tbuckley/cabot-search huggingface dataset:
Postmarketing Vaccine Safety Assessments
Authors: Kathryn M. Edwards, Marie R. Griffin
Journal: JAMA (2024)

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Struggling to Stem the Tide of Child Maltreatment
Authors: Samantha Schilling, Joanne N. Wood, Cindy W. Christian
Journal: JAMA (2024)

US Preventive Services Task Force; Michael J. Barry, MD; Wanda K. Nicholson, MD, MPH, MBA; Michael Silverstein, MD, MPH; David Chelmow, MD; Tumaini Rucker Coker, MD, MBA; Esa M. Davis, MD, MPH; Carlos Roberto Jaén, MD, PhD, MS; M. (Tonette) Krousel-Wood, MD, MSPH; Sei Lee, MD, MAS; Li Li, MD, PhD, MPH; Goutham Rao, MD; John M. Ruiz, PhD; James J. Stevermer, MD, MSPH; Joel Tsevat, MD, MPH; Sandra Millon Underwood, PhD, RN; Sarah Wiehe, MD, MPH
EHR Data and Inclusion of Multiracial Asian American, Native Hawaiian, and Pacific Islander People—Opportunities for Advancing Data-Centered Equity in Health Research
Authors: Alexander C. Adia, Kevin H. Nguyen, Ninez A. Ponce
Journal: JAMA Network Open (2024)

Adrian M. Bacong, PhD, MPH; Sophia L. Gibbs, MS; A. Gabriela Rosales, MS; Timothy B. Frankland, MA; Jiang Li, PhD; Yihe G. Daida, PhD; Stephen P. Fortmann, MD; Latha Palaniappan, MD, MS
Mary Ann Matthews
Authors: Nicola Payne
Journal: BMJ (2024)

into a family who lived by their Christian beliefs, so it was no surprise she chose a career in medicine.She became a young GP partner at South View Lodge, Bromley, in 1980, serving that community for 34 years.Mary lived her faith, and her patients knew that after work every Friday night, she helped run a youth club for young people living in the borough.She also taught in Sunday school.With her husband, Martin, Mary used family holidays from 1997 onwards to visit Kenya, founding a charity-Footsteps International-to care for orphans and street boys she met.At the time of her death, the Sunshine Centre in Naivasha cared for 144 street boys, providing them with security, food, and education and the opportunity to earn a living and care for families of their own.
Priority effects transcend scales and disciplines in biology
Authors: J.T. Stroud, B.M. Delory, E.M. Barnes, J.M. Chase, L. De Meester, J. Dieskau, T.N. Grainger, F.W. Halliday, P. Kardol, T.M. Knight, E. Ladouceur, C.J. Little, C. Roscher, J.M. Sarneel, V.M. Temperton, T.L.H. van Steijn, C.M. Werner, C.W. Wood, T. Fukami
Journal: Trends in Ecology & Evolution (2024)
Integrative polygenic risk score improves the prediction accuracy of complex traits and diseases
Authors: Buu Truong, Leland E. Hull, Yunfeng Ruan, Qin Qin Huang, Whitney Hornsby, Hilary Martin, David A. van Heel, Ying Wang, Alicia R. Martin, S. Hong Lee, Pradeep Natarajan
Journal: Cell Genomics (2024)

Polygenic risk scores (PRSs) are an emerging tool to predict the clinical phenotypes and outcomes of individuals. We propose PRSmix, a framework that leverages the PRS corpus of a target trait to improve prediction accuracy, and PRSmix+, which incorporates genetically correlated traits to better capture the human genetic architecture for 47 and 32 diseases/traits in European and South Asian ancestries, respectively. PRSmix demonstrated a mean prediction accuracy improvement of 1.20-fold (95% confidence interval [CI], [1.10; 1.3]; p = 9.17 × 10
Marizomib for patients with newly diagnosed glioblastoma: A randomized phase 3 trial
Authors: Patrick Roth, Thierry Gorlia, Jaap C Reijneveld, Filip de Vos, Ahmed Idbaih, Jean-Sébastien Frenel, Emilie Le Rhun, Juan Manuel Sepulveda, James Perry, G Laura Masucci, Pierre Freres, Hal Hirte, Clemens Seidel, Annemiek Walenkamp, Slavka Lukacova, Paul Meijnders, Andre Blais, Francois Ducray, Vincent Verschaeve, Garth Nicholas, Carmen Balana, Daniela A Bota, Matthias Preusser, Sarah Nuyens, Fréderic Dhermain, Martin van den Bent, Chris J O’Callaghan, Maureen Vanlancker, Warren Mason, Michael Weller
Journal: Neuro-Oncology (2024)

Abstract Background Standard treatment for patients with newly diagnosed glioblastoma includes surgery, radiotherapy (RT), and temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). The proteasome has long been considered a promising therapeutic target because of its role as a central biological hub in tumor cells. Marizomib is a novel pan-proteasome inhibitor that crosses the blood–brain barrier. Methods European Organisation for Research and Treatment of Cancer 1709/Canadian Cancer Trials Group CE.8 was a multicenter, randomized, controlled, open-label phase 3 superiority trial. Key eligibility criteria included newly diagnosed glioblastoma, age &amp;gt; 18 years and Karnofsky performance status &amp;gt; 70. Patients were randomized in a 1:1 ratio. The primary objective was to compare overall survival (OS) in patients receiving marizomib in addition to TMZ/RT→TMZ with patients receiving the only standard treatment in the whole population and in the subgroup of patients with MGMT promoter-unmethylated tumors. Results The trial was opened at 82 institutions in Europe, Canada, and the U.S. A total of 749 patients (99.9% of the planned 750) were randomized. OS was not different between the standard and the marizomib arm (median 17 vs. 16.5 months; HR = 1.04; P = .64). PFS was not statistically different either (median 6.0 vs. 6.3 months; HR = 0.97; P = .67). In patients with MGMT promoter-unmethylated tumors, OS was also not different between standard therapy and marizomib (median 14.5 vs. 15.1 months, HR = 1.13; P = .27). More CTCAE grade 3/4 treatment-emergent adverse events were observed in the marizomib arm than in the standard arm. Conclusions Adding marizomib to standard temozolomide-based radiochemotherapy resulted in more toxicity, but did not improve OS or PFS in patients with newly diagnosed glioblastoma.
A Novel CaCu‐Metal–Organic‐Framework Based Multimodal Treatment Platform for Enhanced Synergistic Therapy of Hepatocellular Carcinoma
Authors: Weijun Chen, Meiyang Yang, Huili Wang, Junling Song, Congjin Mei, Lipeng Qiu, Jinghua Chen
Journal: Advanced Healthcare Materials (2024)

Abstract Metal ions have attracted a lot of interest in antitumor therapy due to their unique mechanism of action. However, multiple death mechanisms associate with metal ions to synergistic antitumors have few studies mainly due to the serious challenges in designing and building metal‐associated multimodal treatment platforms. Hence, a series of glutathione‐activatable CaCu‐based metal–organic‐frameworks loaded with doxorubicin and ovalbumin are successfully designed and synthesized with an “all in one” strategy, which is modified by galactosamine‐linked hyaluronic acid to prepare multimodal treatment platform (SCC/DOX@OVA‐HG) for targeted delivery and synergistic antitumor therapy. SCC/DOX@OVA‐HG can be rapidly degraded by the overexpressed glutathione and then releases the “cargoes” in the tumor microenvironment. The released Cu + efficiently catalyzes H 2 O 2 to produce highly toxic ROS for CDT, and the up‐regulation of calcium ion concentration in tumor cells induced by the released Ca 2+ enables calcium overload therapy, which synergically enhances the metal‐related death pattern. Meanwhile, OVA combined with Ca 2+ /Cu 2+ further activates macrophages into an M1‐like phenotype to accelerate tumor cell death through immunotherapy. Besides, the released DOX can also insert into the DNA double helix for chemotherapy. Consequently, the developed SCC/DOX@OVA‐HG reveals significantly improved antitumor efficacy through a multimodal synergistic therapy of chemotherapy, chemodynamic therapy, calcium overload, and immunotherapy.
ATG-101 Is a Tetravalent PD-L1×4-1BB Bispecific Antibody That Stimulates Antitumor Immunity through PD-L1 Blockade and PD-L1–Directed 4-1BB Activation
Authors: Hui Yuwen, Huajing Wang, Tengteng Li, Yijing Ren, Yun-kai Zhang, Peng Chen, Ao Sun, Gang Bian, Bohua Li, David Flowers, Marc Presler, Kalyanasundaram Subramanian, Jia Xue, Jingjing Wang, Kevin Lynch, Jay Mei, Xiaowen He, Bo Shan, Bing Hou
Journal: Cancer Research (2024)

Immune checkpoint inhibitors (ICI) have transformed cancer treatment. However, only a minority of patients achieve a profound response. Many patients are innately resistant while others acquire resistance to ICIs. Furthermore, hepatotoxicity and suboptimal efficacy have hampered the clinical development of agonists of 4-1BB, a promising immune-stimulating target. To effectively target 4-1BB and treat diseases resistant to ICIs, we engineered ATG-101, a tetravalent "2+2″ PD-L1×4-1BB bispecific antibody. ATG-101 bound PD-L1 and 4-1BB concurrently, with a greater affinity for PD-L1, and potently activated 4-1BB+ T cells when cross-linked with PD-L1-positive cells. ATG-101 activated exhausted T cells upon PD-L1 binding, indicating a possible role in reversing T-cell dysfunction. ATG-101 displayed potent antitumor activity in numerous in vivo tumor models, including those resistant or refractory to ICIs. ATG-101 greatly increased the proliferation of CD8+ T cells, the infiltration of effector memory T cells, and the ratio of CD8+ T/regulatory T cells in the tumor microenvironment (TME), rendering an immunologically "cold" tumor "hot." Comprehensive characterization of the TME after ATG-101 treatment using single-cell RNA sequencing further revealed an altered immune landscape that reflected increased antitumor immunity. ATG-101 was well tolerated and did not induce hepatotoxicity in non-human primates. According to computational semimechanistic pharmacology modeling, 4-1BB/ATG-101/PD-L1 trimer formation and PD-L1 receptor occupancy were both maximized at around 2 mg/kg of ATG-101, providing guidance regarding the optimal biological dose for clinical trials. In summary, by localizing to PD-L1-rich microenvironments and activating 4-1BB+ immune cells in a PD-L1 cross-linking-dependent manner, ATG-101 safely inhibits growth of ICI resistant and refractory tumors.
A partial Drp1 knockout improves autophagy flux independent of mitochondrial function
Authors: Rebecca Z. Fan, Carolina Sportelli, Yanhao Lai, Said S. Salehe, Jennifer R. Pinnell, Harry J. Brown, Jason R. Richardson, Shouqing Luo, Kim Tieu
Journal: Molecular Neurodegeneration (2024)

Abstract Background Dynamin-related protein 1 (Drp1) plays a critical role in mitochondrial dynamics. Partial inhibition of this protein is protective in experimental models of neurological disorders such as Parkinson’s disease and Alzheimer’s disease. The protective mechanism has been attributed primarily to improved mitochondrial function. However, the observations that Drp1 inhibition reduces protein aggregation in such neurological disorders suggest the involvement of autophagy. To investigate this potential novel protective mechanism of Drp1 inhibition, a model with impaired autophagy without mitochondrial involvement is needed. Methods We characterized the effects of manganese (Mn), which causes parkinsonian-like symptoms in humans, on autophagy and mitochondria by performing dose-response studies in two cell culture models (stable autophagy HeLa reporter cells and N27 rat immortalized dopamine neuronal cells). Mitochondrial function was assessed using the Seahorse Flux Analyzer. Autophagy flux was monitored by quantifying the number of autophagosomes and autolysosomes, as well as the levels of other autophagy proteins. To strengthen the in vitro data, multiple mouse models (autophagy reporter mice and mutant Drp1 +/− mice and their wild-type littermates) were orally treated with a low chronic Mn regimen that was previously reported to increase α-synuclein aggregation and transmission via exosomes. RNAseq, laser captured microdissection, immunofluorescence, immunoblotting, stereological cell counting, and behavioural studies were used. Results in vitro data demonstrate that at low non-toxic concentrations, Mn impaired autophagy flux but not mitochondrial function and morphology. In the mouse midbrain, RNAseq data further confirmed autophagy pathways were dysregulated but not mitochondrial related genes. Additionally, Mn selectively impaired autophagy in the nigral dopamine neurons but not the nearby nigral GABA neurons. In cells with a partial Drp1-knockdown and Drp1 +/− mice, Mn induced autophagic impairment was significantly prevented. Consistent with these observations, Mn increased the levels of proteinase-K resistant α-synuclein and Drp1-knockdown protected against this pathology. Conclusions This study demonstrates that improved autophagy flux is a separate mechanism conferred by Drp1 inhibition independent of its role in mitochondrial fission. Given that impaired autophagy and mitochondrial dysfunction are two prominent features of neurodegenerative diseases, the combined protective mechanisms targeting these two pathways conferred by Drp1 inhibition make this protein an attractive therapeutic target. Graphical Abstract
The 'middle-aging' brain
Authors: Sebastian Dohm-Hansen, Jane A. English, Aonghus Lavelle, Carlos P. Fitzsimons, Paul J. Lucassen, Yvonne M. Nolan
Journal: Trends in Neurosciences (2024)

Middle age has historically been an understudied period of life compared to older age, when cognitive and brain health decline are most pronounced, but the scope for intervention may be limited. However, recent research suggests that middle age could mark a shift in brain aging. We review emerging evidence on multiple levels of analysis indicating that midlife is a period defined by unique central and peripheral processes that shape future cognitive trajectories and brain health. Informed by recent developments in aging research and lifespan studies in humans and animal models, we highlight the utility of modeling non-linear changes in study samples with wide subject age ranges to distinguish life stage-specific processes from those acting linearly throughout the lifespan.
Distinct molecular profiles drive multifaceted characteristics of colorectal cancer metastatic seeds
Authors: Yuanyuan Zhao, Bing Zhang, Yiming Ma, Mengmeng Guo, Fuqiang Zhao, Jianan Chen, Bingzhi Wang, Hua Jin, Fulai Zhou, Jiawei Guan, Qian Zhao, Qian Liu, Hongying Wang, Fangqing Zhao, Xia Wang
Journal: The Journal of Experimental Medicine (2024)

Metastasis of primary tumors remains a challenge for early diagnosis and prevention. The cellular properties and molecular drivers of metastatically competent clones within primary tumors remain unclear. Here, we generated 10–16 single cell–derived lines from each of three colorectal cancer (CRC) tumors to identify and characterize metastatic seeds. We found that intrinsic factors conferred clones with distinct metastatic potential and cellular communication capabilities, determining organ-specific metastasis. Poorly differentiated or highly metastatic clones, rather than drug-resistant clones, exhibited poor clinical prognostic impact. Personalized genetic alterations, instead of mutation burden, determined the occurrence of metastatic potential during clonal evolution. Additionally, we developed a gene signature for capturing metastatic potential of primary CRC tumors and demonstrated a strategy for identifying metastatic drivers using isogenic clones with distinct metastatic potential in primary tumors. This study provides insight into the origin and mechanisms of metastasis and will help develop potential anti-metastatic therapeutic targets for CRC patients.
Origins of Second Malignancies in Children and Mutational Footprint of Chemotherapy in Normal Tissues
Authors: Mònica Sánchez-Guixé, Ferran Muiños, Morena Pinheiro-Santin, Víctor González-Huici, Carlos J. Rodriguez-Hernandez, Alexandra Avgustinova, Cinzia Lavarino, Abel González-Pérez, Jaume Mora, Núria López-Bigas
Journal: Cancer Discovery (2024)

Pediatric cancers are rare diseases, and children without known germline predisposing conditions who develop a second malignancy during developmental ages are extremely rare. We present four such clinical cases and, through whole-genome and error-correcting ultra-deep duplex sequencing of tumor and normal samples, we explored the origin of the second malignancy in four children, uncovering different routes of development. The exposure to cytotoxic therapies was linked to the emergence of a secondary acute myeloid leukemia. A common somatic mutation acquired early during embryonic development was the driver of two solid malignancies in another child. In two cases, the two tumors developed from completely independent clones diverging during embryogenesis. Importantly, we demonstrate that platinum-based therapies contributed at least one order of magnitude more mutations per day of exposure than aging to normal tissues in these children. Using whole-genome and error-correcting ultra-deep duplex sequencing, we uncover different origins for second neoplasms in four children. We also uncover the presence of platinum-related mutations across 10 normal tissues of exposed individuals, highlighting the impact that the use of cytotoxic therapies may have on cancer survivors. See related commentary by Pacyna and Nangalia, p. 900. This article is featured in Selected Articles from This Issue, p. 897.
Including a diverse set of voices to address biological invasions
Authors: Martin A. Nuñez, Tom August, Sven Bacher, Bella S. Galil, Philip E. Hulme, Tohru Ikeda, Melodie A. McGeoch, Alejandro Ordonez, Sebataolo Rahlao, Tanara Renard Truong, Aníbal Pauchard, Helen E. Roy, K.V. Sankaran, Evangelina Schwindt, Hanno Seebens, Andy W. Sheppard, Peter Stoett, Vigdis Vandvik, Laura A. Meyerson
Journal: Trends in Ecology & Evolution (2024)
Systemic racism and racial inequities in periodontal health: The long journey from upstream determinants to downstream treatment
Authors: Eleanor Fleming, George W. Taylor, Harold Woody Neighbors
Journal: Periodontology 2000 (2024)

Abstract Racial disparities in the prevalence of periodontal disease are consistent and persistent. The epidemiology of periodontal disease demonstrates racial inequities: non‐Hispanic Black (14.7%), Mexican American (13.4%), and other Hispanic adults (7.8%) experience a higher prevalence of severe periodontal disease than non‐Hispanic White adults (5.9%). Epidemiologic and clinical research on periodontal health suffers from the same problem that has plagued the health equity movement, an over emphasis on describing racial inequities coupled with few interventions that reduce racial health inequity. Over the decades that racial inequities in periodontal disease have been observed, many have argued that systemic racism is the fundamental driver of racial health inequity. This paper interrogates the roles of systemic racism, dental education, clinical treatment, and patient behavior in periodontal disease. We describe how, together, these mechanisms contribute to racial disparities in periodontal outcomes. However, it is insufficient for oral health equity scientists to only describe and discuss the negative effects of systemic racism. The imperative is to create antiracist strategies designed to eliminate systemic racism. Health equity scientists must also specify how dental systems operate in a racist manner and create effective clinical strategies designed to reduce racial disparities in periodontal disease.
Insulin signalling regulates Pink1 mRNA localization via modulation of AMPK activity to support PINK1 function in neurons
Authors: J. Tabitha Hees, Simone Wanderoy, Jana Lindner, Marlena Helms, Hariharan Murali Mahadevan, Angelika B. Harbauer
Journal: Nature Metabolism (2024)

Abstract Mitochondrial quality control failure is frequently observed in neurodegenerative diseases. The detection of damaged mitochondria by stabilization of PTEN-induced kinase 1 (PINK1) requires transport of Pink1 messenger RNA (mRNA) by tethering it to the mitochondrial surface. Here, we report that inhibition of AMP-activated protein kinase (AMPK) by activation of the insulin signalling cascade prevents Pink1 mRNA binding to mitochondria. Mechanistically, AMPK phosphorylates the RNA anchor complex subunit SYNJ2BP within its PDZ domain, a phosphorylation site that is necessary for its interaction with the RNA-binding protein SYNJ2. Notably, loss of mitochondrial Pink1 mRNA association upon insulin addition is required for PINK1 protein activation and its function as a ubiquitin kinase in the mitophagy pathway, thus placing PINK1 function under metabolic control. Induction of insulin resistance in vitro by the key genetic Alzheimer risk factor apolipoprotein E4 retains Pink1 mRNA at the mitochondria and prevents proper PINK1 activity, especially in neurites. Our results thus identify a metabolic switch controlling Pink1 mRNA localization and PINK1 activity via insulin and AMPK signalling in neurons and propose a mechanistic connection between insulin resistance and mitochondrial dysfunction.
Synthetic dual co-stimulation increases the potency of HIT and TCR-targeted cell therapies
Authors: Anton Dobrin, Pieter L. Lindenbergh, Yuzhe Shi, Karlo Perica, Hongyao Xie, Nayan Jain, Andrew Chow, Jedd D. Wolchok, Taha Merghoub, Michel Sadelain, Mohamad Hamieh
Journal: Nature Cancer (2024)

Chimeric antigen receptor T cells have dramatically improved the treatment of hematologic malignancies. T cell antigen receptor (TCR)-based cell therapies are yet to achieve comparable outcomes. Importantly, chimeric antigen receptors not only target selected antigens but also reprogram T cell functions through the co-stimulatory pathways that they engage upon antigen recognition. We show here that a fusion receptor comprising the CD80 ectodomain and the 4-1BB cytoplasmic domain, termed 80BB, acts as both a ligand and a receptor to engage the CD28 and 4-1BB pathways, thereby increasing the antitumor potency of human leukocyte antigen-independent TCR (HIT) receptor- or TCR-engineered T cells and tumor-infiltrating lymphocytes. Furthermore, 80BB serves as a switch receptor that provides agonistic 4-1BB co-stimulation upon its ligation by the inhibitory CTLA4 molecule. By combining multiple co-stimulatory features in a single antigen-agnostic synthetic receptor, 80BB is a promising tool to sustain CD3-dependent T cell responses in a wide range of targeted immunotherapies.