tbuckley/cabot-search huggingface dataset:
Paclitaxel and Carboplatin in Combination with Low-intensity Pulsed Ultrasound for Glioblastoma
Authors: Karl J. Habashy, Crismita Dmello, Li Chen, Victor A. Arrieta, Kwang-Soo Kim, Andrew Gould, Mark W. Youngblood, Guillaume Bouchoux, Kirsten B. Burdett, Hui Zhang, Michael Canney, Roger Stupp, Adam M. Sonabend
Journal: Clinical Cancer Research (2024)

Abstract Purpose: We recently reported on clinical trials for patients with recurrent glioblastoma where low-intensity pulsed ultrasound and microbubbles (LIPU/MB) improved paclitaxel or carboplatin delivery into the brain. Here, we report variable local tumor control with paclitaxel at the maximal/target dose in our phase I trial (NCT04528680). To address this, we investigated the combination of paclitaxel with carboplatin in preclinical glioma models. Experimental Design: We performed MRI-based analysis to evaluate disease control in patients from our trial. We studied the cytotoxicity of paclitaxel and carboplatin against 11 human glioma lines as monotherapy and in combination at concentrations derived from human intraoperative studies. Synergy was assessed with the Loewe model and the survival benefit evaluated in two xenografts. We examined the effects on cell cycle progression, DNA damage, and apoptosis. Results: Patients treated with paclitaxel and LIPU/MB exhibited variable local tumor control, which correlated with overall survival. We observed limited cross-resistance to paclitaxel and carboplatin in glioma lines, with almost a third of them being exclusively susceptible to one drug. This combination led to susceptibility of 81% of lines and synergy in 55% of them. The combination proved more efficacious in two intracranial xenografts when administered with LIPU/MB, leading to complementary effects on cell cycle arrest. Conclusions: Combining paclitaxel and carboplatin in gliomas may be more efficacious than monotherapy, as in other cancers, due to synergy and independent susceptibility to each drug. These results form the basis for an ongoing phase II trial (NCT04528680) where we investigate this combination with LIPU/MB.
Integrating the gut microbiome and pharmacology
Authors: Andrew A. Verdegaal, Andrew L. Goodman
Journal: Science Translational Medicine (2024)

The gut microbiome harbors trillions of organisms that contribute to human health and disease. These bacteria can also affect the properties of medical drugs used to treat these diseases, and drugs, in turn, can reshape the microbiome. Research addressing interdependent microbiome-host-drug interactions thus has broad impact. In this Review, we discuss these interactions from the perspective of drug bioavailability, absorption, metabolism, excretion, toxicity, and drug-mediated microbiome modulation. We survey approaches that aim to uncover the mechanisms underlying these effects and opportunities to translate this knowledge into new strategies to improve the development, administration, and monitoring of medical drugs.
Bone morphogenetic protein 9 is a candidate prognostic biomarker and host-directed therapy target for sepsis
Authors: Haobo Bai, Qian Lu, Chunxiang Wu, Fang Xu, Jiayu Liu, Ke Wang, Hao Ding, Yibing Yin, Yi Liu, Xiaofei Lai, Ju Cao
Journal: Science Translational Medicine (2024)

Defining next-generation immune therapeutics for the treatment of sepsis will involve biomarker-based therapeutic decision-making. Bone morphogenetic protein 9 (BMP9) is a cytokine in the transforming growth factor–β superfamily. Here, circulating BMP9 concentrations were quantified in two independent cohorts of patients with sepsis. Decreased concentrations of serum BMP9 were observed in the patients with sepsis at the time of admission as compared with healthy controls. Concentrations of BMP9 at the time of admission were also associated with 28-day mortality, because patients with sepsis at a higher risk of death had lower BMP9 concentrations. The mechanism driving the contribution of BMP9 to host immunity was further investigated using in vivo murine sepsis models and in vitro cell models. We found that BMP9 treatment improved outcome in mice with experimental sepsis. BMP9-treated mice exhibited increased macrophage influx into the peritoneal cavity and more efficient bacterial clearance than untreated mice. In vitro, BMP9 promoted macrophage recruitment, phagocytosis, and subsequent bacterial killing. We further found that deletion of the type 1 BMP receptor ALK1 in macrophages abolished BMP9-mediated protection against polymicrobial sepsis in vivo. Further experiments indicated that the regulation of macrophage activation by the BMP9-ALK1 axis was mainly mediated through the suppressor of mother against decapentaplegic 1/5 signaling pathway. Together, these results suggest that BMP9 can both serve as a biomarker for patient stratification with an independent prognostic value and be developed as a host-directed therapy for sepsis.
Cerebrospinal Fluid cfDNA Sequencing for Classification of Central Nervous System Glioma
Authors: Florian Iser, Felix Hinz, Dirk C. Hoffmann, Niklas Grassl, Cansu Güngör, Jochen Meyer, Laura Dörner, Lea Hofmann, Vanessa Kelbch, Kirsten Göbel, Mustafa Ahmed Mahmutoglu, Philipp Vollmuth, Areeba Patel, Duy Nguyen, Leon D. Kaulen, Iris Mildenberger, Katharina Sahm, Kendra Maaß, Kristian W. Pajtler, Ganesh M. Shankar, Markus Weiler, Brigitte Wildemann, Frank Winkler, Andreas von Deimling, Michael Platten, Wolfgang Wick, Felix Sahm, Tobias Kessler
Journal: Clinical Cancer Research (2024)

Primary central nervous system (CNS) gliomas can be classified by characteristic genetic alterations. In addition to solid tissue obtained via surgery or biopsy, cell-free DNA (cfDNA) from cerebrospinal fluid (CSF) is an alternative source of material for genomic analyses.
TGF-βR2 signaling coordinates pulmonary vascular repair after viral injury in mice and human tissue
Authors: Gan Zhao, Lulu Xue, Aaron I. Weiner, Ningqiang Gong, Stephanie Adams-Tzivelekidis, Joanna Wong, Maria E. Gentile, Ana N. Nottingham, Maria C. Basil, Susan M. Lin, Terren K. Niethamer, Joshua M. Diamond, Christian A. Bermudez, Edward Cantu, Xuexiang Han, Yaqi Cao, Mohamad-Gabriel Alameh, Drew Weissman, Edward E. Morrisey, Michael J. Mitchell, Andrew E. Vaughan
Journal: Science Translational Medicine (2024)

Disruption of pulmonary vascular homeostasis is a central feature of viral pneumonia, wherein endothelial cell (EC) death and subsequent angiogenic responses are critical determinants of the outcome of severe lung injury. A more granular understanding of the fundamental mechanisms driving reconstitution of lung endothelium is necessary to facilitate therapeutic vascular repair. Here, we demonstrated that TGF-β signaling through TGF-βR2 (transforming growth factor–β receptor 2) is activated in pulmonary ECs upon influenza infection, and mice deficient in endothelial Tgfbr2 exhibited prolonged injury and diminished vascular repair. Loss of endothelial Tgfbr2 prevented autocrine Vegfa (vascular endothelial growth factor α) expression, reduced endothelial proliferation, and impaired renewal of aerocytes thought to be critical for alveolar gas exchange. Angiogenic responses through TGF-βR2 were attributable to leucine-rich α-2-glycoprotein 1, a proangiogenic factor that counterbalances canonical angiostatic TGF-β signaling. Further, we developed a lipid nanoparticle that targets the pulmonary endothelium, Lung-LNP (LuLNP). Delivery of Vegfa mRNA, a critical TGF-βR2 downstream effector, by LuLNPs improved the impaired regeneration phenotype of EC Tgfbr2 deficiency during influenza injury. These studies defined a role for TGF-βR2 in lung endothelial repair and demonstrated efficacy of an efficient and safe endothelial-targeted LNP capable of delivering therapeutic mRNA cargo for vascular repair in influenza infection.
Regulatory T cells suppress myeloma-specific immunity during autologous stem cell mobilization and transplantation
Authors: Shuichiro Takahashi, Simone A. Minnie, Kathleen S. Ensbey, Christine R. Schmidt, Tomoko Sekiguchi, Samuel R. W. Legg, Ping Zhang, Motoko Koyama, Stuart D. Olver, Alika D. Collinge, Sara Keshmiri, Melissa L. Comstock, Antiopi Varelias, Damian J. Green, Geoffrey R. Hill
Journal: Blood (2024)

Autologous stem cell transplantation (ASCT) is the standard of care consolidation therapy for eligible patients with myeloma but most patients eventually progress, an event associated with features of immune escape. Novel approaches to enhance antimyeloma immunity after ASCT represent a major unmet need. Here, we demonstrate that patient-mobilized stem cell grafts contain high numbers of effector CD8 T cells and immunosuppressive regulatory T cells (Tregs). We showed that bone marrow (BM)-residing T cells are efficiently mobilized during stem cell mobilization (SCM) and hypothesized that mobilized and highly suppressive BM-derived Tregs might limit antimyeloma immunity during SCM. Thus, we performed ASCT in a preclinical myeloma model with or without stringent Treg depletion during SCM. Treg depletion generated SCM grafts containing polyfunctional CD8 T effector memory cells, which dramatically enhanced myeloma control after ASCT. Thus, we explored clinically tractable translational approaches to mimic this scenario. Antibody-based approaches resulted in only partial Treg depletion and were inadequate to recapitulate this effect. In contrast, a synthetic interleukin-2 (IL-2)/IL-15 mimetic that stimulates the IL-2 receptor on CD8 T cells without binding to the high-affinity IL-2Ra used by Tregs efficiently expanded polyfunctional CD8 T cells in mobilized grafts and protected recipients from myeloma progression after ASCT. We confirmed that Treg depletion during stem cell mobilization can mitigate constraints on tumor immunity and result in profound myeloma control after ASCT. Direct and selective cytokine signaling of CD8 T cells can recapitulate this effect and represent a clinically testable strategy to improve responses after ASCT.
Three Dengue Vaccines — What Now?
Authors: Scott B Halstead
Journal: New England Journal of Medicine (2024)

In 2019, the four serotypes of the mosquito-borne dengue virus (DENV) caused an estimated 56 million cases of disease and 5000 to 40,000 deaths in a global swath of tropical and near-tropical countries, defying control and motivating the development of vaccines.1 Outcomes of clinical trials of dengue vaccines are necessarily governed by the biologic and immunologic behavior of DENV in humans. Initial infection with any DENV serotype in persons who have not previously been infected with DENV typically results in at most mild-to-moderate febrile illnesses of short duration. These initial infections provide lifelong protection against reinfection with the same immunologic . . .
Hierarchical Dendritic Photonic Crystal Beads for Efficient Isolation and Proteomic Analysis of Multiple Cell Types
Authors: Wenya Chang, Yu Li, Yuhan Cai, Shu Wang, Xiaorong Song, Jie Sun, Dawei Deng, Zhongze Gu, Zhuoying Xie
Journal: Advanced Healthcare Materials (2024)

Abstract Cell types with different morphology, and function collaborate to maintain organ function. As such, analyzing proteomic differences and connections between different types of cells forms the foundation for establishing functional connectomes and developing in vitro organoid simulation experiments. However, the efficiency of cell type isolation from organs is limited by time, equipment, and cost. Here, hierarchical dendritic photonic crystal beads (HDPCBs) featuring high‐density functional groups via the self‐assembly of dendritic mesoporous structure SiO 2 nanoparticles (DM‐SiO 2 ) and grafting dendrimers onto the surface of dendritic mesoporous photonic crystal beads (DMPCBs) is developed. This platform integrates multitype cell separation with in situ protein cleavage processes. Efficient simultaneous isolation of Kupffer cells and Liver Sinusoidal Endothelial cells (LSECs) from liver, with high specificity and convenient operation in a short separation time are demonstrated. The results reveal 2832 and 3442 unique proteins identified in Kupffer cells and LSECs using only 50 HDPCBs, respectively. 764 and 629 over‐expressed proteins associated with the function of Kupffer cells and LSECs are found, respectively. The work offers a new method for efficiently isolating multiple cell types from tissues and downstream proteomic analysis, ultimately facilitating the identification of primary cell compositions and functions.
Structural stigma and LGBTQ+ health: a narrative review of quantitative studies
Authors: Mark L Hatzenbuehler, Micah R Lattanner, Sarah McKetta, John E Pachankis
Journal: The Lancet Public Health (2024)

Health disparities related to sexual orientation and gender identity exist across multiple outcomes. Scholarship has begun to evaluate whether structural stigma-ie, societal-level conditions, cultural norms, and institutional policies that constrain opportunities, resources, and wellbeing-contributes to health burdens among LGBTQ+ individuals. We conducted a comprehensive review of quantitative studies examining this hypothesis. We found 98 articles that linked objective (ie, non-self-reported) measures of structural stigma to mental (n=57), behavioural (ie, substance use; n=27; HIV/AIDS or sexually transmitted infection; n=20), and physical (n=20) health outcomes. There was generally consistent evidence that structural stigma increases risk of poor health among LGBTQ+ individuals. Several methodological strengths were identified, including the use of multiple measures (eg, laws or policies [59%, 58 of 98]), designs (eg, quasi-experiments [21%, 21 of 98]), and samples (eg, probability-based [56%, 55 of 98]). However, important gaps exist. Just over half of studies included area-level covariates or non-LGBTQ+ comparison groups, which are necessary to address alternative explanations for the observed associations. Additionally, while studies (n=90) have begun to identify candidate mechanisms, only nine (10%) formally tested mediation. We offer suggestions for future research to advance this literature, which has implications not only for the identification of structural determinants of LGBTQ+ health but also for the development of public health interventions that reduce LGBTQ+ health disparities.
Effects of antineoplastic and immunomodulating agents on postvaccination SARS-CoV-2 breakthrough infections, antibody response, and serological cytokine profile
Authors: Jacob New, Jason Cham, Lana Smith, Leah Puglisi, Tridu Huynh, Sunil Kurian, Samantha Bagsic, Russel Fielding, Lee Hong, Priya Reddy, Ki Suk Eum, Allison Martin, Bethany Barrick, Christopher Marsh, Michael Quigley, Laura J Nicholson, Amitabh C Pandey
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Despite immunization, patients on antineoplastic and immunomodulating agents have a heightened risk of COVID-19 infection. However, accurately attributing this risk to specific medications remains challenging. Methods An observational cohort study from December 11, 2020 to September 22, 2022, within a large healthcare system in San Diego, California, USA was designed to identify medications associated with greatest risk of postimmunization SARS-CoV-2 infection. Adults prescribed WHO Anatomical Therapeutic Chemical (ATC) classified antineoplastic and immunomodulating medications were matched (by age, sex, race, and number of immunizations) with control patients not prescribed these medications yielding a population of 26 724 patients for analysis. From this population, 218 blood samples were collected from an enrolled subset to assess serological response and cytokine profile in relation to immunization. Results Prescription of WHO ATC classified antineoplastic and immunomodulatory agents was associated with elevated postimmunization SARS-CoV-2 infection risk (HR 1.50, 95% CI 1.38 to 1.63). While multiple immunization doses demonstrated a decreased association with postimmunization SARS-CoV-2 infection risk, antineoplastic and immunomodulatory treated patients with four doses remained at heightened risk (HR 1.23, 95% CI 1.06 to 1.43). Risk variation was identified among medication subclasses, with PD-1/PD-L1 inhibiting monoclonal antibodies, calcineurin inhibitors, and CD20 monoclonal antibody inhibitors identified to associate with increased risk of postimmunization SARS-CoV-2 infection. Antineoplastic and immunomodulatory treated patients also displayed a reduced IgG antibody response to SARS-CoV-2 epitopes alongside a unique serum cytokine profile. Conclusions Antineoplastic and immunomodulating medications associate with an elevated risk of postimmunization SARS-CoV-2 infection in a drug-specific manner. This comprehensive, unbiased analysis of all WHO ATC classified antineoplastic and immunomodulating medications identifies medications associated with greatest risk. These findings are crucial in guiding and refining vaccination strategies for patients prescribed these treatments, ensuring optimized protection for this susceptible population in future COVID-19 variant surges and potentially for other RNA immunization targets.
Bone formation by human paediatric marrow stromal cells in a functional allogeneic immune system
Authors: Virginia Palomares Cabeza, Niamh Fahy, Caoimhe H. Kiernan, Andrea Lolli, Janneke Witte-Bouma, Shorouk Fahmy Garcia, Ana Merino, Nicole Kops, Yanto Ridwan, Eppo B. Wolvius, Pieter A.J. Brama, Martin J. Hoogduijn, Eric Farrell
Journal: Biomaterials (2024)

Allogeneic stem-cell based regenerative medicine is a promising approach for bone defect repair. The use of chondrogenically differentiated human marrow stromal cells (MSCs) has been shown to lead to bone formation by endochondral ossification in immunodeficient pre-clinical models. However, an insight into the interactions between the allogeneic immune system and the human MSC-derived bone grafts has not been fully achieved yet. The choice of a potent source of MSCs isolated from pediatric donors with consistent differentiation and high proliferation abilities, as well as low immunogenicity, could increase the chance of success for bone allografts. In this study, we employed an immunodeficient animal model humanised with allogeneic immune cells to study the immune responses towards chondrogenically differentiated human pediatric MSCs (ch-pMSCs). We show that ch-differentiated pMSCs remained non-immunogenic to allogeneic CD4 and CD8 T cells in an in vitro co-culture model. After subcutaneous implantation in mice, ch-pMSC-derived grafts were able to initiate bone mineralisation in the presence of an allogeneic immune system for 3 weeks without the onset of immune responses. Re-exposing the splenocytes of the humanised animals to pMSCs did not trigger further T cell proliferation, suggesting an absence of secondary immune responses. Moreover, ch-pMSCs generated mature bone after 8 weeks of implantation that persisted for up to 6 more weeks in the presence of an allogeneic immune system. These data collectively show that human allogeneic chondrogenically differentiated pediatric MSCs might be a safe and potent option for bone defect repair in the tissue engineering and regenerative medicine setting.
Intraoperative application of intelligent, responsive, self-assembling hydrogel rectifies oxygen and energy metabolism in traumatically injured brain
Authors: Yuhan Han, Weiji Weng, Yongkang Zhang, Qiyuan Feng, Yuxiao Ma, Ankang Quan, Xianhua Fu, Xinxin Zhao, Loren Skudder-Hill, Jiyao Jiang, Yan Zhou, Honglin Chen, Junfeng Feng
Journal: Biomaterials (2024)

In managing severe traumatic brain injury (TBI), emergency surgery involving the removal of damaged brain tissue and intracerebral hemorrhage is a priority. Secondary brain injury caused by oxidative stress and energy metabolic disorders, triggered by both primary mechanical brain damage and surgical insult, is also a determining factor in the prognosis of TBI. Unfortunately, the effectiveness of traditional postoperative intravenous neuroprotective agents therapy is often limited by the lack of targeting, timeliness, and side effects when neuroprotective agents systemically delivered. Here, we have developed injectable, intelligent, self-assembling hydrogels (P-RT/2DG) that can achieve precise treatment through intraoperative application to the target area. P-RT/2DG hydrogels were prepared by integrating a reactive oxygen species (ROS)-responsive thioketal linker (RT) into polyethylene glycol. By scavenging ROS and releasing 2-deoxyglucose (2DG) during degradation, these hydrogels functioned both in antioxidation and energy metabolism to inhibit the vicious cycle of post-TBI ROS-lactate which provoked secondary injury. In vitro and in vivo tests confirmed the absence of systemic side effects and the neuroprotective function of P-RT/2DG hydrogels in reducing edema, nerve cell apoptosis, neuroinflammation, and maintaining the blood-brain barrier. Our study thus provides a potential treatment strategy with novel hydrogels in TBI.
Management of infliximab refractory immune checkpoint inhibitor gastrointestinal toxicity: a multicenter case series
Authors: Catriona Harvey, Kazi J Nahar, Janet McKeown, Serigne N Lo, Sheima Farag, Nadia Yousaf, Kate Young, Liselotte Tas, Aafke Meerveld-Eggink, Christian Blank, Austin Thomas, Jennifer McQuade, Bastian Schilling, Douglas B Johnson, Roberto Martín Huertas, Ana Arance, Joanna Lee, Lisa Zimmer, Georgina V Long, Matteo S Carlino, Yinghong Wang, Alexander Maxwell Menzies
Journal: Journal for ImmunoTherapy of Cancer (2024)

Immune checkpoint inhibitor (ICI) gastrointestinal toxicity (gastritis, enteritis, colitis) is a major cause of morbidity and treatment-related death. Guidelines agree steroid-refractory cases warrant infliximab, however best management of infliximab-refractory ICI gastrointestinal toxicity (IRIGItox) is unknown.