tbuckley/cabot-search huggingface dataset:
Abstract A045: Engineered systems for tumor modeling facilitate the assessment of theraputic interventions
Authors: Joseph Mueller, Ryan Yao, Kim Selting, Catherine Best-Popescu, Brendan Harley, Sara Pedron-Haba
Journal: Cancer Research (2024)

Abstract Brain cancers remain some of the most challenging tumors to treat. The goal of our research is to use a 3D in vitro model to acquire in-depth understanding of the unique environment of brain tumors in order to find new biomarkers of disease and develop more efficient therapeutic approaches. Glioblastomas (GBM) present a very poor prognosis, they exhibit high infiltration into brain parenchyma, impairing surgical resection and leading to recurrence. The recurrent tumor is predominantly more aggressive and resistant to available therapeutic strategies. Brain extracellular matrix (ECM) plays a key role in glioblastoma invasion and therapeutic resistance. In particular, the aberrant biosynthesis of the main component of brain ECM, hyaluronic acid (HA), has been associated to pathological conditions. We investigate the influence of tumor extracellular microenvironment in glioblastoma progression. We focus on the tumor-associated HA biosynthesis in response to biophysical alterations, such as hypoxia and stiffness, and after radio and chemotherapeutic interventions. The ability to manipulate tumor ECM can improve therapeutic outcomes and restrict glioblastoma growth and infiltration. Citation Format: Joseph Mueller, Ryan Yao, Kim Selting, Catherine Best-Popescu, Brendan Harley, Sara Pedron-Haba. Engineered systems for tumor modeling facilitate the assessment of theraputic interventions [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A045.
Abstract A008: Disruption of SLFN5 enhances vulnerability to APR-246, a mutant p53 reactivator in glioblastoma
Authors: Ricardo E. Perez, Frank Eckerdt, Leonidas C. Platanias
Journal: Cancer Research (2024)

Abstract Glioblastoma multiforme (GBM) or grade 4 IDHWT glioma is the most malignant brain tumor with a median survival of ~15 months. Current treatment options are limited to a combination of surgery, radiation, and the alkylating agent temozolomide (TMZ). However, despite this aggressive treatment regimen, patients inevitably develop recurrent tumors, which depict a high degree of resistance to DNA damage induced by TMZ and irradiation. Therefore, it is imperative to better understand cellular signals contributing to GBM tumorigenesis and therapy resistance. We have previously established potential roles for members of the protein family of schlafens (SLFNs) in GBM. SLFNs have established roles in cell differentiation, cell proliferation, immune responses, and an expanding role in cancer biology. Several human SLFNs have been linked to chemosensitivity in various cancer types. In particular, SLFN5 mRNA levels progressively increased from grade 2 to grade 4 glioma suggesting a possible therapeutic target for GBM. Therefore, in an effort to better understand the role of SLFN5 in GBM tumorigenesis, CRISPR/Cas9-mediated SLFN5 knockout glioblastoma cell lines and PDX lines were generated. Cells lacking expression of SLFN5 showed increased DNA damage signaling, as judged by elevated basal levels of the DNA damage marker γH2AX and persistent phosphorylation of Chk2. Gene ontology analysis indicated increased expression of p53 pathway components in SLFN5 knockout cells. In GBM, p53 activity is commonly deregulated due to high mutations in the p53 pathway. In line with this, SLFN5 knockout cells depicted increased sensitivity to the mutant p53 reactivator APR-246 correlating with p53 mutational status. APR-246 induced PARP cleavage in SLFN5 knockout cells was rescued by the ROS scavenger N-acetyl-D-cysteine (NAC). Our results suggest increased DNA damage signaling in SLFN5 deficient cells. Furthermore, mutant p53 reactivator APR-246 induced apoptosis is dependent on ROS signaling. In summary, we provide evidence for a protective role of SLFN5 to limit DNA damage and ROS signaling in GBM. Citation Format: Ricardo E. Perez, Frank Eckerdt, Leonidas C. Platanias. Disruption of SLFN5 enhances vulnerability to APR-246, a mutant p53 reactivator in glioblastoma [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A008.
Abstract A017: Cell-specific photodynamic therapy for high grade gliomas
Authors: Alberto Guillermo Arias
Journal: Cancer Research (2024)

Abstract High grade gliomas (HGG) are infiltrative tumors. Surgery is the initial treatment, aiming to alleviate intracranial pressure and reduce tumor volume. Additional treatment includes radiotherapy and chemotherapy with Temozolomide. Despite these interventions, the 5-year survival rate for HGG patients remains below 10%, with a median survival of less than 2 years. Thus, there is an urgent need for novel therapeutic approaches In this talk I will present in vitro studies on a novel therapeutic approach using cell-specific Photodynamic Therapy. This therapy uses a drug that is activated by light exposure, called photosensitizer, generating reactive oxygen species capable of inducing cell death. This type of treatment has been used in clinical practice for decades, but its use in cancer treatment is rather new and is currently being evaluated in clinical trials in different cancer types. Here, we used a new cyclic peptide obtained through in vivo panning that can bind selectively to HGG cell lines. This peptide was coupled to the photosensitizer "Verteporfin". In vitro studies showed high toxicity and specificity of this peptide using different conditions, doses and incubation periods. Using immunodeficient mice with intracranial and also subcutaneous tumor induction, we studied the biodistribution of this peptide, showing higher accumulation in the tumor than in the healthy brain. These preliminary results set the ground for upcoming in vivo preclinical studies. Furthermore, we seek to explore the diagnostic and therapeutic potential of our HGG-specific peptide by coupling it to the radionuclide Lutetium 177. Citation Format: Alberto Guillermo Arias. Cell-specific photodynamic therapy for high grade gliomas [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A017.
Abstract A021: Exosome delivered combinatorial treatment for malignant brain tumors
Authors: Sydney Thomas, Karthik Gourishetti, Karthik Rangavajhula, Deepak Bhere
Journal: Cancer Research (2024)

Abstract Glioblastoma (GBM), a World Health Organization (WHO) Grade IV astrocytoma, is a highly aggressive brain tumor with poor prognosis. Current therapeutic approaches, which include surgery, chemotherapy, and radiation therapy, are largely ineffective and often result in tumor recurrence. Several characteristics of the tumors make them challenging to treat, including their protection by the blood-brain barrier, which hinders effective treatment delivery. Our research addresses this issue by using exosomes, which are small cell-derived vesicles, as delivery vehicles for microRNA (miR) therapies. Dysregulation of miR expression has been implicated in tumorigenesis, and targeting these dysregulated miRs is emerging as a promising approach to tumor treatment. In particular, miR-7 and miR-124 have been identified as tumor-suppressive miRs that are downregulated in various tumors, including GBM. In this study, stem cell-derived exosomes loaded with miR-7 and miR-124 have been evaluated as a combinatorial approach for treating GBM. In our work, human adipose stem cells (ADSCs) were transduced with the target miR-7 and miR-124 plasmids and cultured in exosome-depleted FBS. The miR-containing exosomes from the ADSCs were then isolated, purified, quantified, and characterized for use in subsequent studies. Murine and human GBM cells as well as primary patient-derived primary GBM cells were treated with miR-7 and miR-124 exosomes, and the efficacy of exosome treatment was determined using cell viability assays and microscopy. The mechanisms of miR modulation of cell proliferation and cell death pathways were analyzed with time-course western blot analysis. Orthotopic animal models of GBM will be used to assess the effectiveness of our methods in vivo. Our results have demonstrated successful delivery of miR-7 and miR-124 to GBM cells via stem cell-derived exosomes. Data show that treatment with these tumor-suppressive miRs halts GBM growth in vitro by modulating multiple pathways involved in tumor growth and progression. While we await results of our in vivo studies, our preliminary data demonstrate that delivery of miR-7 and miR-124 via stem cell-derived exosomes is a promising therapeutic approach for treating GBM. Citation Format: Sydney Thomas, Karthik Gourishetti, Karthik Rangavajhula, Deepak Bhere. Exosome delivered combinatorial treatment for malignant brain tumors [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A021.
Abstract A036: Female spouse caregivers of patients with glioblastoma want better education and communication from health care professionals regarding what to expect during the disease progression
Authors: Diana L. Coman, Megan P. Chard, Barbara J. Lutz, Laurie A. Minns
Journal: Cancer Research (2024)

Abstract The purpose of this study was to understand the challenges and unmet needs of primary spousal caregivers of patients with glioblastoma multiforme (GBM) through a qualitative analysis of letters written by current and former caregivers. GBM is a devastating and terminal cancer that results in memory loss, cognitive declines, personality changes, neuropsychiatric symptoms, and physical impairments that greatly affect quality of life of both the patient with GBM and their primary caregiver, who is often a spouse or partner. Open-ended letters (n=101) written by self-identified female spouse caregivers were analyzed using reflexive thematic analysis (IRB #22-0103). The six phases of reflexive thematic analysis involved 1) data familiarization, 2) systematic data coding, 3) generation of initial themes, 4) development and reviewing themes, 5) refinement and re-naming of themes and 6) writing the report to provide insight into caregiver’s experience. Seven distinct themes were identified from the letters. Three of the themes related to the patient experiences: 1) medical details of the disease trajectory (87%), 2) interactions of the patient/caregiver dyad with health care workers (67%), and 3) the changing patient condition over time (98%). Four themes focused on the caregiver experience: 1) caregiver challenges (80%), 2) caregiver responses (77%), 3) caregiver coping strategies (85%), and description of tangible needs that would help other caregivers in the future (91%). When mapped to the four phases of the caregiving trajectory: acute disease phase, living with disease progression, end of life phase, and the bereavement phase, caregivers needed better communication and support in every phase. The highest caregiver needs were for better education about GBM from health care professionals regarding what to expect and better communication with health care providers about disease progression, treatment options, and anticipated patient, caregiver, and family needs (65%). Caregivers indicated they wanted to be listened to and included in medical decision-making. These findings on the primary caregivers’ experiences provide opportunities to guide more timely and tailored interventions to provide support and improve care for patient/caregiver dyads to help mitigate the burden of this progressive disease and improve quality of life for caregivers and their patients with GBM. Citation Format: Diana L. Coman, Megan P. Chard, Barbara J. Lutz, Laurie A. Minns. Female spouse caregivers of patients with glioblastoma want better education and communication from health care professionals regarding what to expect during the disease progression [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A036.
Abstract A028: Subclonal lineage recording in glioblastoma using CRISPR base editing
Authors: Abigail C. Marshall, Aaron McKenna
Journal: Cancer Research (2024)

Abstract Novel lineage tracing approaches are needed to undercover lineage relationships between diverse cells in complex tumors such as glioblastoma (GBM). Intratumoral heterogeneity in GBM drives treatment resistance and recurrence. This intratumoral heterogeneity is reflected by multiple cellular states seen within tumors and across patients. Unfortunately, little is known about their lineage relationships and shared origins. Here we’ve developed a novel lineage tracing technology to track the clonal and subclonal evolution in patient-derived GBM models. Our adenine base editor lineage tracing (ABELT) system uses a Cas9 adenine base editor (ABE) to induce heritable single-nucleotide changes in the 3’ untranslated region of endogenous transcripts. These heritable marks distinguish individual clonal populations and can be used to trace the relationship between progeny within each clone. We demonstrate our system's in vitro lineage tracing capacity and show that the ABELT system faithfully records lineage, which is recoverable with unmodified single-cell RNA sequencing approaches. We then track the relationships between evolving cellular states across multiple divisions in an evolving GBM model. Our ABELT technology enables the rapid engineering and lineage tracing of cancer models incompatible with previous approaches. This novel approach will enable our group and others to explore GBM intratumoral heterogeneity with subclonal resolution to determine transcriptional plasticity that ultimately leads to treatment resistance. Citation Format: Abigail C. Marshall, Aaron McKenna. Subclonal lineage recording in glioblastoma using CRISPR base editing [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A028.
Abstract A043: Pericytes orchestrate a tumor-suppressive microenvironment by impinging on the crosstalk between macrophages and tumor-initiating cells in glioblastoma multiforme
Authors: Sebastian Braun, Clara Oudenaarden, Paulina Bolivar, Jonas Sjölund, Eugenia Cordero, Rebecca Roslund, Elinn Johansson, Alexander Pietras, Kristian Pietras
Journal: Cancer Research (2024)

Abstract Glioblastoma multiforme (GBM) is characterized by fast progression, infiltrative growth pattern and a high rate of relapse. A defining feature of GBM is the existence of spatially and functionally distinct cellular niches, i.e. a hypoxic niche, a leading-edge niche, and a peri-vascular niche, in which malignant cells engage in paracrine crosstalk with cell types comprising the tumor microenvironment, including immune cells, astrocytes, and vascular cells. Here, by analysis of single-cell transcriptomic data of human GBM and transgenic mouse models of GBM, we unexpectedly identified pericytes intimately associated with the endothelium as the most active paracrine signaling hub within the tumor parenchyma. Exclusive signaling axes emanating from pericytes were received by endothelial cells, malignant cells, astrocytes, and immune cells. Depletion of pericytes through genetic engineering in several different transgenic and orthotopic mouse models of GBM demonstrated accelerated tumor progression, a disrupted blood-brain-barrier, and premature death of pericyte-poor mice. Mechanistic studies revealed that pericyte deficiency altered the cellular composition of GBM, remodeled the endothelium, and impacted on the immune cell landscape. Specifically, endothelial cells deprived of pericyte association upregulated Colony Stimulating Factor (CSF)-1, which in turn attracted peri-vascular tumor-associated macrophages polarized towards an immune-suppressive phenotype. In the absence of pericytes, the recruited macrophages expressed Hepatocyte Growth Factor (HGF), which reinforced activation of its receptor tyrosine kinase c-Met on a subset of GBM cells harboring an extreme mesenchymal-like state. Indeed, orthotopic implantation of isolated c-Met-expressing GBM cells corroborated their superior tumor-initiating capability and invasive phenotype, compared to cells negative for c-Met. Taken together, we infer that the pericyte represents a critical modulator of GBM development by orchestrating a tumor-suppressive microenvironment; our findings thus highlight the importance of pericyte preservation in the face of current and future GBM therapies. Citation Format: Sebastian Braun, Clara Oudenaarden, Paulina Bolivar, Jonas Sjölund, Eugenia Cordero, Rebecca Roslund, Elinn Johansson, Alexander Pietras, Kristian Pietras. Pericytes orchestrate a tumor-suppressive microenvironment by impinging on the crosstalk between macrophages and tumor-initiating cells in glioblastoma multiforme [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A043.
Abstract B018: Epigenetic targeting improves glioblastoma cell sensitivity to chemotherapy
Authors: Golnaz Asaadi Tehrani, Becca Kubick, Meenal Datta
Journal: Cancer Research (2024)

Abstract Histone deacetylase inhibitors (HDACi) have emerged as a new class of anti-tumor agents for various types of cancers, including glioblastoma (GBM). Recent studies have shown that targeting the GBM epigenome can enhance the effects of standard clinical therapies. Here, we utilized the human U87-GBM cell line to evaluate the cytotoxic properties of three blood-brain-barrier-penetrating HDACi, suberoylanilide hydroxamic acid (SAHA, or Vorinostat), valproic acid (VPA), and CAY10603, both as monotherapies and in combination with the chemotherapeutic agent temozolomide (TMZ). Combination Index (CI) was quantified by MTT assay and human normal astrocytes (HNAs, SV40T) were used as cytotoxic controls. We found that HDACi significantly reduced cell viability and increased cell death of human GBM cells, but not HNAs. Combination therapy of HDACi with TMZ generated increased cytotoxic activity in comparison to TMZ monotherapy, with the combination of VPA and TMZ having the strongest effect (30% viability following VPA/TMZ treatment, compared to 42% SAHA/TMZ, 45% CAY10603/TMZ, and 85% TMZ alone). In contrast, when evaluating epi-drugs as monotherapies, at intermediate concentrations, 1.9 μM CAY10603 was most effective in decreasing U87-GBM cell viability (27%) particularly at micromolar concentrations, compared to 3.7 μM SAHA (36%) and 1.5 mM VPA (51%). In HNAs, CAY10603, SAHA, and VPA decreased cell viability to 80%, 87%, and 90%, respectively.These findings suggest that HDACi synergize with TMZ to enhance its cytotoxicity. The promising anti-tumor effects these HDACi-s warrant preclinical studies. Citation Format: Golnaz Asaadi Tehrani, Becca Kubick, Meenal Datta. Epigenetic targeting improves glioblastoma cell sensitivity to chemotherapy [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B018.
Genetic Approaches to Study Rheumatic Diseases and Its Implications in Clinical Practice
Authors: Dorota Rowczenio, Ivona Aksentijevich
Journal: Arthritis & Rheumatology (2024)

Patients with rare and complex rheumatic diseases (RDs) present with immense clinical variability inherent to all immunologic diseases. In addition to systemic and organ-specific inflammation, patients may display features of immunodeficiency or allergy, which may represent major diagnostic and therapeutic challenges. The person's genetic architecture has been a well-established risk factor for patients with RDs, albeit to variable degrees. Patients with early-onset diseases and/or positive family history (FH) have a strong genetic component, whereas patients with late-onset RDs demonstrate a more complex interplay of genetic and environmental risk factors. Overall, the genetic studies in patients with RDs have been instrumental to our understanding of innate and adaptive immunity in human health and disease. The elucidation of the molecular causes underlying rare diseases has played a major role in the identification of genes that are critical in the regulation of inflammatory responses. In addition, studies of patients with rare disorders may help determine the mechanisms of more complex autoimmune diseases by identifying variants with small effect sizes in the same genes. In contrast, studies of patients with common RDs are conducted in cohorts of patients with well-established phenotypes and ancestry-matched controls, and they aim to discover disease-related pathways that can inform the development of novel targeted therapies. Knowing the genetic cause of a disease has helped patients and families understand the disease progression and outcome. Here, we discuss the current understanding of genetic heritability and challenges in the diagnosis of RDs in patients and how this field may develop in the future.
Reactivation of Epstein–Barr virus among intensive care patients: a prospective observational study
Authors: François Guiouillier, Jean Derely, Alexandre Salvadori, Jonas Pochard, Jérôme Le Goff, Thibault Martinez, Florent Raffin, Philippe Laitselart, Charlotte Beaucreux, Sonia Priou, Pierre-Louis Conan, Vincent Foissaud, Aurélie Servonnet, Philippe Vest, Mathieu Boutonnet, Stéphane de Rudnicki, Christine Bigaillon, Nicolas Libert
Journal: Intensive Care Medicine (2024)
Correction: Phase-3 trial of recombinant human alkaline phosphatase for patients with sepsis-associated acute kidney injury (REVIVAL)
Authors: Peter Pickkers, Derek C. Angus, Kristie Bass, Rinaldo Bellomo, Erik van den Berg, Juliane Bernholz, Morten H. Bestle, Kent Doi, Chistopher J. Doig, Ricard Ferrer, Bruno Francois, Henrik Gammelager, Ulf Goettrup Pedersen, Eric Hoste, Susanne Iversen, Michael Joannidis, John A. Kellum, Kathleen Liu, Melanie Meersch, Ravindra Mehta, Scott Millington, Patrick T. Murray, Alistair Nichol, Marlies Ostermann, Ville Pettilä, Christoffer Solling, Matthias Winkel, Paul J. Young, Alexander Zarbock, Angus Carter, Dietmar Fries, Philip Eller, Ludovic Gérard, Nicolas DeSchryver, Elisabeth Diltoer, Vincent Huberlant, Isabelle Michaux, Patrick M. Honore, Tom Fivez, Christopher Doig, Gordon Wood, John Boyd, Alexis Turgeon, Maj Kamper, Thomas Strøm, Sussanne Iversen, Hendrik Gammelager, Bodil Steen Rasmussen, Christoffer Grant Sølling, Morten Hyllander Mæller, Thorbjoern Groefte, Nilanjan Dey, Ulf Gøttrup Pedersen, Mila Valkonen, Panu Uusalo, Ville Jalkanen, Ferhat Meziani, Jermie Lemarie, Gaetan Plantefeve, Konstantimos Bachoumas, Jean Louis Dufour, Anne-Laure Fedou, Pierre Asfar, Xavier Monnet, Christophe Vinsonneau, Sebastien Gibot, Christophe Guitton, Jean-Pierre Quenot, Gregoire Muller, Jean Yves Lefrant, Emmanuelle Mercier, Alexandre Mebazaa, Andreas Kortgen, Sebastian Fichtner, Stefan Kluge, Gernot Marx, Ignatio Martin-Loeches, Bairbre McNicolas, Hidenobu Kamohara, Masahiro Harada, Takuo Nakagami, Shingo Adachi, Kohei Ota, Ryo Furuya, Ayumu Tsuruoka, Yasuaki Mizushima, Satoki Inoue, Pieter Tuinman, F Wim Roozendaal, Bert Beishuizen, Oscar Hoiting, Tom Dormans, Arthur Van Zanten, Paul Young, Anthony Williams, Colin McArthur, Pawel Twardowski, Shay McGuinness, Ricard Ferrer Roca, Carol Lorencio Cardenas, Anna Navas Perez, Fernando Martinez Sagasti, Ingeborg Welters, Matt Wise, Sam Waddy, Niall MacCallum, Raghaven Murugan, Hernando Gomez, Larry Busse, David Boldt, Andrew Bernard, Daniel Files, Benjamin Margolis, Jarrod Mosier, Jonathon Truwit, Felix Zamora, Danielle Davison, Matthew Exline, Nathan Nielsen, Duncan Hite
Journal: Intensive Care Medicine (2024)