tbuckley/cabot-search huggingface dataset:
Medulloblastoma in children with Fanconi anemia: Association with FA-D1/FA-N, SHH type and poor survival independent of treatment strategies
Authors: Marthe Sönksen, Denise Obrecht-Sturm, Pablo Hernáiz Driever, Axel Sauerbrey, Norbert Graf, Udo Kontny, Christian Reimann, Mina Langhein, Uwe R Kordes, Rudolf Schwarz, Tobias Obser, Felix Boschann, Ulrich Schüller, Lea Altendorf, Tobias Goschzik, Torsten Pietsch, Martin Mynarek, Stefan Rutkowski
Journal: Neuro-Oncology (2024)

The outcome of children with medulloblastoma (MB) and Fanconi Anemia (FA), an inherited DNA repair deficiency, has not been described systematically. Treatment is complicated by high vulnerability to treatment-associated side effects, yet structured data are lacking. This study aims to give a comprehensive overview of clinical and molecular characteristics of pediatric FA MB patients. Clinical data including detailed information on the treatment and toxicities of 6 previously unreported FA MB patients were supplemented with data of 16 published cases. We identified 22 cases of children with FA and MB with clinical data available. All MBs with subgroup reporting were SHH-activated (n = 9), confirmed by methylation profiling in 5 patients. FA MB patients exclusively belonged to complementation groups FA-D1 (n = 16) or FA-N (n = 3). Patients were treated with postoperative chemotherapy only (50%) or radiotherapy (RT) ± chemotherapy (27%). Of 23% did not receive adjuvant therapy. Excessive treatment-related toxicities were frequent. Severe hematological toxicity occurred in 91% of patients treated with alkylating chemotherapy, while non-alkylating agents and RT were less toxic. Median overall survival (OS) was 1 year (95%CI: 0.3-1.8). 1-year-progression-free-survival (PFS) was 26.3% ± 10.1% and 1-year-OS was 42.1% ± 11.3%. Adjuvant therapy prolonged survival (1y-OS/1y-PFS 0%/0% without adjuvant therapy vs. 53.3% ± 12.9%/33.3 ± 12.2% with adjuvant therapy, P = .006/P = .086). MB in FA patients is strongly associated with SHH activation and FA-D1/FA-N. Despite the dismal prognosis, adjuvant therapy may prolong survival. Non-alkylating chemotherapy and RT are feasible in selected patients with careful monitoring of toxicities and dose adjustments. Curative therapy for FA MB-SHH remains an unmet medical need.
Polyvinylpyrrolidone-curcumin nanoparticles with immune regulatory and metabolism regulatory effects for the treatment of experimental autoimmune uveitis
Authors: Fan Cao, Kun Liang, Wei-Wei Tang, Qin-Yu Ni, Zhi-Yu Ji, Chen-Kai Zha, Ya-Kun Wang, Zheng-Xuan Jiang, Shengping Hou, Li-Ming Tao, Xianwen Wang
Journal: Journal of Controlled Release (2024)
Genome-wide polygenic risk scores predict risk of glioma and molecular subtypes
Authors: Taishi Nakase, Geno A Guerra, Quinn T Ostrom, Tian Ge, Beatrice S Melin, Margaret Wrensch, John K Wiencke, Robert B Jenkins, Jeanette E Eckel-Passow, Melissa L Bondy, Stephen S Francis, Linda Kachuri
Journal: Neuro-Oncology (2024)

Abstract Background Polygenic risk scores (PRS) aggregate the contribution of many risk variants to provide a personalized genetic susceptibility profile. Since sample sizes of glioma genome-wide association studies (GWAS) remain modest, there is a need to efficiently capture genetic risk using available data. Methods We applied a method based on continuous shrinkage priors (PRS-CS) to model the joint effects of over 1 million common variants on disease risk and compared this to an approach (PRS-CT) that only selects a limited set of independent variants that reach genome-wide significance (P &amp;lt; 5 × 10–8). PRS models were trained using GWAS stratified by histological (10 346 cases and 14 687 controls) and molecular subtype (2632 cases and 2445 controls), and validated in 2 independent cohorts. Results PRS-CS was generally more predictive than PRS-CT with a median increase in explained variance (R2) of 24% (interquartile range = 11–30%) across glioma subtypes. Improvements were pronounced for glioblastoma (GBM), with PRS-CS yielding larger odds ratios (OR) per standard deviation (SD) (OR = 1.93, P = 2.0 × 10–54 vs. OR = 1.83, P = 9.4 × 10–50) and higher explained variance (R2 = 2.82% vs. R2 = 2.56%). Individuals in the 80th percentile of the PRS-CS distribution had a significantly higher risk of GBM (0.107%) at age 60 compared to those with average PRS (0.046%, P = 2.4 × 10–12). Lifetime absolute risk reached 1.18% for glioma and 0.76% for IDH wildtype tumors for individuals in the 95th PRS percentile. PRS-CS augmented the classification of IDH mutation status in cases when added to demographic factors (AUC = 0.839 vs. AUC = 0.895, PΔAUC = 6.8 × 10–9). Conclusions Genome-wide PRS has the potential to enhance the detection of high-risk individuals and help distinguish between prognostic glioma subtypes.
Aluminum oxyhydroxide-Poly(I:C) combination adjuvant with balanced immunostimulatory potentials for prophylactic vaccines
Authors: Zhiying Yao, Zhihui Liang, Min Li, Huiyang Wang, Yubin Ma, Yiyang Guo, Chen Chen, Changying Xue, Bingbing Sun
Journal: Journal of Controlled Release (2024)
Scarlett McNally: Alternative manifestos can help us plan our future
Authors: Scarlett McNally
Journal: BMJ (2024)

Life comes in waves.We remember the exciting events, but most of our life is routine.It's similar with health.As a surgeon, I realise that people think of health as operations, scans, decisions, and lifesaving interventions.As a patient, I'm grateful that these amazing treatments exist.But we must think of prevention as an important part of health, since 40% of ill health is preventable and most of it relates to our environments and how we live.
Gene-environment interactions within a precision environmental health framework
Authors: Alison A. Motsinger-Reif, David M. Reif, Farida S. Akhtari, John S. House, C. Ryan Campbell, Kyle P. Messier, David C. Fargo, Tiffany A. Bowen, Srikanth S. Nadadur, Charles P. Schmitt, Kristianna G. Pettibone, David M. Balshaw, Cindy P. Lawler, Shelia A. Newton, Gwen W. Collman, Aubrey K. Miller, B. Alex Merrick, Yuxia Cui, Benedict Anchang, Quaker E. Harmon, Kimberly A. McAllister, Rick Woychik
Journal: Cell Genomics (2024)

Understanding the complex interplay of genetic and environmental factors in disease etiology and the role of gene-environment interactions (GEIs) across human development stages is important. We review the state of GEI research, including challenges in measuring environmental factors and advantages of GEI analysis in understanding disease mechanisms. We discuss the evolution of GEI studies from candidate gene-environment studies to genome-wide interaction studies (GWISs) and the role of multi-omics in mediating GEI effects. We review advancements in GEI analysis methods and the importance of large-scale datasets. We also address the translation of GEI findings into precision environmental health (PEH), showcasing real-world applications in healthcare and disease prevention. Additionally, we highlight societal considerations in GEI research, including environmental justice, the return of results to participants, and data privacy. Overall, we underscore the significance of GEI for disease prediction and prevention and advocate for integrating the exposome into PEH omics studies.
Engineering a targeted and safe bone anabolic gene therapy to treat osteoporosis in alveolar bone loss
Authors: Chujiao Lin, Yeon-Suk Yang, Hong Ma, Zhihao Chen, Dong Chen, Aijaz Ahmad John, Jun Xie, Guangping Gao, Jae-Hyuck Shim
Journal: Molecular Therapy (2024)

Alveolar bone loss in elderly populations is highly prevalent and increases the risk of tooth loss, gum disease susceptibility, and facial deformity. Unfortunately, there are very limited treatment options available. Here, we developed a bone-targeted gene therapy that reverses alveolar bone loss in patients with osteoporosis by targeting the adaptor protein Schnurri-3 (SHN3). SHN3 is a promising therapeutic target for alveolar bone regeneration, because SHN3 expression is elevated in the mandible tissues of humans and mice with osteoporosis while deletion of SHN3 in mice greatly increases alveolar bone and tooth dentin mass. We used a bone-targeted recombinant adeno-associated virus (rAAV) carrying an artificial microRNA (miRNA) that silences SHN3 expression to restore alveolar bone loss in mouse models of both postmenopausal and senile osteoporosis by enhancing WNT signaling and osteoblast function. In addition, rAAV-mediated silencing of SHN3 enhanced bone formation and collagen production of human skeletal organoids in xenograft mice. Finally, rAAV expression in the mandible was tightly controlled via liver- and heart-specific miRNA-mediated repression or via a vibration-inducible mechanism. Collectively, our results demonstrate that AAV-based bone anabolic gene therapy is a promising strategy to treat alveolar bone loss in osteoporosis. Alveolar bone loss in elderly populations is highly prevalent and increases the risk of tooth loss, gum disease susceptibility, and facial deformity. Unfortunately, there are very limited treatment options available. Here, we developed a bone-targeted gene therapy that reverses alveolar bone loss in patients with osteoporosis by targeting the adaptor protein Schnurri-3 (SHN3). SHN3 is a promising therapeutic target for alveolar bone regeneration, because SHN3 expression is elevated in the mandible tissues of humans and mice with osteoporosis while deletion of SHN3 in mice greatly increases alveolar bone and tooth dentin mass. We used a bone-targeted recombinant adeno-associated virus (rAAV) carrying an artificial microRNA (miRNA) that silences SHN3 expression to restore alveolar bone loss in mouse models of both postmenopausal and senile osteoporosis by enhancing WNT signaling and osteoblast function. In addition, rAAV-mediated silencing of SHN3 enhanced bone formation and collagen production of human skeletal organoids in xenograft mice. Finally, rAAV expression in the mandible was tightly controlled via liver- and heart-specific miRNA-mediated repression or via a vibration-inducible mechanism. Collectively, our results demonstrate that AAV-based bone anabolic gene therapy is a promising strategy to treat alveolar bone loss in osteoporosis.
An aptamer-mediated base editing platform for simultaneous knockin and multiple gene knockout for allogeneic CAR-T cells generation
Authors: Immacolata Porreca, Robert Blassberg, Jennifer Harbottle, Bronwyn Joubert, Olga Mielczarek, Jesse Stombaugh, Kevin Hemphill, Jonathan Sumner, Deividas Pazeraitis, Julia Liz Touza, Margherita Francescatto, Mike Firth, Tommaso Selmi, Juan Carlos Collantes, Zaklina Strezoska, Benjamin Taylor, Shengkan Jin, Ceri M. Wiggins, Anja van Brabant Smith, John J. Lambourne
Journal: Molecular Therapy (2024)

Gene editing technologies hold promise for enabling the next generation of adoptive cellular therapies. In conventional gene editing platforms that rely on nuclease activity, such as clustered regularly interspaced short palindromic repeats CRISPR-associated protein 9 (CRISPR-Cas9), allow efficient introduction of genetic modifications; however, these modifications occur via the generation of DNA double-strand breaks (DSBs) and can lead to unwanted genomic alterations and genotoxicity. Here, we apply a novel modular RNA aptamer-mediated Pin-point base editing platform to simultaneously introduce multiple gene knockouts and site-specific integration of a transgene in human primary T cells. We demonstrate high editing efficiency and purity at all target sites and significantly reduced frequency of chromosomal translocations compared with the conventional CRISPR-Cas9 system. Site-specific knockin of a chimeric antigen receptor and multiplex gene knockout are achieved within a single intervention and without the requirement for additional sequence-targeting components. The ability to perform complex genome editing efficiently and precisely highlights the potential of the Pin-point platform for application in a range of advanced cell therapies.
In situ hydrogel based on Cu–Fe3O4 nanoclusters exploits oxidative stress and the ferroptosis/cuproptosis pathway for chemodynamic therapy
Authors: Yiqun Zhang, Ni Zhang, Jianghao Xing, Yiwei Sun, Xu Jin, Cailiang Shen, Liang Cheng, Yuanyin Wang, Xianwen Wang
Journal: Biomaterials (2024)
Deficiency of galactosyl-ceramidase in adult oligodendrocytes worsens disease severity during chronic experimental allergic encephalomyelitis
Authors: Natalia Saldivia, Gregory Heller, Diego Zelada, Jason Whitehair, Nikhil Venkat, Ashna Konjeti, Reina Savitzky, Shayla Samano, Daniel Simchuk, Richard van Breemen, Maria I. Givogri, Ernesto R. Bongarzone
Journal: Molecular Therapy (2024)

Galactosyl-ceramidase (GALC) is a ubiquitous lysosomal enzyme crucial for the correct myelination of the mammalian nervous system during early postnatal development. However, the physiological consequence of GALC deficiency in the adult brain remains unknown. In this study, we found that mice with conditional ablation of GALC activity in post-myelinating oligodendrocytes were lethally sensitized when challenged with chronic experimental allergic encephalomyelitis (EAE), in contrast with the non-lethal dysmyelination observed in Galc-ablated mice without the EAE challenge. Mechanistically, we found strong inflammatory demyelination without remyelination and an impaired fusion of lysosomes and autophagosomes with accumulation of myelin debris after a transcription factor EB-dependent increase in the lysosomal autophagosome flux. These results indicate that the physiological impact of GALC deficiency is highly influenced by the cell context (oligodendroglial vs. global expression), the presence of inflammation, and the developmental time when it happens (pre-myelination vs. post-myelination). We conclude that Galc expression in adult oligodendrocytes is crucial for the maintenance of adult central myelin and to decrease vulnerability to additional demyelinating insults. Galactosyl-ceramidase (GALC) is a ubiquitous lysosomal enzyme crucial for the correct myelination of the mammalian nervous system during early postnatal development. However, the physiological consequence of GALC deficiency in the adult brain remains unknown. In this study, we found that mice with conditional ablation of GALC activity in post-myelinating oligodendrocytes were lethally sensitized when challenged with chronic experimental allergic encephalomyelitis (EAE), in contrast with the non-lethal dysmyelination observed in Galc-ablated mice without the EAE challenge. Mechanistically, we found strong inflammatory demyelination without remyelination and an impaired fusion of lysosomes and autophagosomes with accumulation of myelin debris after a transcription factor EB-dependent increase in the lysosomal autophagosome flux. These results indicate that the physiological impact of GALC deficiency is highly influenced by the cell context (oligodendroglial vs. global expression), the presence of inflammation, and the developmental time when it happens (pre-myelination vs. post-myelination). We conclude that Galc expression in adult oligodendrocytes is crucial for the maintenance of adult central myelin and to decrease vulnerability to additional demyelinating insults.
Endoscopic treatment of a large Brunner’s gland hamartoma in the duodenum
Authors: Ha Eun Lee, Gwang Ha Kim, Kyungbin Kim
Journal: Endoscopy (2024)

A 62-year-old woman visited our hospital for further evaluation of a large elongated polypoid mass in the duodenum, which was incidentally discovered during a health check-up endoscopy. The patient had a medical history of hypertension and hyperlipidemia. At endoscopy, a 10-cm subepithelial mass with a long stalk was observed in the second portion of the duodenum ([Fig. 1] a); nodular mucosal changes were observed in the distal portion of the mass ([Fig. 1] b). Endoscopic ultrasonography (EUS) revealed that the mass was a heterogeneously mixed echogenic lesion with cystic changes in the deep mucosal and submucosal layers [Fig. 1] c).
Into the pancreas: an underwater world filled with an intraductal papillary mucinous neoplasm seen via peroral pancreatoscopy
Authors: Kazuki Hirano, Kosuke Maehara, Daisuke Hattori, Yoshiki Sato, Tetsuo Tamura, Rikako Koyama, Tsunao Imamura
Journal: Endoscopy (2024)

Although peroral pancreatoscopy (POPS) has been developed for detailed visualization of intraductal lesions, the images obtained are often inadequate because of the difficulty of insertion, the proximity of the pancreatoscope to the lesion, or visualization challenges due to mucus. Performance can be improved when it is combined with intraductal ultrasonography (IDUS) [1], narrow-band imaging (NBI) [2], and probe-based confocal laser endomicroscopy (pCLE) [3]; however, POPS alone has not achieved high quality intraductal imaging and is still under development.
Endoscopic ultrasound-guided entero-colostomy with lumen-apposing metal stent as a rescue treatment for malignant intestinal occlusion: a multicenter study
Authors: Benedetto Neri, Serena Stigliano, Dario Biasutto, Nicolò Citterio, Andrea Lisotti, Pietro Fusaroli, Benedetto Mangiavillano, Gianfranco Donatelli, Giuseppe Tonini, Francesco Maria Di Matteo
Journal: Endoscopy (2024)

Surgery is the first-choice treatment for malignant intestinal obstruction (MIO); however, many patients are deemed unfit for surgery. Endoscopic ultrasound-guided entero-colostomy (EUS-EC) with a lumen-apposing metal stent (LAMS) could represent a new treatment option.
Experiences of telehealth during and after the COVID-19 pandemic and preferences for future care of people with systemic sclerosis: a cross-sectional study
Authors: Elsa-Lynn Nassar, Gabrielle Virgili-Gervais, Marie-Eve Carrier, Linda Kwakkenbos, Richard S Henry, Sophie Hu, Sabrina Provencher, Meira Golberg, Susan J Bartlett, Luc Mouthon, Scott B Patten, John Varga, Andrea Benedetti, Brett D Thombs, Claire E. Adams, Karen Gottesman, Marie Hudson, Laura K. Hummers, Amanda Lawrie-Jones, Vanessa L. Malcarne, Maureen D. Mayes, Michelle Richard, Robyn K. Wojeck, Ghassan El-Baalbaki, Kim Fligelstone, Tracy Frech, Daphna Harel, Monique Hinchcliff, Sindhu R. Johnson, Maggie Larche, Catarina Leite, Christelle Nguyen, Karen Nielsen, Janet Pope, François Rannou, Tatiana Sofia Rodriguez-Reyna, Anne A. Schouffoer, Maria E. Suarez-Almazor, Christian Agard, Laurent Alric, Marc André, Floryan Beaslay, Elana J. Bernstein, Sabine Berthier, Lyne Bissonnette, Sophie Blaise, Eva Bories, Alessandra Bruns, Carlotta Cacciatore, Patricia Carreira, Marion Casadevall, Benjamin Chaigne, Lorinda Chung, Benjamin Crichi, Thylbert Deltombe, Christopher Denton, Tannvir Desroche, Robyn Domsic, James V. Dunne, Bertrand Dunogue, Regina Fare, Dominique Farge-Bancel, Paul R. Fortin, Loraine Gauzère, Anne Gerber, Jessica K. Gordon, Brigitte Granel-Rey, Aurélien Guffroy, Geneviève Gyger, Eric Hachulla, Sabrina Hoa, Michael Hughes, Alena Ikic, Nader Khalidi, Kimberly S. Lakin, Marc Lambert, David Launay, Yvonne C. Lee, Paul Legendre, Hélène Maillard, Nancy Maltez, Joanne Manning, Isabelle Marie, Maria Martin Lopez, Thierry Martin, Ariel Masetto, Arsène Mekinian, Sheila Melchor Díaz, Morgane Mourguet, Mandana Nikpour, Louis Olagne, Vincent Poindron, Susanna Proudman, Grégory Pugnet, Loïc Raffray, Alexis Régent, Frederic Renou, Sébastien Rivière, David Robinson, Esther Rodríguez Almazar, Sophie Roux, Perrine Smets, Vincent Sobanski, Robert F. Spiera, Virginia Steen, Evelyn Sutton, Carter Thorne, Damien Vagner, Pearce Wilcox, Mara Cañedo Ayala, Vanessa Cook, Cassidy Dal Santo, Tiffany Dal Santo, Monica D'onofrio, Marieke Alexandra Neyer
Journal: The Lancet Rheumatology (2024)
Child abuse and neglect-related murders in South Africa: a comparison of two national surveys in 2009 and 2017
Authors: Naeemah Abrahams, Shibe Mhlongo, Esnat Chirwa, Bianca Dekel, Asiphe Ketelo, Carl Lombard, Nwabisa Shai, Leane Ramsoomar, Shanaaz Mathews, Gérard Labuschagne, Richard Matzopoulos, Megan Prinsloo, Lorna J Martin, Rachel Jewkes
Journal: The Lancet Child & Adolescent Health (2024)
Changes in prevalence and incidence of dementia and risk factors for dementia: an analysis from cohort studies
Authors: Naaheed Mukadam, Frank J Wolters, Sebastian Walsh, Lindsay Wallace, Carol Brayne, Fiona E Matthews, Simona Sacuiu, Ingmar Skoog, Sudha Seshadri, Alexa Beiser, Saptaparni Ghosh, Gill Livingston
Journal: The Lancet Public Health (2024)
Changes in opioid prescribing during the COVID-19 pandemic in England: an interrupted time-series analysis in the OpenSAFELY-TPP cohort
Authors: Andrea L Schaffer, Colm D Andrews, Andrew D Brown, Richard Croker, William J Hulme, Linda Nab, Jane Quinlan, Victoria Speed, Christopher Wood, Milan Wiedemann, Jon Massey, Peter Inglesby, Seb C J Bacon, Amir Mehrkar, Chris Bates, Ben Goldacre, Alex J Walker, Brian MacKenna, Lucy Bridges, Benjamin FC Butler-Cole, Simon Davy, Iain Dillingham, David Evans, Louis Fisher, Amelia Green, Liam Hart, George Hickman, Steven Maude, Thomas O'Dwyer, Rebecca M Smith, Pete Stokes, Tom Ward, Johnathan Cockburn, Sam Harper, Frank Hester, John Parry
Journal: The Lancet Public Health (2024)

The COVID-19 pandemic disrupted health-care delivery, including difficulty accessing in-person care, which could have increased the need for strong pharmacological pain relief. Due to the risks associated with overprescribing of opioids, especially to vulnerable populations, we aimed to quantify changes to measures during the COVID-19 pandemic, overall, and by key subgroups.
Livebirth rate after one frozen embryo transfer in ovulatory women starting with natural, modified natural, or artificial endometrial preparation in Viet Nam: an open-label randomised controlled trial
Authors: Vu N A Ho, Toan D Pham, Nam T Nguyen, Rui Wang, Robert J Norman, Ben W Mol, Tuong M Ho, Lan N Vuong
Journal: The Lancet (2024)
Risks of adverse obstetric outcomes among female survivors of adolescent and young adult cancer in England (TYACSS): a population-based, retrospective cohort study
Authors: Ceren Sunguc, David L Winter, Emma J Heymer, Gavin Rudge, Angela Polanco, Katherine A Birchenall, Melanie Griffin, Richard A Anderson, W Hamish B Wallace, Michael M Hawkins, Raoul C Reulen
Journal: The Lancet Oncology (2024)

There are limited data on the risks of obstetric complications among survivors of adolescent and young adult cancer with most previous studies only reporting risks for all types of cancers combined. The aim of this study was to quantify deficits in birth rates and risks of obstetric complications for female survivors of 17 specific types of adolescent and young adult cancer.