tbuckley/cabot-search huggingface dataset:
Predictable Clinical Benefits without Evidence of Synergy in Trials of Combination Therapies with Immune-Checkpoint Inhibitors
Authors: Adam C. Palmer, Benjamin Izar, Haeun Hwangbo, Peter K. Sorger
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Combinations of immune-checkpoint inhibitors (ICI) with other cancer therapies have been approved for advanced cancers in multiple indications, and numerous trials are under way to test new combinations. However, the mechanisms that account for the superiority of approved ICI combinations relative to their constituent monotherapies remain unknown. Experimental Design: We analyzed 13 phase III clinical trials testing combinations of ICIs with each other or other drugs in patients with advanced melanoma and lung, breast, gastric, kidney, and head and neck cancers. The clinical activity of the individual constituent therapies, measured in the same or a closely matched trial cohort, was used to compute progression-free survival (PFS) curves expected under a model of independent drug action. To identify additive or synergistic efficacy, PFS expected under this null model was compared with observed PFS by Cox regression. Results: PFS elicited by approved combination therapies with ICIs could be accurately predicted from monotherapy data using the independent drug action model (Pearson r = 0.98, P &amp;lt; 5 × 10−9, N = 4,173 patients, 8 types of cancer). We found no evidence of drug additivity or synergy except in one trial in which such interactions might have extended median PFS by 9 days. Conclusions: Combining ICIs with other cancer therapies affords predictable and clinically meaningful benefit by providing patients with multiple chances of response to a single agent. Conversely, there exists no evidence in phase III trials that other therapies interact with and enhance the activity of ICIs. These findings can inform the design and testing of new ICI combination therapies while emphasizing the importance of developing better predictors (biomarkers) of ICI response.
Enhanced but variant-dependent serological and cellular immune responses to third-dose BNT162b2 vaccination in patients with multiple myeloma
Authors: Julius C. Enssle, Julia Campe, Sarah Büchel, Alina Moter, Frederic See, Katharina Grießbaum, Michael A. Rieger, Sebastian Wolf, Olivier Ballo, Björn Steffen, Hubert Serve, Holger F. Rabenau, Marek Widera, Melanie Bremm, Sabine Huenecke, Sandra Ciesek, Ivana von Metzler, Evelyn Ullrich
Journal: Cancer Cell (2022)
Combinatorial targeting of Hippo-STRIPAK and PARP elicits synthetic lethality in gastrointestinal cancers
Authors: Liwei An, Zhifa Cao, Pingping Nie, Hui Zhang, Zhenzhu Tong, Fan Chen, Yang Tang, Yi Han, Wenjia Wang, Zhangting Zhao, Qingya Zhao, Yuqin Yang, Yuanzhi Xu, Gemin Fang, Lei Shi, Huixiong Xu, Haiqing Ma, Shi Jiao, Zhaocai Zhou
Journal: Journal of Clinical Investigation (2022)

The striatin-interacting phosphatase and kinase (STRIPAK) complexes integrate extracellular stimuli that result in intracellular activities. Previously, we discovered that STRIPAK is a key machinery responsible for loss of the Hippo tumor suppressor signal in cancer. Here, we identified the Hippo-STRIPAK complex as an essential player in the control of DNA double-stranded break (DSB) repair and genomic stability. Specifically, we found that the mammalian STE20-like protein kinases 1 and 2 (MST1/2), independent of classical Hippo signaling, directly phosphorylated zinc finger MYND type–containing 8 (ZMYND8) and hence resulted in the suppression of DNA repair in the nucleus. In response to genotoxic stress, the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway was determined to relay nuclear DNA damage signals to the dynamic assembly of Hippo-STRIPAK via TANK-binding kinase 1–induced (TBK1-induced) structural stabilization of the suppressor of IKBKE 1– sarcolemma membrane–associated protein (SIKE1-SLMAP) arm. As such, we found that STRIPAK-mediated MST1/2 inactivation increased the DSB repair capacity of cancer cells and endowed these cells with resistance to radio- and chemotherapy and poly(ADP-ribose)polymerase (PARP) inhibition. Importantly, targeting the STRIPAK assembly with each of 3 distinct peptide inhibitors efficiently recovered the kinase activity of MST1/2 to suppress DNA repair and resensitize cancer cells to PARP inhibitors in both animal- and patient-derived tumor models. Overall, our findings not only uncover what we believe to be a previously unrecognized role for STRIPAK in modulating DSB repair but also provide translational implications of cotargeting STRIPAK and PARP for a new type of synthetic lethality anticancer therapy.
CRISPR/Cas therapeutic strategies for autosomal dominant disorders
Authors: Salvatore Marco Caruso, Peter M.J. Quinn, Bruna Lopes da Costa, Stephen H. Tsang
Journal: Journal of Clinical Investigation (2022)

Autosomal dominant disorders present unique challenges, as therapeutics must often distinguish between healthy and diseased alleles while maintaining high efficiency, specificity, and safety. For this task, CRISPR/Cas remains particularly promising. Various CRISPR/Cas systems, like homology-directed repair, base editors, and prime editors, have been demonstrated to selectively edit mutant alleles either by incorporating these mutations into sgRNA sequences (near the protospacer-adjacent motif ["near the PAM"]) or by targeting a novel PAM generated by the mutation ("in the PAM"). However, these probability-based designs are not always assured, necessitating generalized, mutation-agnostic strategies like ablate-and-replace and single-nucleotide polymorphism editing. Here, we detail recent advancements in CRISPR therapeutics to treat a wide range of autosomal dominant disorders and discuss how they are altering the landscape for future therapies.
Evidence-Based Medical Therapy in Patients With Heart Failure With Reduced Ejection Fraction and Chronic Kidney Disease
Authors: Iris E. Beldhuis, Carolyn S.P. Lam, Jeffrey M. Testani, Adriaan A. Voors, Harriette G.C. Van Spall, Jozine M. ter Maaten, Kevin Damman
Journal: Circulation (2022)

Chronic kidney disease (CKD) as identified by a reduced estimated glomerular filtration rate (eGFR) is a common comorbidity in patients with heart failure with reduced ejection fraction (HFrEF). The presence of CKD is associated with more severe heart failure, and CKD itself is a strong independent risk factor of poor cardiovascular outcome. Furthermore, the presence of CKD often influences the decision to start, uptitrate, or discontinue possible life-saving HFrEF therapies. Because pivotal HFrEF randomized clinical trials have historically excluded patients with stage 4 and 5 CKD (eGFR <30 mL/min/1.73 m
Nanofiber Topographies Enhance Platelet‐Fibrinogen Scaffold Interactions
Authors: Martin Kenny, Stephani Stamboroski, Reem Taher, Dorothea Brüggemann, Ingmar Schoen
Journal: Advanced Healthcare Materials (2022)

Abstract The initial contact with blood and its components, including plasma proteins and platelets, directs the body's response to foreign materials. Natural scaffolds of extracellular matrix or fibrin contain fibrils with nanoscale dimensions, but how platelets specifically respond to the topography and architecture of fibrous materials is still incompletely understood. Here, planar and nanofiber scaffolds are fabricated from native fibrinogen to characterize the morphology of adherent platelets and activation markers for phosphatidylserine exposure and α ‐granule secretion by confocal fluorescence microscopy and scanning electron microscopy. Different fibrinogen topographies equally support the spreading and α‐granule secretion of washed platelets. In contrast, preincubation of the scaffolds with plasma diminishes platelet spreading on planar fibrinogen surfaces but not on nanofibers. The data show that the enhanced interactions of platelets with nanofibers result from a higher locally accessible surface area, effectively increasing the ligand density for integrin‐mediated responses. Overall, fibrinogen nanofibers direct platelets toward robust adhesion formation and α ‐granule secretion while minimizing their procoagulant activity. Similar results on fibrinogen‐coated polydimethylsiloxane substrates with micrometer‐sized 3D features suggest that surface topography could be used more generally to steer blood‐materials interactions on different length scales for enhancing the initial wound healing steps.
Iron-dependent epigenetic modulation promotes pathogenic T cell differentiation in lupus
Authors: Xiaofei Gao, Yang Song, Jiali Wu, Shuang Lu, Xiaoli Min, Limin Liu, Longyuan Hu, Meiling Zheng, Pei Du, Yaqin Yu, Hai Long, Haijing Wu, Sujie Jia, Di Yu, Qianjin Lu, Ming Zhao
Journal: Journal of Clinical Investigation (2022)

The trace element iron affects immune responses and vaccination, but knowledge of its role in autoimmune diseases is limited. Expansion of pathogenic T cells, especially T follicular helper (Tfh) cells, has great significance to systemic lupus erythematosus (SLE) pathogenesis. Here, we show an important role of iron in regulation of pathogenic T cell differentiation in SLE. We found that iron overload promoted Tfh cell expansion, proinflammatory cytokine secretion, and autoantibody production in lupus-prone mice. Mice treated with a high-iron diet exhibited an increased proportion of Tfh cell and antigen-specific GC response. Iron supplementation contributed to Tfh cell differentiation. In contrast, iron chelation inhibited Tfh cell differentiation. We demonstrated that the miR-21/BDH2 axis drove iron accumulation during Tfh cell differentiation and further promoted Fe2+-dependent TET enzyme activity and BCL6 gene demethylation. Thus, maintaining iron homeostasis might be critical for eliminating pathogenic Th cells and might help improve the management of patients with SLE.
Metabolic disorders on cognitive dysfunction after traumatic brain injury
Authors: Jin-qing Lai, Yan-Chuan Shi, Shu Lin, Xiang-Rong Chen
Journal: Trends in Endocrinology and Metabolism (2022)

Cognitive dysfunction is a common adverse consequence of traumatic brain injury (TBI). After brain injury, the brain and other organs trigger a series of complex metabolic changes, including reduced glucose metabolism, enhanced lipid peroxidation, disordered neurotransmitter secretion, and imbalanced trace element synthesis. In recent years, several research and clinical studies have demonstrated that brain metabolism directly or indirectly affects cognitive dysfunction after TBI, but the mechanisms remain unclear. Drugs that improve the symptoms of cognitive dysfunction caused by TBI are under investigation and treatments that target metabolic processes are expected to improve cognitive function in the future. This review explores the impact of metabolic disorders on cognitive dysfunction after TBI and provides new strategies for the treatment of metabolic disorders.
Engineering multifunctional bioactive citrate-based biomaterials for tissue engineering
Authors: Min Wang, Peng Xu, Bo Lei
Journal: Bioactive Materials (2022)

Developing bioactive biomaterials with highly controlled functions is crucial to enhancing their applications in regenerative medicine. Citrate-based polymers are the few bioactive polymer biomaterials used in biomedicine because of their facile synthesis, controllable structure, biocompatibility, biomimetic viscoelastic mechanical behavior, and functional groups available for modification. In recent years, various multifunctional designs and biomedical applications, including cardiovascular, orthopedic, muscle tissue, skin tissue, nerve and spinal cord, bioimaging, and drug or gene delivery based on citrate-based polymers, have been extensively studied, and many of them have good clinical application potential. In this review, we summarize recent progress in the multifunctional design and biomedical applications of citrate-based polymers. We also discuss the further development of multifunctional citrate-based polymers with tailored properties to meet the requirements of various biomedical applications.
EGFR Inhibition Potentiates FGFR Inhibitor Therapy and Overcomes Resistance in FGFR2 Fusion–Positive Cholangiocarcinoma
Authors: Qibiao Wu, Yuanli Zhen, Lei Shi, Phuong Vu, Patricia Greninger, Ramzi Adil, Joshua Merritt, Regina Egan, Meng-Ju Wu, Xunqin Yin, Cristina R. Ferrone, Vikram Deshpande, Islam Baiev, Christopher J. Pinto, Daniel E. McLoughlin, Charlotte S. Walmsley, James R. Stone, John D. Gordan, Andrew X. Zhu, Dejan Juric, Lipika Goyal, Cyril H. Benes, Nabeel Bardeesy
Journal: Cancer Discovery (2022)

FGFR inhibitors are approved for the treatment of advanced cholangiocarcinoma harboring FGFR2 fusions. However, the response rate is moderate, and resistance emerges rapidly due to acquired secondary FGFR2 mutations or due to other less-defined mechanisms. Here, we conducted high-throughput combination drug screens, biochemical analysis, and therapeutic studies using patient-derived models of FGFR2 fusion-positive cholangiocarcinoma to gain insight into these clinical profiles and uncover improved treatment strategies. We found that feedback activation of EGFR signaling limits FGFR inhibitor efficacy, restricting cell death induction in sensitive models and causing resistance in insensitive models lacking secondary FGFR2 mutations. Inhibition of wild-type EGFR potentiated responses to FGFR inhibitors in both contexts, durably suppressing MEK/ERK and mTOR signaling, increasing apoptosis, and causing marked tumor regressions in vivo. Our findings reveal EGFR-dependent adaptive signaling as an important mechanism limiting FGFR inhibitor efficacy and driving resistance and support clinical testing of FGFR/EGFR inhibitor therapy for FGFR2 fusion-positive cholangiocarcinoma. We demonstrate that feedback activation of EGFR signaling limits the effectiveness of FGFR inhibitor therapy and drives adaptive resistance in patient-derived models of FGFR2 fusion-positive cholangiocarcinoma. These studies support the potential of combination treatment with FGFR and EGFR inhibitors as an improved treatment for patients with FGFR2-driven cholangiocarcinoma. This article is highlighted in the In This Issue feature, p. 1171.
Macrophage efferocytosis with VEGFC and lymphangiogenesis: rescuing the broken heart
Authors: Patricia A. D’Amore, Pilar Alcaide
Journal: Journal of Clinical Investigation (2022)

Cardiac repair following ischemic injury is indispensable for survival and requires a coordinated cellular response involving the mobilization of immune cells from the secondary lymphoid organs to the site of damage. Efferocytosis, the engulfment of cell debris and dying cells by innate immune cells, along with lymphangiogenesis, the formation of new lymphatic vessels, are emerging as central to the cardiac healing response. In this issue of the JCI, Glinton et al. used state-of-the-art approaches to demonstrate that efferocytosis induced vascular endothelial growth factor C (VEGFC) in myeloid cells and stimulated lymphangiogenesis and cardiac repair. These findings provide impactful mechanistic information that can be leveraged to therapeutically target pathways in cardiac repair and ischemic heart failure.
Tumor Lysis Syndrome and AKI: Beyond Crystal Mechanisms
Authors: Marine Arnaud, Maud Loiselle, Camille Vaganay, Stéphanie Pons, Emmanuel Letavernier, Jordane Demonchy, Sofiane Fodil, Manal Nouacer, Sandrine Placier, Perrine Frère, Eden Arrii, Julien Lion, Nuala Mooney, Raphael Itzykson, Chakib Djediat, Alexandre Puissant, Lara Zafrani
Journal: Journal of the American Society of Nephrology (2022)

Significance Statement The pathophysiology of AKI during tumor lysis syndrome (TLS) is not fully understood. We aimed to decipher crystal-dependent and crystal-independent mechanisms of TLS-induced AKI. Analyzing urine and blood from patients with TLS provided data on crystal-independent mechanisms of the pathogenesis of AKI during TLS. We also explored mechanisms of TLS-induced AKI in vitro and in vivo in a murine model of TLS (syngeneic mice with acute myeloid leukemia receiving chemotherapy). We found that extracellular histones released in huge amounts during TLS profoundly alter the endothelium. Nonanticoagulant heparin mitigated AKI in this model. Background The pathophysiology of AKI during tumor lysis syndrome (TLS) is not well understood due to the paucity of data. We aimed to decipher crystal-dependent and crystal-independent mechanisms of TLS-induced AKI. Methods Crystalluria, plasma cytokine levels, and extracellular histones levels were measured in two cohorts of patients with TLS. We developed a model of TLS in syngeneic mice with acute myeloid leukemia, and analyzed ultrastructural changes in kidneys and endothelial permeability using intravital confocal microscopy. In parallel, we studied the endothelial toxicity of extracellular histones in vitro. Results The study provides the first evidence that previously described crystal-dependent mechanisms are insufficient to explain TLS-induced AKI. Extracellular histones that are released in huge amounts during TLS caused profound endothelial alterations in the mouse model. The mechanisms of histone-mediated damage implicates endothelial cell activation mediated by Toll-like receptor 4. Heparin inhibits extracellular histones and mitigates endothelial dysfunction during TLS. Conclusion This study sheds new light on the pathophysiology of TLS-induced AKI and suggests that extracellular histones may constitute a novel target for therapeutic intervention in TLS when endothelial dysfunction occurs.
Phase 1b Clinical Trial with Alpelisib plus Olaparib for Patients with Advanced Triple-Negative Breast Cancer
Authors: Felipe Batalini, Niya Xiong, Nabihah Tayob, Madeline Polak, Julia Eismann, Lewis C. Cantley, Geoffrey I. Shapiro, Viktor Adalsteinsson, Eric P. Winer, Panagiotis A. Konstantinopoulos, Alan D'Andrea, Elizabeth M. Swisher, Ursula A. Matulonis, Gerburg M. Wulf, Erica L. Mayer
Journal: Clinical Cancer Research (2022)

We had previously reported on the safety and the recommended phase 2 dose (RP2D) of olaparib in combination with the PI3Kα-specific inhibitor alpelisib in patients with high-grade serous ovarian cancer as studied in a phase 1b trial (NCT01623349). Here, we report on the breast cancer cohort from that study.
Current insights into the bone marrow niche: From biology in vivo to bioengineering ex vivo
Authors: Yinbo Xiao, ChanelleA.S. McGuinness, W. Sebastian Doherty-Boyd, Manuel Salmeron-Sanchez, Hannah Donnelly, Matthew J. Dalby
Journal: Biomaterials (2022)

Hematopoietic stem cells (HSCs) are fundamental to the generation of the body's blood and immune cells. They reside primarily within the bone marrow (BM) niche microenvironment, which provides signals responsible for the regulation of HSC activities. While our understanding of these signalling mechanisms continues to improve, our ability to recapitulate them in vitro to harness the clinical potential of the HSC populations is still lacking. Recent studies have applied novel engineering techniques combined with traditional in vitro work to establish ex vivo BM niche models. These models exhibit promising potential for research and clinical applications. In this review, BM niche factors that regulate the HSCs in vivo are discussed and their applications in the engineering of BM biomaterial-based platforms are considered. Many questions remain regarding the heterogeneity of niche components and the interactions of HSCs with their microenvironment. A greater understanding of the niche would help to elucidate these remaining questions, leading to the development of novel therapeutic tools.
Nitric-oxide enriched plasma-activated water inactivates 229E coronavirus and alters antiviral response genes in human lung host cells
Authors: Nagendra Kumar Kaushik, Pradeep Bhartiya, Neha Kaushik, Yungoh Shin, Linh Nhat Nguyen, Jang Sick Park, Doyoung Kim, Eun Ha Choi
Journal: Bioactive Materials (2022)

The ongoing pandemic caused by the novel coronavirus, SARS-CoV-2, is influencing global health. Moreover, there is a major threat of future coronaviruses affecting the entire world in a similar, or even more dreadful, manner. Therefore, effective and biocompatible therapeutic options against coronaviruses are urgently needed. To address this challenge, medical specialists require a well-informed and safe approach to treating human coronaviruses (HCoVs). Herein, an environmental friendly approach for viral inactivation, based on plasma technology, was considered. A microwave plasma system was employed for the generation of the high amount of gaseous nitric oxide to prepare nitric oxide enriched plasma-activated water (NO-PAW), the effects of which on coronaviruses, have not been reported to date. To determine these effects, alpha-HCoV-229E was used in an experimental model. We found that NO-PAW treatment effectively inhibited coronavirus infection in host lung cells, visualized by evaluating the cytopathic effect and expression level of spike proteins. Interestingly, NO-PAW showed minimal toxicity towards lung host cells, suggesting its potential for therapeutic application. Moreover, this new approach resulted in viral inactivation and greatly improved the gene levels involved in host antiviral responses. Together, our findings provide evidence of an initiation point for further progress toward the clinical development of antiviral treatments, including such coronaviruses.
Loss of the collagen IV modifier prolyl 3-hydroxylase 2 causes thin basement membrane nephropathy
Authors: Hande Aypek, Christoph Krisp, Shun Lu, Shuya Liu, Dominik Kylies, Oliver Kretz, Guochao Wu, Manuela Moritz, Kerstin Amann, Kerstin Benz, Ping Tong, Zheng-mao Hu, Sulaiman M. Alsulaiman, Arif O. Khan, Maik Grohmann, Timo Wagner, Janina Müller-Deile, Hartmut Schlüter, Victor G. Puelles, Carsten Bergmann, Tobias B. Huber, Florian Grahammer
Journal: Journal of Clinical Investigation (2022)

The glomerular filtration barrier (GFB) produces primary urine and is composed of a fenestrated endothelium, a glomerular basement membrane (GBM), podocytes, and a slit diaphragm. Impairment of the GFB leads to albuminuria and microhematuria. The GBM is generated via secreted proteins from both endothelial cells and podocytes and is supposed to majorly contribute to filtration selectivity. While genetic mutations or variations of GBM components have been recently proposed to be a common cause of glomerular diseases, pathways modifying and stabilizing the GBM remain incompletely understood. Here, we identified prolyl 3-hydroxylase 2 (P3H2) as a regulator of the GBM in an a cohort of patients with albuminuria. P3H2 hydroxylates the 3' of prolines in collagen IV subchains in the endoplasmic reticulum. Characterization of a P3h2ΔPod mouse line revealed that the absence of P3H2 protein in podocytes induced a thin basement membrane nephropathy (TBMN) phenotype with a thinner GBM than that in WT mice and the development of microhematuria and microalbuminuria over time. Mechanistically, differential quantitative proteomics of the GBM identified a significant decrease in the abundance of collagen IV subchains and their interaction partners in P3h2ΔPod mice. To our knowledge, P3H2 protein is the first identified GBM modifier, and loss or mutation of P3H2 causes TBMN and focal segmental glomerulosclerosis in mice and humans.