tbuckley/cabot-search huggingface dataset:
Death and end of life in France after COVID-19
Authors: Philippe Charlier
Journal: The Lancet (2023)

At the instigation of the President, Emmanuel Macron, an intense debate on ethical tensions relating to end-of-life medical practices has started in France . Unlike in some other European countries, euthanasia is not practised in France. The semantic choice made by legislators (passive chosen death rather than euthanasia, and active chosen death rather than assisted suicide) clearly shows the discomfort that politicians and jurists have with end-of-life medical management. Before initiating the legislative process, we must listen to health-care professionals1Bloomer MJ Walshe C What mediates end-of-life care choices?.Lancet Public Health. 2021; 6: e139-e140Summary Full Text Full Text PDF PubMed Scopus (3) Google Scholar and the French people, especially individuals who are waiting or hoping for death. The COVID-19 pandemic has undeniably changed burial practices and interrupted both bereavement support and funerary rituals.2Charlier P The COVID-19 pandemic: a veritable storm of ethical tensions.Ethics Med Public Health. 2021; 17: 100652Crossref Scopus (2) Google Scholar Answering several essential questions is a non-negotiable preliminary for legislating: is active assistance in dying always an act of care? Does assistance in dying constitute the ultimate care or, on the contrary, the ultimate abandonment of care? Can we oppose the right to die to the duty to live? Do people have a duty to live and not rather a right to live? No one wants to suffer, cause suffering, or lose their dignity.3Krakauer EL Rajagopal MR End-of-life care across the world: a global moral failing.Lancet. 2016; 388: 444-446Summary Full Text Full Text PDF PubMed Scopus (7) Google Scholar Everyone wants to die peacefully both for themselves but also for their caregivers and family. French law speaks of end of life, not of death. The concept of death remains taboo, just like the word cancer, which in France is avoided by using the term long illness. This non-use of the appropriate medical term poses a problem and recalls the bourgeois paternalism of medicine in high-income countries that had the right of life and death (but also of truth and lies) over its patient and their families. Inflicting death is violence, but not providing the means for a good death4Engelhardt Jr, HT Iltis AS End-of-life: the traditional Christian view.Lancet. 2005; 366: 1045-1049Summary Full Text Full Text PDF PubMed Scopus (53) Google Scholar by improving conditions in which death occurs is also violence. Can assistance in dying become legally punishable? We must find balance between increasing freedom and autonomy of the dying patients, without unreasonably advocating suicide. We must relearn how to die, we must accept to live in close contact with death. I declare no competing interests.
A friend in a forest of radiation-immune interactions: BAMBI improves antitumor effects by limiting radioresistance
Authors: Sean Sachdev
Journal: Journal of Clinical Investigation (2023)

Radiation therapy (RT) remains one of the most effective and utilized oncologic treatments available. While it can directly yield tumor cell death, its impact on the immune microenvironment is more complex, promoting either an antitumor response or, conversely, a tumor-promoting state. TGF-β, induced by RT, yields a more immunosuppressive environment, including potentially blunting response to immune-checkpoint blockade. In this issue of the JCI, Wang and colleagues demonstrate that RT reduced expression of bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI), a TGF-β pseudoreceptor. Limiting this effect, or increasing BAMBI, improved RT-induced tumor cell killing, tumor response, and antitumor immune effects. This realization points to a pathway of potential clinical translation.
Nucleic acid sensing promotes inflammatory monocyte migration through biased coagulation factor VIIa signaling
Authors: Hortensia Zelaya, Kristin Grunz, T. Son Nguyen, Anxhela Habibi, Claudius Witzler, Sabine Reyda, Irene Gonzalez-Menendez, Leticia Quintanilla-Martinez, Markus Bosmann, Hartmut Weiler, Wolfram Ruf
Journal: Blood (2023)
Perioperative and long-term survival outcomes of pancreatectomy with arterial resection in borderline resectable or locally advanced pancreatic cancer following neoadjuvant therapy: a systematic review and meta-analysis
Authors: Kang Xue, Xing Huang, Pengcheng Zhao, Yi Zhang, Bole Tian
Journal: International Journal of Surgery (2023)

Background: Pancreatic cancer frequently involves the surrounding major arteries, preventing surgeons from making a radical excision. Neoadjuvant therapy (NAT) can lessen the size of local tumors and eliminate potential micrommetastases. However, systematic and evidence-based recommendations for the treatment of arterial resection (AR) after NAT in pancreatic cancer are scarce. Method: A computerized search of the Medline, Embase, Cochrane Library databases, and Clinicaltrials was performed to identify studies reporting the outcomes of patients who underwent pancreatectomy with AR and NAT for pancreatic cancer. Studies that reported perioperative and/or long-term results after pancreatectomy with AR and NAT were eligible for inclusion. The quality of the evidence was assessed with Newcastle–Ottawa Quality Assessment Form of bias tool. Data were pooled and analyzed by Stata 14.0 software. Result: Nine studies with an overall sample size of 215 met our eligibility criteria and were included in the meta-analysis. All studies were retrospective studies, and the methodological quality was moderate. The pooled morbidity and mortality rates were 51% (95% CI: 41–61%; I ²= 0.0%) and 2% (95% CI: 0–0.08; I ²=33.3%), respectively. Meta-analysis showed that the overall R0 resection rate was 79% (CI: 70–86%, I ²=15.5%). Comparative data on R0 rates of patients who underwent pancreatectomy with and without NAT showed a significant difference in favor of the former group with moderate statistical heterogeneity (Relative risk=1.21; 95% CI: 0.776–1.915; I ²=48.0%). The median 1-, 2-, 3-, and 5-year survival rates of patients who had AR were 92.3% (range: 72.7–100%), 64.8% (range: 25–78.8%), 51.6% (range: 16.7–63.6%), and 14% (range: 0–41.1%), respectively. Data on median progression-free survival ranged from 5.25 to 36.3 months, and the median overall survival ranged from 17 to 44.9 months. Conclusions: Pancreatectomy with major AR following NAT has the potential to enhance the survival rate of patients with unresectable pancreatic cancer involving the arteries by achieving R0 resection, despite a significant risk of postoperative complications. However, to validate the feasibility and effectiveness of this procedure, prospective controlled studies are necessary to address limitations arising from small sample sizes and potential biases inherent in retrospective studies.
Minimal Residual Disease Status Predicts Outcome in Patients With Previously Untreated Follicular Lymphoma: A Prospective Analysis of the Phase III GALLIUM Study
Authors: Christiane Pott, Vindi Jurinovic, Judith Trotman, Britta Kehden, Michael Unterhalt, Michael Herold, Richard van der Jagt, Ann Janssens, Michael Kneba, Jiri Mayer, Moya Young, Christian Schmidt, Andrea Knapp, Tina Nielsen, Helen Brown, Nathalie Spielewoy, Chris Harbron, Alessia Bottos, Kirsten Mundt, Robert Marcus, Wolfgang Hiddemann, Eva Hoster
Journal: Journal of Clinical Oncology (2023)

We report an analysis of minimal residual/detectable disease (MRD) as a predictor of outcome in previously untreated patients with follicular lymphoma (FL) from the randomized, multicenter GALLIUM (ClinicalTrials.gov identifier: NCT01332968) trial.
A novel skin grafting modality: prefabricated large sheet of postage-stamp autografts and allografts to repair extensive burn wounds; a prospective matched-control study
Authors: Chuan’an Shen, Bohan Zhang, Xinzhu Liu, Jianhua Cai, Tianjun Sun, Dongjie Li, Huping Deng, Huageng Yuan
Journal: International Journal of Surgery (2023)

Background: The excessively long operative time has been the greatest barrier to the success of transplanting postage-stamp auto- and allografts directly and piece-by-piece onto extensive burn wounds. To solve this challenge, the authors present a novel grafting modality, that is, the prefabricated-large-sheet grafting that moves the labor-intensive and time-consuming process of grafts-positioning before grafting and thereby markedly shortens the operative time. Methods: Twenty-one operations using the novel modality were performed on 11 patients with extensive deep burns. The grafting time using the novel modality was recorded and compared with that of the conventional piece-by-piece grafting. Eventually, the take rates of the two modalities were compared. Results: All patients were healed and discharged. The average grafting time per unit area (100 cm 2 ) of prefabricated-large-sheet grafting and piece-by-piece grafting were (0.41±0.09) min and (7.46±1.07) min, respectively, and the difference is statistically significant( P &lt;0.001). The average take rate of the prefabricated sheets was (85.43±6.14)% and that of the piece-by-piece transplanted grafts was (87.29±5.23)% and there is no significant difference( P &gt;0.05). Conclusions: The prefabricated-large-sheet grafting significantly reduces the intraoperative grafting time while ensures uniformity of the skin grafts and secures good outcomes, thereby making the intermingled transplantation of postage-stamp auto- and allografts, which has been an excellent modality per se but limited to repair small residual wounds, now feasible to repair extensive deep burn wounds. It is worth wider understanding and application in the treatment of extensive deep burns.
ADORA2A-driven proline synthesis triggers epigenetic reprogramming in neuroendocrine prostate and lung cancers
Authors: Na Jing, Kai Zhang, Xinyu Chen, Kaiyuan Liu, Jinming Wang, Lingling Xiao, Wentian Zhang, Pengfei Ma, Penghui Xu, Chaping Cheng, Deng Wang, Huifang Zhao, Yuman He, Zhongzhong Ji, Zhixiang Xin, Yujiao Sun, Yingchao Zhang, Wei Bao, Yiming Gong, Liancheng Fan, Yiyi Ji, Guanglei Zhuang, Qi Wang, Baijun Dong, Pengcheng Zhang, Wei Xue, Wei-Qiang Gao, Helen He Zhu
Journal: Journal of Clinical Investigation (2023)

Cell lineage plasticity is one of the major causes for the failure of targeted therapies in various cancers. However, the driver and actionable drug targets in promoting cancer cell lineage plasticity are scarcely identified. Here, we found that a G protein-coupled receptor, ADORA2A, is specifically upregulated during neuroendocrine differentiation, a common form of lineage plasticity in prostate cancer and lung cancer following targeted therapies. Activation of the ADORA2A signaling rewires the proline metabolism via an ERK/MYC/PYCR cascade. Increased proline synthesis promotes deacetylases SIRT6/7-mediated deacetylation of histone H3 at lysine 27 (H3K27), and thereby biases a global transcriptional output toward a neuroendocrine lineage profile. Ablation of Adora2a in genetically engineered mouse models inhibits the development and progression of neuroendocrine prostate and lung cancers, and, intriguingly, prevents the adenocarcinoma-to-neuroendocrine phenotypic transition. Importantly, pharmacological blockade of ADORA2A profoundly represses neuroendocrine prostate and lung cancer growth in vivo. Therefore, we believe that ADORA2A can be used as a promising therapeutic target to govern the epigenetic reprogramming in neuroendocrine malignancies.
Conformationally regulated “nanozyme-like” cerium oxide with multiple free radical scavenging activities for osteoimmunology modulation and vascularized osseointegration
Authors: Shusen Bao, Dongmei Yu, Zhen Tang, Hao Wu, Hao Zhang, Ning Wang, Yichao Liu, Hai Huang, Chaozong Liu, Xiaokang Li, Zheng Guo
Journal: Bioactive Materials (2023)

Given post-operative aseptic loosening in orthopedic disease treatment, osteointegration occurs at the bone-implant interface as a holistic process, including immunoregulation (e.g., macrophage polarization), angiogenesis and osteogenesis in sequence. In order to achieve early rapid and satisfactory osseointegration, different nano-shaped (nanocone, nanopolyhedron and nanoflower abbr. NC, NP & NF) cerium oxide (CeO2-x) coatings, endowed with "nanozyme-like" activities for multiple free radical elimination and osteoimmunology regulation, were hydrothermally synthesized on titanium alloy (TC4). In vitro cell experiments showed that nano-CeO2-x coated TC4 not only induced polarization of RAW264.7 cells toward M2 phenotype, but also promoted angiogenesis and vascularization of endothelial cells along with differentiation and mineralization of osteogenic precursor cells. Improvements in M2-polarized macrophage, angiogenesis, and bone regeneration were further confirmed in a rat femoral condyle model. Among the above three nano-morphologies, NF exhibited the best osseoinetegration. RNA sequencing and mechanism exploration suggested that the inhibition of PI3K-AKT signaling pathway was essential for immunomodulatory capacity of NF. In conclusion, it provided promising insights into the immunomodulatory exploitation of orthopedic implants.
A p53 score derived from <i>TP53</i> CRISPR/Cas9 HMCLs predicts survival and reveals major role of BAX in BH3 mimetics response
Authors: Romane Durand, Géraldine Descamps, Céline Bellanger, Christelle Dousset, Sophie Maïga, Jean-Baptiste Alberge, Jennifer Derrien, Jonathan Cruard, Stéphane Minvielle, Nicoletta Libera Lilli, Catherine Godon, Yannick Le Bris, Benoit Tessoulin, Martine Amiot, Patricia Gomez-Bougie, Cyrille Touzeau, Philippe Moreau, David Chiron, Agnès Moreau-Aubry, Catherine Pellat-Deceunynck
Journal: Blood (2023)
Adipose-derived mesenchymal stem cells (MSCs) are a superior cell source for bone tissue engineering
Authors: Yannian Gou, Yanran Huang, Wenping Luo, Yanan Li, Piao Zhao, Jiamin Zhong, Xiangyu Dong, Meichun Guo, Aohua Li, Ailing Hao, Guozhi Zhao, Yonghui Wang, Yi Zhu, Hui Zhang, Yunhan Shi, William Wagstaff, Hue H Luu, Lewis L Shi, Russell R Reid, Tong-Chuan He, Jiaming Fan
Journal: Bioactive Materials (2023)

Effective bone regeneration through tissue engineering requires a combination of osteogenic progenitors, osteoinductive biofactors and biocompatible scaffold materials. Mesenchymal stem cells (MSCs) represent the most promising seed cells for bone tissue engineering. As multipotent stem cells that can self-renew and differentiate into multiple lineages including bone and fat, MSCs can be isolated from numerous tissues and exhibit varied differentiation potential. To identify an optimal progenitor cell source for bone tissue engineering, we analyzed the proliferative activity and osteogenic potential of four commonly-used mouse MSC sources, including immortalized mouse embryonic fibroblasts (iMEF), immortalized mouse bone marrow stromal stem cells (imBMSC), immortalized mouse calvarial mesenchymal progenitors (iCAL), and immortalized mouse adipose-derived mesenchymal stem cells (iMAD). We found that iMAD exhibited highest osteogenic and adipogenic capabilities upon BMP9 stimulation
Active DHEA uptake in the prostate gland correlates with aggressive prostate cancer
Authors: Xuebin Zhang, Zengming Wang, Shengsong Huang, Dongyin He, Weiwei Yan, Qian Zhuang, Zixian Wang, Chenyang Wang, Qilong Tan, Ziqun Liu, Tao Yang, Ying Liu, Ruobing Ren, Jing Li, William Butler, Huiru Tang, Gong-Hong Wei, Xin Li, Denglong Wu, Zhenfei Li
Journal: Journal of Clinical Investigation (2023)

Strategies for patient stratification and early intervention are required to improve clinical benefits for patients with prostate cancer. Here, we found that active DHEA utilization in the prostate gland correlated with tumor aggressiveness at early disease stages, and 3βHSD1 inhibitors were promising for early intervention. [3H]-labeled DHEA consumption was traced in fresh prostatic biopsies ex vivo. Active DHEA utilization was more frequently found in patients with metastatic disease or therapy-resistant disease. Genetic and transcriptomic features associated with the potency of prostatic DHEA utilization were analyzed to generate clinically accessible approaches for patient stratification. UBE3D, by regulating 3βHSD1 homeostasis, was discovered to be a regulator of patient metabolic heterogeneity. Equilin suppressed DHEA utilization and inhibited tumor growth as a potent 3βHSD1 antagonist, providing a promising strategy for the early treatment of aggressive prostate cancer. Overall, our findings indicate that patients with active prostatic DHEA utilization might benefit from 3βHSD1 inhibitors as early intervention.
Nucleotide modifications enable rational design of TLR7-selective ligands by blocking RNase cleavage
Authors: Ann-Jay Tong, Rebecca Leylek, Anna-Maria Herzner, Diamanda Rigas, Sara Wichner, Craig Blanchette, Siri Tahtinen, Christopher C. Kemball, Ira Mellman, Benjamin Haley, Emily C. Freund, Lélia Delamarre
Journal: The Journal of Experimental Medicine (2023)

Toll-like receptors 7 (TLR7) and 8 (TLR8) each sense single-stranded RNA (ssRNA), but their activation results in different immune activation profiles. Attempts to selectively target either TLR7 or TLR8 have been hindered by their high degree of homology. However, recent studies revealed that TLR7 and TLR8 bind different ligands resulting from the processing of ssRNA by endolysosomal RNases. We demonstrate that by introducing precise 2′ sugar-modified bases into oligoribonucleotides (ORNs) containing known TLR7 and TLR8 binding motifs, we could prevent RNase-mediated degradation into the monomeric uridine required for TLR8 activation while preserving TLR7 activation. Furthermore, a novel, optimized protocol for CRISPR-Cas9 knockout in primary human plasmacytoid dendritic cells showed that TLR7 activation is dependent on RNase processing of ORNs and revealed a previously undescribed role for RNase 6 in degrading ORNs into TLR ligands. Finally, 2′ sugar-modified ORNs demonstrated robust innate immune activation in mice. Altogether, we identified a strategy for creating tunable TLR7-selective agonists.
Mezigdomide is effective alone and in combination with menin inhibition in preclinical models of <i>KMT2A</i>-r and <i>NPM1c</i> AML
Authors: Wallace Bourgeois, Jevon A. Cutler, Brandon J. Aubrey, Daniela V. Wenge, Florian Perner, Cynthia Martucci, Jill A. Henrich, Kelly Klega, Radosław P. Nowak, Katherine A. Donovan, Meaghan Boileau, Yanhe Wen, Charlie Hatton, Athina A. Apazidis, Sarah Naomi Olsen, Nadia Kirmani, Yana Pikman, Jessica A. Pollard, Jennifer A. Perry, Adam S. Sperling, Benjamin L. Ebert, Gerard M. McGeehan, Brian D. Crompton, Eric S. Fischer, Scott A. Armstrong
Journal: Blood (2023)
HER2 and HLA-A*02 dual CAR-T cells utilize LOH in a NOT logic gate to address on-target off-tumor toxicity
Authors: David Bassan, Leehee Weinberger, Jason Yi, Tanya Kim, Michael R Weist, Gregor B Adams, Orit Foord, Neta Chaim, Sarit Tabak, Nir Bujanover, Yael Lopesco, Kristina Vucci, Caitlin Schnair, Limor Levy-Knafo, Richard L Kendall, Frank J Calzone, Adi Sharbi-Yunger
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background One of the major challenges in chimeric antigen receptor (CAR)-T cell therapy for solid tumors is the potential for on-target off-tumor toxicity due to the expression of CAR tumor antigens in essential tissues and organs. Here, we describe a dual CAR NOT gate incorporating an inhibitory CAR (iCAR) recognizing HLA-A*02 (“A2”) that enables effective treatment with a potent HER2 activating CAR (aCAR) in the context of A2 loss of heterozygosity (LOH). Methods A CAR-T cell screen was conducted to identify inhibitory domains derived from natural immune receptors (iDomains) to be used in a NOT gate, to kill A2 − HER2 + lung cancer cell lines but spare A2 + HER2 + lung cancer cell-lines with high specificity. The extensive analysis of lead candidates included T-cell activation and killing, assays of reversibility and durability in sequential challenges, target cell specificity in mixed 3D spheroids and 2D cultures, and the characterization of CAR expression level and cell-trafficking. Results A leukocyte immunoglobulin-like receptor B1 (LIR1) iDomain iCAR was identified as most effective in regulating the cytotoxicity of a second generation HER2 aCAR. Target transfer experiments demonstrated that the ‘on’ and ‘off’ cell state of the LIR1 NOT gate CAR-T cell is both durable and reversible. Protection required iCAR signaling and was associated with reduced aCAR and iCAR surface expression. iCAR regulation was sufficient to generate high target specificity in a 3D adjacent spheroid assay designed to model the interface between clonal A2 LOH foci and normal tissue. However, we observed significant bystander killing of A2 + cells in admix culture through aCAR dependent and independent mechanisms. LIR1 NOT gate CAR-T cells conferred protection against H1703-A2 + tumors and high efficacy against H1703-A2 − tumors in-vivo. We observed that the iCAR is inactive in A2 + donors due to cis-binding, but Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) knockout of HLA-A fully restored iCAR activity. Conclusions We have preclinically validated an iCAR NOT gate technology broadly applicable for targeting HER2 expression in the context of A2 LOH. This approach is designed to prevent off tumor toxicity while allowing highly potent antitumor activity.
Identification and surveillance of rare relapse-initiating stem cells during complete remission after transplantation
Authors: Marios Dimitriou, Teresa Mortera-Blanco, Magnus Tobiasson, Stefania Mazzi, Madeleine Lehander, Kari Högstrand, Mohsen Karimi, Gunilla Walldin, Monika Jansson, Sofie Vonlanthen, Per Ljungman, Saskia Langemeijer, Tetsuichi Yoshizato, Eva Hellström-Lindberg, Petter S. Woll, Sten Eirik W. Jacobsen
Journal: Blood (2023)

Abstract Relapse after complete remission (CR) remains the main cause of mortality after allogeneic stem cell transplantation for hematological malignancies and, therefore, improved biomarkers for early prediction of relapse remains a critical goal toward development and assessment of preemptive relapse treatment. Because the significance of cancer stem cells as a source of relapses remains unclear, we investigated whether mutational screening for persistence of rare cancer stem cells would enhance measurable residual disease (MRD) and early relapse prediction after transplantation. In a retrospective study of patients who relapsed and patients who achieved continuous-CR with myelodysplastic syndromes and related myeloid malignancies, combined flow cytometric cell sorting and mutational screening for persistence of rare relapse-initiating stem cells was performed in the bone marrow at multiple CR time points after transplantation. In 25 CR samples from 15 patients that later relapsed, only 9 samples were MRD-positive in mononuclear cells (MNCs) whereas flowcytometric-sorted hematopoietic stem and progenitor cells (HSPCs) were MRD-positive in all samples, and always with a higher variant allele frequency than in MNCs (mean, 97-fold). MRD-positivity in HSPCs preceded MNCs in multiple sequential samples, in some cases preceding relapse by &amp;gt;2 years. In contrast, in 13 patients in long-term continuous-CR, HSPCs remained MRD-negative. Enhanced MRD sensitivity was also observed in total CD34+ cells, but HSPCs were always more clonally involved (mean, 8-fold). In conclusion, identification of relapse-initiating cancer stem cells and mutational MRD screening for their persistence consistently enhances MRD sensitivity and earlier prediction of relapse after allogeneic stem cell transplantation.
Hematopoietic and eosinophil-specific LNK(SH2B3) deficiency promotes eosinophilia and arterial thrombosis
Authors: Huijuan Dou, Ranran Wang, Mojdeh Tavallaie, Tong Xiao, Malgorzata Olszewska, Eirini P. Papapetrou, Alan R. Tall, Nan Wang
Journal: Blood (2023)