tbuckley/cabot-search huggingface dataset:
Visual Outcomes and Risk of Endophthalmitis in Open Globe Injuries without Intraocular Foreign Bodies with Delayed Repair
Authors: Marisa G. Tieger, Nakul Singh, Racquel Bitar, Kevin Makhoul, Helia Ashourizadeh, Tomasz P. Stryjewski, Grayson W. Armstrong, Dean Eliott
Journal: Ophthalmology (2024)
Tethered IL15-IL15Rα augments antitumor activity of CD19 CAR-T cells but displays long-term toxicity in an immunocompetent lymphoma mouse model
Authors: Inés Sánchez-Moreno, Aritz Lasarte-Cia, Celia Martín-Otal, Noelia Casares, Flor Navarro, Marta Gorraiz, Patricia Sarrión, Sandra Hervas-Stubbs, Lorea Jordana, Juan Roberto Rodriguez-Madoz, Jesús San Miguel, Felipe Prosper, Juan Jose Lasarte, Teresa Lozano
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Adoptive cell therapy using genetically modified T cells to express chimeric antigen receptors (CAR-T) has shown encouraging results, particularly in certain blood cancers. Nevertheless, over 40% of B cell malignancy patients experience a relapse after CAR-T therapy, likely due to inadequate persistence of the modified T cells in the body. IL15, known for its pro-survival and proliferative properties, has been suggested for incorporation into the fourth generation of CAR-T cells to enhance their persistence. However, the potential systemic toxicity associated with this cytokine warrants further evaluation. Methods We analyzed the persistence, antitumor efficacy and potential toxicity of anti-mouse CD19 CAR-T cells which express a membrane-bound IL15-IL15Rα chimeric protein (CD19/mbIL15q CAR-T), in BALB/c mice challenged with A20 tumor cells as well as in NSG mice. Results Conventional CD19 CAR-T cells showed low persistence and poor efficacy in BALB/c mice treated with mild lymphodepletion regimens (total body irradiation (TBI) of 1 Gy). CD19/mbIL15q CAR-T exhibits prolonged persistence and enhanced in vivo efficacy, effectively eliminating established A20 B cell lymphoma. However, this CD19/mbIL15q CAR-T displays important long-term toxicities, with marked splenomegaly, weight loss, transaminase elevations, and significant inflammatory findings in some tissues. Mice survival is highly compromised after CD19/mbIL15q CAR-T cell transfer, particularly if a high TBI regimen is applied before CAR-T cell transfer. Conclusion Tethered IL15-IL15Rα augments the antitumor activity of CD19 CAR-T cells but displays long-term toxicity in immunocompetent mice. Inducible systems to regulate IL15-IL15Rα expression could be considered to control this toxicity.
Second-generation checkpoint inhibitors and Treg depletion synergize with a mouse cancer vaccine in accordance with tumor microenvironment characterization
Authors: William Becker, Purevdorj B Olkhanud, Noriko Seishima, Paloma A Moreno, Katherine C Goldfarbmuren, Hoyoung M Maeng, Jay A Berzofsky
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Despite advances in checkpoint inhibitor (CPI) therapy for cancer treatment, many cancers remain resistant. Tumors deemed “cold” based on lack of T cell infiltration show reduced potential for CPI therapy. Cancer vaccines may overcome the inadequacy of existing T cells by inducing the needed antitumor T cell response to synergize with CPIs and overcome resistance. Methods CT26 and TC1 tumor cells were injected subcutaneously into mice. Mice were treated with combinations of CPIs alone or a cancer vaccine specific to the tumor antigen E7 present in TC1 cells. CPIs for the TC1 model were selected because of immunophenotyping TC1 tumors. Antitumor and protumor immunity, tumor size and survival, sequence and timing of vaccine and CPI administration, and efficacy of treatment in young and aged mice were probed. Results While “hot” CT26 tumors are treatable with combinations of second-generation CPIs alone or with anti-TGFβ, “cold” TC1 tumor reduction requires the synergy of a tumor-antigen-specific vaccine in combination with two CPIs, anti-TIGIT and anti-PD-L1, predicted by tumor microenvironment (TME) characterization. The synergistic triple combination delays tumor growth better than any pairwise combination and improves survival in a CD8+T cell-dependent manner. Depletion of CD4+T cells improved the treatment response, and depleting regulatory T cells (Treg) revealed Tregs to be inhibiting the response as also predicted from TME analysis. We found the sequence of CPI and vaccine administration dictates the success of the treatment, and the triple combination administered concurrently induces the highest E7-specific T cell response. Contrary to young mice, in aged mice, the cancer vaccine alone is ineffective, requiring the CPIs to delay tumor growth. Conclusions These findings show how pre-existing or vaccine-mediated de novo T cell responses can both be amplified by and facilitate synergistic CPIs and Treg depletion that together lead to greater survival, and how analysis of the TME can help rationally design combination therapies and precision medicine to enhance clinical response to CPI and cancer vaccine therapy.
Mapping the complexity and diversity of tertiary lymphoid structures in primary and peritoneal metastatic gastric cancer
Authors: Tessa S Groen-van Schooten, Rosalia Franco Fernandez, Nicole C T van Grieken, Emma N Bos, Jens Seidel, Job Saris, Carolina Martínez-Ciarpaglini, Tania C Fleitas, Daniela S Thommen, Tanja D de Gruijl, Joep Grootjans, Sarah Derks
Journal: Journal for ImmunoTherapy of Cancer (2024)

Tertiary lymphoid structures (TLSs) are thought to stimulate antitumor immunity and positively impact prognosis and response to immune checkpoint blockade. In gastric cancers (GCs), however, TLSs are predominantly found in GC with poor prognosis and limited treatment response. We, therefore, hypothesize that immune cell composition and function of TLS depends on tumor location and the tumor immune environment.
Bendamustine is a safe and effective lymphodepletion agent for axicabtagene ciloleucel in patients with refractory or relapsed large B-cell lymphoma
Authors: Sushma Bharadwaj, Eric Lau, Mark P Hamilton, Anmol Goyal, Hrishi Srinagesh, Alexandria Jensen, Dasom Lee, Jayasindhu Mallampet, Sarah Elkordy, Shriya Syal, Sunita Patil, Theresa Latchford, Bita Sahaf, Sally Arai, Laura J Johnston, Robert Lowsky, Robert Negrin, Andrew R Rezvani, Judith Shizuru, Everett H Meyer, Parveen Shiraz, Lekha Mikkilineni, Wen-Kai Weng, Melody Smith, Surbhi Sidana, Lori Muffly, Holden T Maecker, Matthew J Frank, Crystal Mackall, David Miklos, Saurabh Dahiya
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Fludarabine in combination with cyclophosphamide (FC) is the standard lymphodepletion regimen for CAR T-cell therapy (CAR T). A national fludarabine shortage in 2022 necessitated the exploration of alternative regimens with many centers employing single-agent bendamustine as lymphodepletion despite a lack of clinical safety and efficacy data. To fill this gap in the literature, we evaluated the safety, efficacy, and expansion kinetics of bendamustine as lymphodepletion prior to axicabtagene ciloleucel (axi-cel) therapy. Methods 84 consecutive patients with relapsed or refractory large B-cell lymphoma treated with axi-cel and managed with a uniform toxicity management plan at Stanford University were studied. 27 patients received alternative lymphodepletion with bendamustine while 57 received FC. Results Best complete response rates were similar (73.7% for FC and 74% for bendamustine, p=0.28) and there was no significant difference in 12-month progression-free survival or overall survival estimates (p=0.17 and p=0.62, respectively). The frequency of high-grade cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome was similar in both the cohorts. Bendamustine cohort experienced lower proportions of hematological toxicities and antibiotic use for neutropenic fever. Immune reconstitution, as measured by quantitative assessment of cellular immunity, was better in bendamustine cohort as compared with FC cohort. CAR T expansion as measured by peak expansion and area under the curve for expansion was comparable between cohorts. Conclusions Bendamustine is a safe and effective alternative lymphodepletion conditioning for axi-cel with lower early hematological toxicity and favorable immune reconstitution.
IFNγ mediates the resistance of tumor cells to distinct NK cell subsets
Authors: Tomáš Hofman, Siu Wang Ng, Irene Garcés-Lázaro, Florian Heigwer, Michael Boutros, Adelheid Cerwenka
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Immune checkpoint blockade targeting the adaptive immune system has revolutionized the treatment of cancer. Despite impressive clinical benefits observed, patient subgroups remain non-responsive underscoring the necessity for combinational therapies harnessing additional immune cells. Natural killer (NK) cells are emerging tools for cancer therapy. However, only subpopulations of NK cells that are differentially controlled by inhibitory receptors exert reactivity against particular cancer types. How to leverage the complete anti-tumor potential of all NK cell subsets without favoring the emergence of NK cell-resistant tumor cells remains unresolved. Methods We performed a genome-wide CRISPR/Cas9 knockout resistance screen in melanoma cells in co-cultures with human primary NK cells. We comprehensively evaluated factors regulating tumor resistance and susceptibility by focusing on NK cell subsets in an allogenic setting. Moreover, we tested therapeutic blocking antibodies currently used in clinical trials. Results Melanoma cells deficient in antigen-presenting or the IFNγ-signaling pathways were depleted in remaining NK cell-co-cultured melanoma cells and displayed enhanced sensitivity to NK cells. Treatment with IFNγ induced potent resistance of melanoma cells to resting, IL-2-cultured and ADCC-activated NK cells that depended on B2M required for the expression of both classical and non-classical MHC-I. IFNγ-induced expression of HLA-E mediated the resistance of melanoma cells to the NKG2A + KIR − and partially to the NKG2A + KIR + NK cell subset. The expression of classical MHC-I by itself was sufficient for the inhibition of the NKG2A − KIR + , but not the NKG2A + KIR + NK cell subset. Treatment of NK cells with monalizumab, an NKG2A blocking mAb, enhanced the reactivity of a corresponding subset of NK cells. The combination of monalizumab with lirilumab, blocking KIR2 receptors, together with DX9, blocking KIR3DL1, was required to restore cytotoxicity of all NK cell subsets against IFNγ-induced resistant tumor cells in melanoma and tumors of different origins. Conclusion Our data reveal that in the context of NK cells, IFNγ induces the resistance of tumor cells by the upregulation of classical and non-classical MHC-I. Moreover, we reveal insights into NK cell subset reactivity and propose a therapeutic strategy involving combinational monalizumab/lirilumab/DX9 treatment to fully restore the antitumor response across NK cell subsets.
Extensive-stage small-cell lung cancer in patients receiving atezolizumab plus carboplatin–etoposide: stratification of outcome based on a composite score that combines gene expression profiling and immune characterization of microenvironment
Authors: Anna Tosi, Martina Lorenzi, Paola Del Bianco, Anna Roma, Alberto Pavan, Antonio Scapinello, Maria Vittoria Resi, Laura Bonanno, Stefano Frega, Fiorella Calabrese, Valentina Guarneri, Antonio Rosato, Giulia Pasello
Journal: Journal for ImmunoTherapy of Cancer (2024)

Purpose Small-cell lung cancer (SCLC) is an aggressive disease with a dismal prognosis. The addition of immune checkpoints inhibitors to standard platinum-based chemotherapy in first-line setting achieves a durable benefit only in a patient subgroup. Thus, the identification of predictive biomarkers is an urgent unmet medical need. Experimental design Tumor samples from naive extensive-stage (ES) SCLC patients receiving atezolizumab plus carboplatin–etoposide were analyzed by gene expression profiling and two 9-color multiplex immunofluorescence panels, to characterize the immune infiltrate and SCLC subtypes. Associations of tissue biomarkers with time-to-treatment failure (TTF), progression-free survival (PFS) and overall survival (OS), were assessed. Results 42 patients were included. Higher expression of exhausted CD8-related genes was independently associated with a longer TTF and PFS while increased density of B lymphocytes correlated with longer TTF and OS. Higher percentage of M2-like macrophages close to tumor cells and of CD8+T cells close to CD4+T lymphocytes correlated with increased risk of TF and longer survival, respectively. A lower risk of TF, disease progression and death was associated with a higher density of ASCL1+tumor cells while the expression of POU2F3 correlated with a shorter survival. A composite score combining the expression of exhausted CD8-related genes, B lymphocyte density, ASCL1 tumor expression and quantification of CD163+macrophages close to tumor cells, was able to stratify patients into high-risk and low-risk groups. Conclusions In conclusion, we identified tissue biomarkers and a combined score that can predict a higher benefit from chemoimmunotherapy in ES-SCLC patients.
Immune predictors of response to immune checkpoint inhibitors in mismatch repair-deficient endometrial cancer
Authors: Juan Francisco Grau Bejar, Elisa Yaniz Galende, Qinghe Zeng, Catherine Genestie, Etienne Rouleau, Marco de Bruyn, Christophe Klein, Audrey Le Formal, Elodie Edmond, Maëva Moreau, Annechien Plat, Sebastien Gouy, Amandine Maulard, Patricia Pautier, Judith Michels, Ana Oaknin, Emeline Colomba-Blameble, Alexandra Leary
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Patients with mismatch repair-deficient (MMRd) endometrial cancer (EC) can derive great benefit from immune checkpoint inhibitors (ICI). However not all responses and predictors of primary resistance are lacking. Methods We compared the immune tumor microenvironment of MMRd EC ICI-responders (Rs) and ICI non-responders (NRs), using spatial multiplexed immune profiling and unsupervised hierarchical clustering analysis. Results Overall, NRs exhibited drastically lower CD8 + , absent terminally differentiated T cells, lack of mature tertiary lymphoid structures and dendritic cells, as well as loss of human leukocyte antigen class I. However, no single marker could predict R versus NR with confidence. Clustering analysis identified a combination of four immune features that demonstrated that accurately predicted ICI response, with a discriminative power of 92%. Finally, 80% of NRs lacked programmed death-ligand 1, however, 60% exhibited another actionable immune checkpoint (T-cell immunoglobulin and mucin containing protein-3, indoleamine 2,3-dioxygenase 1, or lymphocyte activation gene 3). Conclusions These findings underscore the potential of immune tumor microenvironment features for identifying patients with MMRd EC and primary resistance to ICI who should be oriented towards trials testing novel immunotherapeutic combinations.
Heterogeneous pseudobulk simulation enables realistic benchmarking of cell-type deconvolution methods
Authors: Mengying Hu, Maria Chikina
Journal: Genome biology (2024)

Abstract Background Computational cell type deconvolution enables the estimation of cell type abundance from bulk tissues and is important for understanding tissue microenviroment, especially in tumor tissues. With rapid development of deconvolution methods, many benchmarking studies have been published aiming for a comprehensive evaluation for these methods. Benchmarking studies rely on cell-type resolved single-cell RNA-seq data to create simulated pseudobulk datasets by adding individual cells-types in controlled proportions. Results In our work, we show that the standard application of this approach, which uses randomly selected single cells, regardless of the intrinsic difference between them, generates synthetic bulk expression values that lack appropriate biological variance. We demonstrate why and how the current bulk simulation pipeline with random cells is unrealistic and propose a heterogeneous simulation strategy as a solution. The heterogeneously simulated bulk samples match up with the variance observed in real bulk datasets and therefore provide concrete benefits for benchmarking in several ways. We demonstrate that conceptual classes of deconvolution methods differ dramatically in their robustness to heterogeneity with reference-free methods performing particularly poorly. For regression-based methods, the heterogeneous simulation provides an explicit framework to disentangle the contributions of reference construction and regression methods to performance. Finally, we perform an extensive benchmark of diverse methods across eight different datasets and find BayesPrism and a hybrid MuSiC/CIBERSORTx approach to be the top performers. Conclusions Our heterogeneous bulk simulation method and the entire benchmarking framework is implemented in a user friendly package https://github.com/humengying0907/deconvBenchmarking and https://doi.org/10.5281/zenodo.8206516 , enabling further developments in deconvolution methods.
Pancreatic STAT5 activation promotes Kras <sup>G12D</sup> -induced and inflammation-induced acinar-to-ductal metaplasia and pancreatic cancer
Authors: Yuli Lin, Shaofeng Pu, Jun Wang, Yaqi Wan, Zhihao Wu, Yangyang Guo, Wenxue Feng, Ying Ying, Shuai Ma, Xiang Jun Meng, Wenquan Wang, Liang Liu, Qing Xia, Xuguang Yang
Journal: Gut (2024)

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy because it is often diagnosed at a late-stage. Signal transducer and activator of transcription 5 (STAT5) is a transcription factor implicated in the progression of various cancer types. However, its role in KRAS-driven pancreatic tumourigenesis remains unclear.
Colorectal cancer and association with anaerobic bacteraemia: a Danish nationwide population-based cohort study
Authors: Ulrik S. Justesen, Mark B. Ellebæk, Niels Qvist, Maria Iachina, Niels Frimodt-Møller, Lillian M. Søes, Sissel Skovgaard, Lars Lemming, Jurgitta Samulioniene, Steen L. Andersen, Ram B. Dessau, Jens K. Møller, John E. Coia, Kim O. Gradel
Journal: Journal of Infection (2024)

We aimed to identify specific anaerobic bacteria causing bacteraemia and a subsequent diagnosis of colorectal cancer.
Discovery of a novel inhibitor of macropinocytosis with antiviral activity
Authors: Bartlomiej Porebski, Wanda Christ, Alba Corman, Martin Haraldsson, Myriam Barz, Louise Lidemalm, Maria Häggblad, Juliana Ilmain, Shane C. Wright, Matilde Murga, Jan Schlegel, Malin Jarvius, Maris Lapins, Erdinc Sezgin, Gira Bhabha, Volker M. Lauschke, Jordi Carreras-Puigvert, Miguel Lafarga, Jonas Klingström, Daniela Hühn, Oscar Fernandez-Capetillo
Journal: Molecular Therapy (2024)

Several viruses hijack various forms of endocytosis in order to infect host cells. Here, we report the discovery of a molecule with antiviral properties that we named virapinib, which limits viral entry by macropinocytosis. The identification of virapinib derives from a chemical screen using high-throughput microscopy, where we identified chemical entities capable of preventing infection with a pseudotype virus expressing the spike (S) protein from SARS-CoV-2. Subsequent experiments confirmed the capacity of virapinib to inhibit infection by SARS-CoV-2, as well as by additional viruses, such as mpox virus and TBEV. Mechanistic analyses revealed that the compound inhibited macropinocytosis, limiting this entry route for the viruses. Importantly, virapinib has no significant toxicity to host cells. In summary, we present the discovery of a molecule that inhibits macropinocytosis, thereby limiting the infectivity of viruses that use this entry route such as SARS-CoV2. Several viruses hijack various forms of endocytosis in order to infect host cells. Here, we report the discovery of a molecule with antiviral properties that we named virapinib, which limits viral entry by macropinocytosis. The identification of virapinib derives from a chemical screen using high-throughput microscopy, where we identified chemical entities capable of preventing infection with a pseudotype virus expressing the spike (S) protein from SARS-CoV-2. Subsequent experiments confirmed the capacity of virapinib to inhibit infection by SARS-CoV-2, as well as by additional viruses, such as mpox virus and TBEV. Mechanistic analyses revealed that the compound inhibited macropinocytosis, limiting this entry route for the viruses. Importantly, virapinib has no significant toxicity to host cells. In summary, we present the discovery of a molecule that inhibits macropinocytosis, thereby limiting the infectivity of viruses that use this entry route such as SARS-CoV2.
Diagnostic measures for monitoring and follow‐up in periodontology and implant dentistry
Authors: Christoph A. Ramseier
Journal: Periodontology 2000 (2024)

This review discusses the role of diagnostic measures in the lifelong management of periodontal disease and peri-implant complications. After active treatment, these conditions require regular monitoring of the supporting structures of teeth and dental implants to assess bone and soft tissue health over time. Several clinical measures have been developed for the routine assessment of periodontal and peri-implant tissues, including periodontal and peri-implant probing, bleeding on probing, intraoral radiography, biomarker analysis, and microbiological testing. This review highlights the evolution of diagnostic practices, integrating traditional methods with emerging technologies such as resonance frequency analysis and ultrasound imaging to provide a holistic view of peri-implant health assessment. In addition to objective measurements, patient risk factors are considered. The goals of periodontal and peri-implant maintenance are to control disease activity and stabilize tissues through supportive care, which includes diagnostic measures at follow-up visits. This enables clinicians to monitor treatment outcomes, assess health status, and detect recurrence or progression early through routine evaluation, allowing additional interventions, including adjustment of supportive therapy intervals, to further improve and maintain periodontal and peri-implant stability over time.