected or that part of the questionnaire was excluded. Overall percentage agreement (accord between checklist criteria and ST initiation status [reference standard]) with corresponding 95% confidence intervals (CIs) was calculated. Results In the ST group (n=1488), 97.0% of patients met at least one criterion from section A, 94.1% from section B, and 92.1% for either section A or B. In the non-ST group (n=208), 100% of patients met at least one criterion from section A, 92.3% from section B, and 92.3% from either section A or B. Among patients in the ST group who met at least one criterion each from section A and B, overall percentage agreement was 81.7% (95% CI: 79.8%, 83.5%). Section C, which addresses “lack of treatment response” could not be evaluated due to the absence of relevant data in the registry. Conclusions Nearly all patients initiating ST met at least one criterion from both section A and B of the “When to Start Systemic Therapy Checklist”, demonstrating a strong alignment between the checklist sections A and B and disease burden of AD patients in the registry. Subsequent research is needed to assess section C due to registry limitations. Future analyses should examine why some patients with high disease burden and severity remain untreated with systemics.
733 - Nemolizumab elicits fast itch response in atopic dermatitis within 2 days: a post hoc analysis of ARCADIA 1 and 2 data
Authors: Jonathan I Silverberg, Linda Stein-Gold, Diamant Thaçi, Andrew E Pink, Kim A Papp, Franz J Legat, Vivian T Laquer, Soo Yeon Cheong, Liliana Ulianov, Anna Ryzhkova, Christophe Piketty
Journal: British Journal of Dermatology (2024)

Abstract Background Itch is the most burdensome symptom of atopic dermatitis (AD) that severely affects sleep and overall and quality of life.1,2 Rapid control of itch could be instrumental in minimizing disease symptoms and the associated burden for patients.3,4 Nemolizumab, an interleukin-31 (IL-31) alpha antagonist, inhibits the IL-31 pathway of itch and inflammation in AD.5 Objectives To evaluate speed of onset of itch relief and sleep improvements with nemolizumab in moderate-to-severe AD. Methods ARCADIA-1 and ARCADIA-2 were two identical, randomized, double-blinded, placebo-controlled studies. Patients (≥12 years) with moderate-to-severe AD and inadequate response to topical corticosteroids (TCS) were randomized (2:1) to receive nemolizumab 30mg every 4 weeks (60mg baseline loading dose) or matching placebo, both with background TCS of low/medium potency with/without topical calcineurin inhibitors (TCI). Results Significant improvements in itch (least squares [LS] mean±standard error [SE] change from baseline [CFB] in Peak Pruritus Numeric Rating Scale [PP-NRS]) were noted in nemolizumab-treated vs placebo-treated patients by Day 1 in ARCADIA-1 (-0.9±0.08 vs -0.4±0.10) and ARCADIA-2 (-1.1±0.09 vs -0.4±0.12), reaching -2.4±0.08 vs -1.2±0.11 and -2.3 ±0.09 vs -0.9±0.12 respectively at Day 14 (p&amp;lt;0.001 for all). Significantly greater proportions of nemolizumab-treated vs placebo-treated patients achieved ≥4-point improvement in PP-NRS by Day 2 in ARCADIA-1 (9.4% vs 3.4%, p&amp;lt;0.01) and Day 1 in ARCADIA-2 (8.2% vs 1.9%, p&amp;lt;0.001) and through Day 14 (ARCADIA-1: 22.7% vs 10.6%, p&amp;lt;0.0001; ARCADIA-2: 23.4% vs 6.8%, p&amp;lt;0.0001). Conclusions Treatment with nemolizumab plus TCS/TCI resulted in rapid, statistically and clinically significant improvements in itch in moderate-to-severe AD.
629 - A novel efficacy index for long-term therapy outcomes expressed by maintenance of EASI 75 and IGA 0,1 response in atopic dermatitis
Authors: Jonathan I Silverberg, Alan Irvine, Peter Foley, James Del Rosso, Alexander Schacht, Martin Dossenbach, Marta Casillas, Erin Johansson, Gaia Gallo, Linda Stein Gold
Journal: British Journal of Dermatology (2024)

Abstract Introduction Atopic dermatitis (AD) is a common, chronic inflammatory disease requiring long-term, continuous therapy, yet in real life, patients may need to temporarily interrupt therapy. Objectives To indirectly compare long-term outcomes with lebrikizumab, tralokinumab, and dupilumab, we present an exploratory efficacy index, which accounts for on-drug and off-drug combined outcomes at Week 52. Methods The data set consisted of patients who, after 16 weeks, responded to treatment, defined as achieving either an IGA 0,1 or EASI 75 score, and who were randomized to receive maintenance dosages of lebrikizumab 250 mg Q4W (ADvocate1; ADvocate2), tralokinumab 300 mg Q2W (ECZTRA1; ECZTRA 2), and dupilumab 300 mg QW, Q2W (SOLO-CONTINUE) or were randomized to withdraw these treatments up to Week 52. The efficacy index is based on a weighted combination of response rates at Week 52, using non-responder imputation results, for IGA 0,1 or EASI 75, for patients who were either in the treatment continuation or the withdrawal arm. Here, we report the efficacy index, in which the weight places equal emphasis on continuing or stopping treatment, and we compare the efficacy index of tralokinumab and dupilumab with lebrikizumab. Results The efficacy index (95% CI) for lebrikizumab, tralokinumab, and dupilumab, respectively, was 53% (45%-61%), 45% (37%-53%), and 34% (28%-40%) with IGA 0,1; 63% (55%-71%), 42% (35%-49%), and 51% (45%-57%) with EASI 75. With IGA 0,1, lebrikizumab was statistically different from dupilumab; with EASI 75, lebrikizumab was statistically different from dupilumab and tralokinumab. Conclusions This novel efficacy index, which accounts for the importance of continuing or stopping therapy after Week 16, may be a useful tool to indirectly compare long-term treatment outcomes. Lebrikizumab’s higher efficacy index may translate to improved long-term management of AD.
<scp>TLR8</scp> is expressed in monocytes in contrast to plasmacytoid dendritic cells and mediates aberrant <scp>IL</scp>‐10 responses in patients with systemic sclerosis (<scp>SSc</scp>)
Authors: Christine Ehlers, Thea Thiele, Hannah Biermann, Stephan Traidl, Luzia Bruns, Annett Ziegler, Matthias Schefzyk, Lea M. Bartsch, Ulrich Kalinke, Torsten Witte, Theresa Graalmann
Journal: Arthritis & Rheumatology (2024)

Systemic sclerosis (SSc) is a severe rheumatic disease causing fibrotic tissue rearrangement. Aberrant toll-like receptor (TLR) 8 transcripts in plasmacytoid dendritic cells (pDCs) were recently linked to SSc pathogenesis, which is at least partially mediated by increased type I interferon (IFN-I) responses. Here, we addressed the functional role of TLR8 signaling in different immune cell subsets of patients with SSc.
PKCα inhibitors promote breast cancer immune evasion by maintaining PD-L1 stability
Authors: Jiaojiao Yu, Yujin Xiang, Yuzhen Gao, Shan Chang, Ren Kong, Xiaoxi Lv, Jinmei Yu, Yunjie Jin, Chenxi Li, Yiran Ma, Zhenhe Wang, Jichao Zhou, Hongyu Yuan, Shuang Shang, Fang Hua, Xiaowei Zhang, Bing Cui, Pingping Li
Journal: Acta Pharmaceutica Sinica B (2024)

Protein kinase C
Demethylzeylasteral induces PD-L1 ubiquitin–proteasome degradation and promotes antitumor immunity via targeting USP22
Authors: Yanyan Zhang, Yun Huang, Dianping Yu, Mengting Xu, Hongmei Hu, Qing Zhang, Minchen Cai, Xiangxin Geng, Hongwei Zhang, Jianhua Xia, Mengmeng Guo, Dong Lu, Hanchi Xu, Linyang Li, Xing Zhang, Qun Wang, Sanhong Liu, Weidong Zhang
Journal: Acta Pharmaceutica Sinica B (2024)

Programmed cell death ligand-1 (PD-L1) is a T cell inhibitory immune checkpoint molecule that interacts with programmed cell death-1 (PD-1) to promote immune escape of tumor cells. Compared with antibody therapies, small molecule drugs show better prospects due to their advantages such as higher bioavailability, better tissue penetration, and reduced risk of immunogenicity. Here, we found that the small molecule demethylzeylasteral (Dem) can significantly downregulate the expression of PD-L1 in colorectal cancer cells and enhance the killing effect of T cells on tumor cells. Mechanistically, Dem binds to the deubiquitinating enzyme USP22 and promotes its degradation, resulting in increased ubiquitination and degradation of PD-L1 through the proteasome pathway. In addition, Dem increased the activity of cytotoxic T cells and reduced the number of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in tumor-infiltrating lymphocytes (TILs), thereby activating the tumor immune microenvironment and inhibiting the growth of subcutaneous MC38 tumors in C57BL/6 mice. Moreover, we also found that the combination of Dem and CTLA4 antibodies can further improve the efficacy of antitumor therapy. Our study reveals the mechanism by which Dem promotes PD-L1 degradation and suggests that the combination of Dem and CTLA4 antibodies may improve the efficacy of immunotherapy.
Erratum to ‘TMPRSS2 inhibitors for the treatment of COVID-19 in adults: a systematic review and meta-analysis of randomized clinical trials of nafamostat and camostat mesylate’ [Clin Microbiol Infect (30) (2024) 743–754]
Authors: María Patricia Hernández-Mitre, Susan C. Morpeth, Balasubramanian Venkatesh, Thomas E. Hills, Joshua Davis, Robert K. Mahar, Grace McPhee, Mark Jones, James Totterdell, Steven Y.C. Tong, Jason A. Roberts
Journal: Clinical Microbiology and Infection (2024)
Replication, safety and immunogenicity of the vectored Ebola vaccine rVSV-ΔG-ZEBOV-GP in a sub-Saharan African paediatric population: a randomised controlled, open-label trial in children aged 1-12 years living in Lambaréné, Gabon
Authors: Ayodele Alabi, Kossiwa Kokou, Saidou Mahmoudou, Ranmali Kavishna, Sravya S. Nakka, Sylvia Rothenberger, Fungai P. Musangomunei, Bisola F. Olubiyi, Juste C. Bie-Ondo, Anita L. Kabwende, Thirumalaisamy P. Velavan, Donata Medaglini, Helder I. Nakaya, Olivier Engler, Ali M. Harandi, Claire-Anne Siegrist, Peter G. Kremsner, Selidji T. Agnandji
Journal: Journal of Infection (2024)

Unlike adults, children experienced stronger and longer vector replication in plasma and shedding in saliva following rVSVΔG-ZEBOV-GP vaccination. The resulting risks of immunosuppression or immune hyperactivation leading to increased Adverse Events (AEs) and altered antibody responses are concerns that have been addressed in the present manuscript.
Prevalence, risk factors and characterisation of individuals with long COVID using Electronic Health Records in over 1.5 million COVID cases in England
Authors: Han-I. Wang, Tim Doran, Michael G. Crooks, Kamlesh Khunti, Melissa Heightman, Arturo Gonzalez-Izquierdo, Muhammad Qummer Ul Arfeen, Antony Loveless, Amitava Banerjee, Christina Van Der Feltz-Cornelis
Journal: Journal of Infection (2024)
Ambient ultraviolet A, ultraviolet B, and risk of melanoma in a nationwide United States cohort, 1984-2014
Authors: Elizabeth K Cahoon, Soutrik Mandal, Ruth M Pfeiffer, David C Wheeler, Michael R Sargen, Bruce H Alexander, Cari M Kitahara, Martha S Linet, Jim Z Mai
Journal: JNCI Journal of the National Cancer Institute (2024)

Ultraviolet radiation (UVR) exposure is the primary risk factor for melanoma, although the relationship is complex. Compared with radiation from UVB wavelengths, UVA makes up a majority of the surface solar UVR, penetrates the skin more deeply, is the principal range emitted by tanning beds, and is less filtered by sunscreens and window glass. Few studies have examined the relationship between ambient UVA and UVB and melanoma risk.
Biomimetic nanocomplex based corneal neovascularization theranostics
Authors: Jinfa Ye, Yuhang Cheng, Xiaofei Wen, Yun Han, Xingyuan Wei, Yiming Wu, Chuan Chen, Min Su, Shundong Cai, Jintao Pan, Gang Liu, Chengchao Chu
Journal: Journal of Controlled Release (2024)
Sudden unexpected death in epilepsy: respiratory vs. cardiac contributions
Authors: Susan Lin, Theodore H Schwartz, Geoffrey S Pitt
Journal: Cardiovascular Research (2024)

Abstract Sudden unexpected death in epilepsy (SUDEP) poses a significant risk to life expectancy for individuals with epilepsy. Mechanistic insight, while incomplete, has advanced through clinical observational studies and animal models. Yet we lack preventative therapies, which will depend on understanding SUDEP mechanisms. Recurrent convulsive seizures are the major SUDEP risk factor. Cardiorespiratory dysfunction precedes SUDEP, but whether cardiac arrhythmias are major proximate culprits for SUDEP remains to be determined. Here, we highlight recent data from mouse models and clinical studies that provide increasing support for respiratory depression and decreasing evidence for tachyarrhythmia-induced SUDEP. Further, we review data from genetic and chemoconvulsant mouse models that have enabled a deeper understanding for how seizures initiated in the central nervous system propagate to the autonomic nervous system and drive seizure-induced respiratory depression and subsequent SUDEP, rather than supporting a proximate cardiac arrhythmia cause. Ongoing research will continue to identify predictive SUDEP biomarkers, improve animal models, and translate basic research into precision medicine approaches. Identifying and understanding the brainstem circuits vulnerable in seizure-induced apnoea will enable therapeutic interventions to enhance the quality of life and life expectancy for individuals with epilepsy.
Novel lipid nanovesicle-loaded dissolving microarray patches for fenretinide in breast cancer chemoprevention
Authors: Alexsandra Conceição Apolinário, Yara A Naser, Fabiana Volpe-Zanutto, Lalitkumar K Vora, Akmal H Sabri, Mingshan Li, Aaron R J Hutton, Helen O McCarthy, Luciana B Lopes, Ryan F Donnelly
Journal: Journal of Controlled Release (2024)

The retinoid fenretinide (FENR) is a promising compound for preventing breast cancer recurrence but faces challenges due to poor solubility and low bioavailability. This study explores the development of dissolving microneedles (MNs) containing FENR-loaded ethosomes for minimally invasive breast cancer chemoprevention, aiming to enhance local drug distribution. Ethosomes were formulated using ethanol, propylene glycol, soya lecithin, water, and polysorbate 80 micelles. MNs were created from poly(vinyl alcohol) and poly(vinylpyrrolidone) hydrogels by adding polymer powder directly into ethosomes suspensions, reducing manufacturing time and cost. Two methods were used to load ethosomes into high-density moulds: 1) only in the needle area, and 2) in both the needle area and baseplate. Dynamic light scattering confirmed nanostructures in the hydrogels and MNs. Micelle-based ethosomes dissolved MNs in 15 min, compared to 30 min for other MNs. Skin deposition studies showed greater drug deposition (up to 10 μg/patch) and enhanced skin permeation of FENR (up to 40 μg) with Method 2. In-vivo studies in rats demonstrated that oral administration resulted in plasma FENR levels below 10 ng/g in the first three hours, whereas MN administration delayed delivery, reaching a maximum plasma concentration of 52 ng/g at 48 h. Skin deposition of FENR from MNs decreased from 3 μg/g on day 1 to <0.3 μg/g by the last day. This study indicates that MNs are a potential minimally invasive dosage form for delivering FENR, offering a new approach for breast cancer chemoprevention.
Fluorogenic RNA-based biomaterials for imaging and tracking the cargo of extracellular vesicles
Authors: Emily E Bonacquisti, Scott W Ferguson, Gable M Wadsworth, Natalie E Jasiewicz, Jinli Wang, Ameya P Chaudhari, Caden C Kussatz, Ana T Nogueira, Daniel P Keeley, Michelle S Itano, Matthew L Bolton, Klaus M Hahn, Priya R Banerjee, Juliane Nguyen
Journal: Journal of Controlled Release (2024)
Comparative effectiveness of vancomycin and metronidazole on event-free survival after initial infection in patients with Clostridioides difficile—a German multicentre cohort study
Authors: Jana Conrad, Katharina Giesbrecht, Rebeca Cruz Aguilar, Stefanie K. Gräfe, Arhamhabib Ullah, Klaus-Peter Hunfeld, Christoph Lübbert, Stefan Pützfeld, Philipp A. Reuken, Marieke Schmitz-Rode, Enrico Schalk, Tobias Schmidt-Wilcke, Stefan Schmiedel, Philipp Solbach, Maria J.G.T. Vehreschild
Journal: Clinical Microbiology and Infection (2024)

ObjectivesThe objective of this study is to examine the comparative effectiveness of vancomycin and metronidazole in a confirmatory analysis of event-free survival (EFS) following initial infection in patients with Clostridioides difficile (C. difficile) from a German multicentre cohort study.MethodsThe IBIS multicentre cohort enrolled patients with an index episode of CDI between August 2017 and September 2020. The primary endpoint was EFS, defined as response to treatment with metronidazole or vancomycin within ten days of initiation, absence of recurrence and death from any cause up to 90 days post-treatment. A Cox proportional hazards model with inverse probability of treatment weighting was used to investigate the comparative effectiveness of this outcome. Additionally, subgroup analyses were performed based on severe and non-severe infections.ResultsOf the 489 patients included, 118 (24%) received initial treatment with metronidazole and 371 (76%) with vancomycin. Of these, 78/118 (66.1%) and 247/371 (66.6%), respectively, responded to treatment within ten days, neither developed a recurrence nor died within 90 days and thus achieved the outcome of EFS. In the subgroup of non-severe infections, 74/293 patients (25.3%) received metronidazole, and 219/293 (74.7%) received vancomycin. Of these, 33/74 (44.6%) metronidazole patients and 150/219 (68.5%) vancomycin patients survived event-free. The Cox proportional hazards model revealed differences in EFS for the overall population and both sub-groups (reference metronidazole: all severity levels: hazard ratio [HR] 0.46, [95% Cl 0.33-0.65]; non-severe: HR 0.39; [95% Cl 0.24-0.60]; severe: HR 0.52; [95% Cl 0.28-0.95]).ConclusionsOur analysis confirms current changes in guidelines, as it supports the superiority of vancomycin compared to metronidazole across all severity levels.
Epigenetic and Oncogenic Inhibitors Cooperatively Drive Differentiation and Kill KRAS<i>-</i>Mutant Colorectal Cancers
Authors: Patrick Loi, Amy E. Schade, Carrie L. Rodriguez, Anjana Krishnan, Naiara Perurena, Van T.M. Nguyen, Yilin Xu, Marina Watanabe, Rachel A. Davis, Alycia Gardner, Natalie F. Pilla, Kaia Mattioli, Olesja Popow, Nuray Gunduz, Tamsin R.M. Lannagan, Samantha Fitzgerald, Ewa T. Sicinska, Jia-Ren Lin, William Tan, Lauren K. Brais, Kevin M. Haigis, Marios Giannakis, Kimmie Ng, Sandro Santagata, Kristian Helin, Owen J. Sansom, Karen Cichowski
Journal: Cancer Discovery (2024)

Abstract Current treatments for KRAS-mutant colorectal cancers are often limited by cellular plasticity and rewiring responses. Here we describe a promising therapeutic strategy that simultaneously targets epigenetic and oncogenic signals. Specifically, we show that inhibitors of histone methyltransferase, EZH2, synergize with various rat sarcoma virus (RAS) pathway inhibitors and promote dramatic tumor regression in vivo. Together these agents cooperatively suppress Wingless and Int-1 (WNT)-driven transcription and drive colorectal cancers into a more differentiated cell state by inducing the Groucho/transducin-like enhancer corepressor, TLE4, along with a network of WNT pathway inhibitors and intestinal differentiation proteins. However, these agents also induce the proapoptotic protein BCL2 modifying factor (BMF), which subsequently kills these more differentiated cells. Accordingly, cell death can be prevented by activating β-catenin, by blocking differentiation, or by ablating BMF expression. Collectively, these studies reveal a new therapeutic approach for treating KRAS-mutant colorectal cancers and illustrate a critical convergence of EZH2 and RAS on oncogenic WNT signals, intestinal differentiation, and apoptosis. Significance: Combined EZH2 and RAS pathway inhibitors kill KRAS-mutant colorectal cancer cells and promote durable tumor regression in vivo. These agents function by cooperatively suppressing the WNT pathway, driving differentiation, and epigenetically reprogramming cells to permit the induction of apoptotic signals, which then kill these more differentiated tumor cells.
Menin Inhibition With Revumenib for <i>KMT2A</i>-Rearranged Relapsed or Refractory Acute Leukemia (AUGMENT-101)
Authors: Ghayas C. Issa, Ibrahim Aldoss, Michael J. Thirman, John DiPersio, Martha Arellano, James S. Blachly, Gabriel N. Mannis, Alexander Perl, David S. Dickens, Christine M. McMahon, Elie Traer, C. Michel Zwaan, Carolyn S. Grove, Richard Stone, Paul J. Shami, Ioannis Mantzaris, Matthew Greenwood, Neerav Shukla, Branko Cuglievan, Tibor Kovacsovics, Yu Gu, Rebecca G. Bagley, Kate Madigan, Yakov Chudnovsky, Huy Van Nguyen, Nicole McNeer, Eytan M. Stein, Andrew Wei, Shaun Fleming, Himalee Sabins, Ibrahim Aldoss, Tibor Kovacsovics, Richard Stone, Martha Arellano, Manish Patel, Chetasi Talati, Jing Chen, Boaz Nachmias, Mael Heiblig, Pau Montesios Fernandez, Montserrat Arnan-Sangerman, Eytan M. Stein, Ioannis Mantzaris, James S. Blachly, Elie Traer, C. Michael Zwaan, Ofir Wolach, Giovanni Marconi, Ashish Bajel, Carolyn S. Grove, Gabriel N. Mannis, Andre Schuh, Michael Thirman, John Byrd, Christine M. McMahon, David S. Dickens, Alexander Perl, Matthew Greenwood, Ghayas C. Issa, James Whitlock, Paul J. Shami, John DiPersio
Journal: Journal of Clinical Oncology (2024)

Revumenib, an oral, small molecule inhibitor of the menin-lysine methyltransferase 2A (KMT2A) interaction, showed promising efficacy and safety in a phase I study of heavily pretreated patients with