tbuckley/cabot-search huggingface dataset:
Efficacy and safety of autologous tumor-infiltrating lymphocytes in recurrent or refractory ovarian cancer, colorectal cancer, and pancreatic ductal adenocarcinoma
Authors: Rodabe Amaria, Anne Knisely, David Vining, Scott Kopetz, Michael J Overman, Milind Javle, Mara B Antonoff, Ching-Wei D Tzeng, Robert A Wolff, Shubham Pant, Kathryn Lito, Kelly Rangel, Bryan Fellman, Ying Yuan, Karen H Lu, Donastas Sakellariou-Thompson, Cara L Haymaker, Marie-Andrée Forget, Patrick Hwu, Chantale Bernatchez, Amir A Jazaeri
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Tumor-infiltrating lymphocyte (TIL) therapy has shown efficacy in metastatic melanoma, non-small cell lung cancer, and other solid tumors. Our preclinical work demonstrated more robust CD8 predominant TIL production when agonistic anti-4-1BB and CD3 antibodies were used in early ex vivo TIL culture. Methods Patients with treatment-refractory metastatic colorectal (CRC), pancreatic (PDAC) and ovarian (OVCA) cancers were eligible. Lymphodepleting chemotherapy was followed by infusion of ex vivo expanded TIL, manufactured at MD Anderson Cancer Center with IL-2 and agonistic stimulation of CD3 and 4-1BB (urelumab). Patients received up to six doses of high-dose IL-2 after TIL infusion. Primary endpoint was evaluation of objective response rate at 12 weeks using Response Evaluation Criteria in Solid Tumors version 1.1 with secondary endpoints including disease control rate (DCR), duration of response, progression-free survival (PFS), overall survival (OS), and safety. Results 17 patients underwent TIL harvest and 16 were treated on protocol ( NCT03610490 ), including 8 CRC, 5 PDAC, and 3 OVCA patients. Median age was 57.5 (range 33–70) and 50% were females. Median number of lines of prior therapy was 2 (range 1–8). No responses were observed at 12 weeks. Ten subjects achieved at least one stable disease (SD) assessment for a DCR of 62.5% (95% CI 35.4% to 84.8%). Best response included prolonged SD in a patient with PDAC lasting 17 months. Median PFS and OS across cohorts were 2.53 months (95% CI 1.54 to 4.11) and 18.86 months (95% CI 4.86 to NR), respectively. Grade 3 or higher toxicities attributable to therapy were seen in 14 subjects (87.5%; 95% CI 61.7% to 98.4%). Infusion product analysis showed the presence of effector memory cells with high expression of CD39 irrespective of tumor type and low expression of checkpoint markers. Conclusions TIL manufactured with assistance of 4-1BB and CD3 agonism is feasible and treatment is associated with no new safety signals. While no responses were observed, a significant portion of patients achieved SD suggesting early/partial immunological effect. Further research is required to identify factors associated with resistance and functionally enhance T cells for a more effective therapy.
Harmonization of tumor mutation burden testing with comprehensive genomic profiling assays: an IQN Path initiative
Authors: Riziero Esposito Abate, Raffaella Pasquale, Alessandra Sacco, Vittorio Simeon, Monica Rosaria Maiello, Daniela Frezzetti, Paolo Chiodini, Nicola Normanno
Journal: Journal for ImmunoTherapy of Cancer (2024)

Although conflicting results emerged from different studies, the tumor mutational burden (TMB) appears as one of most reliable biomarkers of sensitivity to immune checkpoint inhibitors. Several laboratories are reporting TMB values when performing comprehensive genomic profiling (CGP) without providing a clinical interpretation, due to the lack of validated cut-off values. The International Quality Network for Pathology launched an initiative to harmonize TMB testing with CGP assay and favor the clinical implementation of this biomarker. TMB evaluation was performed with three commercially available CGP panels, TruSight Oncology 500 (TSO500), Oncomine Comprehensive Plus Assay (OCA) and QIAseq Multimodal Panel (QIA), versus the reference assay FoundationOne CDx (F1CDx). Archived clinical samples derived from 60 patients with non-small cell lung cancer were used for TMB assessment. Adjusted cut-off values for each panel were calculated. Testing was successful for 91.7%, 100%, 96.7% and 100% of cases using F1CDx, TSO500, OCA and QIA, respectively. The matrix comparison analysis, between the F1CDx and CGP assays, showed a linear correlation for all three panels, with a higher correlation between F1CDx and TSO500 (rho=0.88) than in the other two comparisons (rho=0.77 for QIA; 0.72 for OCA). The TSO500 showed the best area under the curve (AUC, value 0.96), with a statistically significant difference when compared with the AUC of OCA (0.83, p value=0.01) and QIA (0.88, p value=0.028). The Youden Index calculation allowed us to extrapolate TMB cut-offs of the different panels corresponding to the 10 mutations/megabase (muts/Mb) cut-off of F1CDx: 10.19, 10.4 and 12.37 muts/Mb for TSO500, OCA and QIA, respectively. Using these values, we calculated the relative accuracy measures for the three panels. TSO500 showed 86% specificity and 96% sensitivity, while OCA and QIA had lower yet similar values of specificity and sensitivity (73% and 88%, respectively). This study estimated TMB cut-off values for commercially available CGP panels. The results showed a good performance of all panels on clinical samples and the calculated cut-offs support better accuracy measures for TSO500. The validated cut-off values can drive clinical interpretation of TMB testing in clinical research and clinical practice.
Phase 1/2 study of monalizumab plus durvalumab in patients with advanced solid tumors
Authors: Sandip P Patel, Teresa Alonso-Gordoa, Susana Banerjee, Ding Wang, Jarushka Naidoo, Nathan E Standifer, Doug C Palmer, Lin-Yang Cheng, Panagiotis Kourtesis, Maria L Ascierto, Mayukh Das, Jennifer R Diamond, Matthew D Hellmann, Benedito A Carneiro
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background The combination of monalizumab (anti-NKG2A/CD94) and durvalumab (anti-programmed death ligand-1) may promote antitumor immunity by targeting innate and adaptive immunity. This phase 1/2 study of monalizumab and durvalumab evaluated safety, antitumor activity, and pharmacodynamics in patients with advanced solid tumors. Main body Immunotherapy-naïve patients aged ≥18 years with advanced disease, Eastern Cooperative Oncology Group performance status of 0–1, and 1–3 prior lines of systemic therapy in the recurrent/metastatic setting were enrolled. In part 1 (dose escalation), patients received durvalumab 1500 mg every 4 weeks (Q4W) with increasing doses of monalizumab Q2W/Q4W (n=15). Dose expansion in part 1 included patients with cervical cancer (n=15; durvalumab 1500 mg Q4W and monalizumab 750 mg Q2W) or metastatic microsatellite stable (MSS)-colorectal cancer (CRC) (n=15; durvalumab 1500 mg Q4W and monalizumab 750 mg Q4W). In part 2 (dose expansion), patients with MSS-CRC (n=40), non-small cell lung cancer (NSCLC; n=20), MSS-endometrial cancer (n=40), or ovarian cancer (n=40) received durvalumab 1500 mg Q4W and monalizumab 750 mg Q2W. The primary endpoint was safety. Secondary endpoints included antitumor activity per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1). Exploratory analyses included assessment of T-cell and natural killer (NK) cell activation and proliferation in peripheral blood and the tumor microenvironment (TME). The study enrolled 185 patients (part 1, 45; part 2, 140). No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. In part 2, the most common treatment-related adverse events were fatigue (12.1%), asthenia (9.3%), diarrhea (9.3%), pruritus (7.9%), and pyrexia (7.1%). In the expansion cohorts, response rates were 0% (cervical), 7.7% (MSS-CRC), 10% (NSCLC), 5.4% (ovarian), and 0% (MSS-endometrial). Sustained NK cell activation, CD8 + T-cell proliferation, increased serum levels of CXCL10 (C-X-C motif chemokine ligand 10) and CXCL11, and increased tumor infiltration of CD8 + and granzyme B + cells were observed. Conclusions Although efficacy was modest, monalizumab plus durvalumab was well tolerated and encouraging immune activation was observed in the peripheral blood and TME. Trial registration number NCT02671435 .
Effect of a multimodal prevention strategy on dialysis-associated infection events in outpatients receiving haemodialysis: The DIPS stepped wedge, cluster-randomized trial
Authors: Beate Weikert, Tobias Siegfried Kramer, Frank Schwab, Chris Graf-Allgeier, Solvy Ingrid Wolke, Petra Gastmeier, Christine Geffers
Journal: Clinical Microbiology and Infection (2024)

Patients with haemodialysis catheters are susceptible to dialysis-associated infections, particularly bloodstream infections. There have been few systematic attempts to reduce this burden. Our study aimed to investigate the effect of a multimodal prevention strategy on dialysis-associated infection events (DAIE) among haemodialysis outpatients.
Clinical pharmacology strategies to accelerate the development of polatuzumab vedotin and summary of key findings
Authors: Michael Z. Liao, Dan Lu, Tong Lu, Leonid Gibiansky, Rong Deng, Divya Samineni, Randall Dere, Andy Lin, Jamie Hirata, Ben-Quan Shen, Donglu Zhang, Dongwei Li, Chunze Li, Dale Miles
Journal: Advanced Drug Delivery Reviews (2024)

The favorable benefit–risk profile of polatuzumab vedotin, as demonstrated in a pivotal Phase Ib/II randomized study (GO29365; NCT02257567), coupled with the need for effective therapies in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), prompted the need to accelerate polatuzumab vedotin development. An integrated, fit-for-purpose clinical pharmacology package was designed to support regulatory approval. To address key clinical pharmacology questions without dedicated clinical pharmacology studies, we leveraged non-clinical and clinicaldata for polatuzumab vedotin, published clinical data for brentuximab vedotin, a similar antibody–drug conjugate, and physiologically based pharmacokinetic and population pharmacokinetic modeling approaches. We review strategies and model-informed outcomes that contributed to regulatory approval of polatuzumab vedotin plus bendamustine and rituximab in R/R DLBCL. These strategies made polatuzumab vedotin available to patients earlier than previously possible; depending on the strength of available data and the regulatory/competitive environment, they may also prove useful in accelerating the development of other agents.
Epithelial overexpression of IL-33 induces eosinophilic esophagitis dependent on IL-13
Authors: Mia Y. Masuda, Grace C. Pyon, Huijun Luo, William E. LeSuer, Arina Putikova, Adelyn Dao, Danna R. Ortiz, Aliviya R. Schulze, Nicholas Fritz, Takao Kobayashi, Koji Iijima, Andres J. Klein-Szanto, Masataka Shimonosono, Samuel Flashner, Masaki Morimoto, Rish K. Pai, Matthew A. Rank, Hiroshi Nakagawa, Hirohito Kita, Benjamin L. Wright, Alfred D. Doyle
Journal: Journal of Allergy and Clinical Immunology (2024)
Trends and Sociodemographic Patterns in Keratoconus Management 2015–2020
Authors: Zeba A. Syed, Maurizio Tomaiuolo, Qiang Zhang, Venkatesh Prajna, Leslie Hyman, Christopher J. Rapuano, Aaron Y. Lee, Cecilia S. Lee, Russ Van Gelder, Alice Lorch, Joan W. Miller, Suzann Pershing, Jeffrey Goldberg
Journal: Ophthalmology (2024)
Tau reduction with artificial microRNAs modulates neuronal physiology and improves tauopathy phenotypes in mice
Authors: Carolina Lucía Facal, Iván Fernández Bessone, Javier Andrés Muñiz, A. Ezequiel Pereyra, Olivia Pedroncini, Indiana Páez-Paz, Ramiro Clerici-Delville, Cayetana Arnaiz, Leandro Urrutia, Germán Falasco, Carla Verónica Argañaraz, Trinidad Saez, Antonia Marin-Burgin, Mariano Soiza-Reilly, Tomás Falzone, María Elena Avale
Journal: Molecular Therapy (2024)

Abnormal tau accumulation is the hallmark of several neurodegenerative diseases, named tauopathies. Strategies aimed at reducing tau in the brain are promising therapeutic interventions, yet more precise therapies would require targeting specific nuclei and neuronal subpopulations affected by disease while avoiding global reduction of physiological tau. Here, we developed artificial microRNAs directed against the human MAPT mRNA to dwindle tau protein by engaging the endogenous RNA interference pathway. In human differentiated neurons in culture, microRNA-mediated tau reduction diminished neuronal firing without affecting neuronal morphology or impairing axonal transport. In the htau mouse model of tauopathy, we locally expressed artificial microRNAs in the prefrontal cortex (PFC), an area particularly vulnerable to initiating tau pathology in this model. Tau knockdown prevented the accumulation of insoluble and hyperphosphorylated tau, modulated firing activity of putative pyramidal neurons, and improved glucose uptake in the PFC. Moreover, such tau reduction prevented cognitive decline in aged htau mice. Our results suggest target engagement of designed tau-microRNAs to effectively reduce tau pathology, providing a proof of concept for a potential therapeutic approach based on local tau knockdown to rescue tauopathy-related phenotypes. Abnormal tau accumulation is the hallmark of several neurodegenerative diseases, named tauopathies. Strategies aimed at reducing tau in the brain are promising therapeutic interventions, yet more precise therapies would require targeting specific nuclei and neuronal subpopulations affected by disease while avoiding global reduction of physiological tau. Here, we developed artificial microRNAs directed against the human MAPT mRNA to dwindle tau protein by engaging the endogenous RNA interference pathway. In human differentiated neurons in culture, microRNA-mediated tau reduction diminished neuronal firing without affecting neuronal morphology or impairing axonal transport. In the htau mouse model of tauopathy, we locally expressed artificial microRNAs in the prefrontal cortex (PFC), an area particularly vulnerable to initiating tau pathology in this model. Tau knockdown prevented the accumulation of insoluble and hyperphosphorylated tau, modulated firing activity of putative pyramidal neurons, and improved glucose uptake in the PFC. Moreover, such tau reduction prevented cognitive decline in aged htau mice. Our results suggest target engagement of designed tau-microRNAs to effectively reduce tau pathology, providing a proof of concept for a potential therapeutic approach based on local tau knockdown to rescue tauopathy-related phenotypes.
Risk of cardiac conduction disorders, and pacemaker implantations among individuals tested for serum Borrelia burgdorferi antibodies, a nationwide, matched, population-based cohort study
Authors: Malte M. Tetens, Lars Haukali Omland, Ram B. Dessau, Svend Ellermann-Eriksen, Nanna S. Andersen, Charlotte Sværke Jørgensen, Christian Østergaard, Jacob Bodilsen, Kirstine K. Søgaard, Jette Bangsborg, Alex Christian Nielsen, Jens Kjølseth Møller, Ming Chen, Jesper Hastrup Svendsen, Niels Obel, Anne-Mette Lebech
Journal: Clinical Microbiology and Infection (2024)
The skin microbiome in pediatric atopic dermatitis and food allergy
Authors: Elizabeth Huiwen Tham, Minghao Chia, Carmen Riggioni, Niranjan Nagarajan, John E. A. Common, Heidi H. Kong
Journal: Allergy (2024)

The skin microbiome is an extensive community of bacteria, fungi, mites, viruses and archaea colonizing the skin. Fluctuations in the composition of the skin microbiome have been observed in atopic dermatitis (AD) and food allergy (FA), particularly in early life, established disease, and associated with therapeutics. However, AD is a multifactorial disease characterized by skin barrier aberrations modulated by genetics, immunology, and environmental influences, thus the skin microbiome is not the sole feature of this disease. Future research should focus on mechanistic understanding of how early-life skin microbial shifts may influence AD and FA onset, to guide potential early intervention strategies or as microbial biomarkers to identify high-risk infants who may benefit from possible microbiome-based biotherapeutic strategies. Harnessing skin microbes as AD biotherapeutics is an emerging field, but more work is needed to investigate whether this approach can lead to sustained clinical responses.
SOD2 promotes the immunosuppressive function of mesenchymal stem cells at the expense of adipocyte differentiation
Authors: Yanan Li, Tingting Wang, Xiaolei Li, Wen Li, Yan Lei, Qianwen Shang, Zhiyuan Zheng, Jiankai Fang, Lijuan Cao, Daojiang Yu, Zhenzhen Meng, Shengchao Zhang, Rui Liu, Chunxiao Liu, Chenchang Xu, Yayun Ding, Yongjing Chen, Eleonora Candi, Gerry Melino, Ying Wang, Yufang Shi, Changshun Shao
Journal: Molecular Therapy (2024)
Time for ‘the change’: increasing awareness of the menopause transition in dermatological training and practice
Authors: Abigail Cline, Kenneth Hupart, Shoshana Marmon
Journal: British Journal of Dermatology (2024)

Dermatologists regularly encounter skin-related manifestations tied to the menopause transition, from hair loss and acne to vaginal dryness and hyperhidrosis. Yet, despite the frequency and significance of these presentations, there remains a conspicuous gap when it comes to training dermatologists in menopause care. This omission is highlighted by the absence of menopause-related content and guidance in dermatological educational materials. This article emphasizes the need for a holistic approach to menopause care in dermatology and suggests strategies to address the existing knowledge and practice gap.
Interstitial Cystitis in Sjögren’s Syndrome
Authors: Hirotaka Yamamoto, Yoshinori Taniguchi
Journal: New England Journal of Medicine (2024)

A 66-year-old woman with primary Sjögren's syndrome presented with a 1-month history of lower abdominal pain and urinary urgency. CT of the abdomen showed bladder-wall thickening and hydronephrosis.
Survival is not enough: understanding the mental burden of cutaneous melanoma
Authors: Mees Diederik Egeler, Bettina Ryll
Journal: British Journal of Dermatology (2024)

Journal Article Corrected proof Survival is not enough: understanding the mental burden of cutaneous melanoma Get access Mees Diederik Egeler, Mees Diederik Egeler Writing - original draft, Writing - review & editing The Netherlands Cancer Institute, Amsterdam, the Netherlands Correspondence: Mees Diederik Egeler. Email: m.egeler@nki.nl https://orcid.org/0000-0002-9905-2809 Search for other works by this author on: Oxford Academic Google Scholar Bettina Ryll Bettina Ryll Writing - original draft, Writing - review & editing Melanoma Patient Network Europe, Uppsala, Sweden Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, ljae050, https://doi.org/10.1093/bjd/ljae050 Published: 03 February 2024 Article history Received: 29 January 2024 Accepted: 31 January 2024 Published: 03 February 2024 Corrected and typeset: 04 March 2024
DLK1/DIO3 locus upregulation by a β-catenin-dependent enhancer drives cell proliferation and liver tumorigenesis
Authors: Julie Sanceau, Lucie Poupel, Camille Joubel, Isabelle Lagoutte, Stefano Caruso, Sandra Pinto, Christèle Desbois-Mouthon, Cécile Godard, Akila Hamimi, Enzo Montmory, Cécile Dulary, Sophie Chantalat, Amélie Roehrig, Kevin Muret, Benjamin Saint-Pierre, Jean-François Deleuze, Sophie Mouillet-Richard, Thierry Forné, Christophe F. Grosset, Jessica Zucman-Rossi, Sabine Colnot, Angélique Gougelet
Journal: Molecular Therapy (2024)

The CTNNB1 gene, encoding β-catenin, is frequently mutated in hepatocellular carcinoma (HCC, ∼30%) and in hepatoblastoma (HB, >80%), in which DLK1/DIO3 locus induction is correlated with CTNNB1 mutations. Here, we aim to decipher how sustained β-catenin activation regulates DLK1/DIO3 locus expression and the role this locus plays in HB and HCC development in mouse models deleted for Apc (ApcΔhep) or Ctnnb1-exon 3 (β-cateninΔExon3) and in human CTNNB1-mutated hepatic cancer cells. We identified an enhancer site bound by TCF-4/β-catenin complexes in an open conformation upon sustained β-catenin activation (DLK1-Wnt responsive element [WRE]) and increasing DLK1/DIO3 locus transcription in β-catenin-mutated human HB and mouse models. DLK1-WRE editing by CRISPR-Cas9 approach impaired DLK1/DIO3 locus expression and slowed tumor growth in subcutaneous CTNNB1-mutated tumor cell grafts, ApcΔhep HB and β-cateninΔExon3 HCC. Tumor growth inhibition resulted either from increased FADD expression and subsequent caspase-3 cleavage in the first case or from decreased expression of cell cycle actors regulated by FoxM1 in the others. Therefore, the DLK1/DIO3 locus is an essential determinant of FoxM1-dependent cell proliferation during β-catenin-driven liver tumorigenesis. Targeting the DLK1-WRE enhancer to silence the DLK1/DIO3 locus might thus represent an interesting therapeutic strategy to restrict tumor growth in primary liver cancers with CTNNB1 mutations.
Construction of functional neural network tissue combining CBD-NT3-modified linear-ordered collagen scaffold and TrkC-modified iPSC-derived neural stem cells for spinal cord injury repair
Authors: Zhaoping Wu, Yi Zhou, Xianglin Hou, Weidong Liu, Wen Yin, Lei Wang, Yudong Cao, Zhipeng Jiang, Youwei Guo, Quan Chen, Wen Xie, Ziqiang Wang, Ning Shi, Yujun Liu, Xiang Gao, Longlong Luo, Jianwu Dai, Caiping Ren, Xingjun Jiang
Journal: Bioactive Materials (2024)

Induced pluripotent stem cells (iPSCs) can be personalized and differentiated into neural stem cells (NSCs), thereby effectively providing a source of transplanted cells for spinal cord injury (SCI). To further improve the repair efficiency of SCI, we designed a functional neural network tissue based on TrkC-modified iPSC-derived NSCs and a CBD-NT3-modified linear-ordered collagen scaffold (LOCS). We confirmed that transplantation of this tissue regenerated neurons and synapses, improved the microenvironment of the injured area, enhanced remodeling of the extracellular matrix, and promoted functional recovery of the hind limbs in a rat SCI model with complete transection. RNA sequencing and metabolomic analyses also confirmed the repair effect of this tissue from multiple perspectives and revealed its potential mechanism for treating SCI. Together, we constructed a functional neural network tissue using human iPSCs-derived NSCs as seed cells based on the interaction of receptors and ligands for the first time. This tissue can effectively improve the therapeutic effect of SCI, thus confirming the feasibility of human iPSCs-derived NSCs and LOCS for SCI repair and providing a valuable direction for SCI research.
Defect engineering to tailor structure-activity relationship in biodegradable nanozymes for tumor therapy by dual-channel death strategies
Authors: Yutian Su, Mengdi Lv, Zheng Huang, Nannan An, Yi Chen, Haoru Wang, Zhengtu Li, Shishan Wu, Feng Ye, Jian Shen, Ao Li
Journal: Journal of Controlled Release (2024)