tbuckley/cabot-search huggingface dataset:
Optimizing lipid nanoparticles for fetal gene delivery in vitro, ex vivo, and aided with machine learning
Authors: Amr Abostait, Mahmoud Abdelkarim, Zeqing Bao, Yuichiro Miyake, Wai Hei Tse, Caterina Di Ciano-Oliveir, Tina Buerki-Thurnherr, Christine Allen, Richard Keijzer, Hagar I Labouta
Journal: Journal of Controlled Release (2024)

There is a clinical need to develop lipid nanoparticles (LNPs) to deliver congenital therapies to the fetus during pregnancy. The aim of these therapies is to restore normal fetal development and prevent irreversible conditions after birth. As a first step, LNPs need to be optimized for transplacental transport, safety on the placental barrier and fetal organs and transfection efficiency. We developed and characterized a library of LNPs of varying compositions and used machine learning (ML) models to delineate the determinants of LNP size and zeta potential. Utilizing different in vitro placental models with the help of a Random Forest algorithm, we could identify the top features driving percentage LNP transport and kinetics at 24 h, out of a total of 18 input features represented by 41 LNP formulations and 48 different transport experiments. We further evaluated the LNPs for safety, placental cell uptake, transfection efficiency in placental trophoblasts and fetal lung fibroblasts. To ensure the integrity of the LNPs following transplacental transport, we screened LNPs for transport and transfection using a high-throughput integrated transport-transfection in vitro model. Finally, we assessed toxicity of the LNPs in a tracheal occlusion fetal lung explant model. LNPs showed little to no toxicity to fetal and placental cells. Immunoglobin G (IgG) orientation on the surface of LNPs, PEGylated lipids, and ionizable lipids had significant effects on placental transport. The Random Forest algorithm identified the top features driving LNPs placental transport percentage and kinetics. Zeta potential emerged in the top driving features. Building on the ML model results, we developed new LNP formulations to further optimize the transport leading to 622 % increase in transport at 24 h versus control LNP formulation. To induce preferential siRNA transfection of fetal lung, we further optimized cationic lipid percentage and the lipid-to-siRNA ratio. Studying LNPs in an integrated placental and fetal lung fibroblasts model showed a strong correlation between zeta potential and fetal lung transfection. Finally, we assessed the toxicity of LNPs in a tracheal occlusion lung explant model. The optimized formulations appeared to be safe on ex vivo fetal lungs as indicated by insignificant changes in apoptosis (Caspase-3) and proliferation (Ki67) markers. In conclusion, we have optimized an LNP formulation that is safe, with high transplacental transport and preferential transfection in fetal lung cells. Our research findings represent an important step toward establishing the safety and effectiveness of LNPs for gene delivery to the fetal organs.
Low energy availability surrogates are associated with Relative Energy Deficiency in Sport outcomes in male athletes
Authors: Bryan Holtzman, Rose K Kelly, Grace H Saville, Lauren McCall, Kaya A Adelzedah, Samantha R Sarafin, Prakruthi Nikam, Isabella Meneguzzi, Abby McIntyre, Emily K Kraus, Kathryn E Ackerman
Journal: British Journal of Sports Medicine (2024)

To determine the association between surrogates of low energy availability (EA) and proposed health and performance outcomes of Relative Energy Deficiency in Sport (REDs) in a clinical sample of adolescent and young adult male athletes.
Evolution of the use, effectiveness and safety of bismuth-containing quadruple therapy for<i>Helicobacter pylori</i>infection between 2013 and 2021: results from the European registry on<i>H. pylori</i>management (Hp-EuReg)
Authors: Llum Olmedo, Xavier Calvet, Emili Gené, Dmitry S Bordin, Irina Voynovan, M Castro-Fernandez, Manuel Pabón-Carrasco, Alma Keco-Huerga, Ángeles Perez-Aisa, Alfredo J Lucendo, Luís Rodrigo, Aiman S Sarsenbaeva, Igor B Khlinov, Galyna Fadieienko, Oleg Zaytsev, Ángel Lanas, Samuel J Martínez-Domínguez, Enrique Alfaro, Laimas Jonaitis, Óscar Núñez, Rinaldo Pellicano, Luis Hernández, Oleksiy Gridnyev, Juozas Kupcinskas, Antonio Gasbarrini, Doron Boltin, Yaron Niv, Gülüstan Babayeva, Ricardo Marcos-Pinto, Bojan Tepes, Marino Venerito, Veronika Papp, Frode Lerang, Mārcis Leja, Perminder S Phull, Wojciech Marlicz, Michael Doulberis, Sinead M Smith, Vladimir Milivojevic, Lumir Kunovsky, Antonio Mestrovic, Tamara Matysiak-Budnik, Halis Simsek, Anna Cano-Català, Ignasi Puig, Leticia Moreira, Pablo Parra, Olga P Nyssen, Francis Megraud, Colm O'Morain, Javier P Gisbert
Journal: Gut (2024)

Bismuth quadruple therapies (BQTs) including bismuth, a proton pump inhibitor (PPI) and two antibiotics have been shown to be highly effective for treating
<i>CRLF2</i>-rearranged B-cell ALL with extramedullary lineage switch to AML following CD19-targeted therapy
Authors: Sara K Silbert, Samantha Scanlon, Hao-Wei Wang, Constance M Yuan, Alyssa Doverte, Jake Wellek, Nisha Patel, Raul Braylan, Mark Ahlman, Evrim B Turkbey, Sandra D Bohling, Karen M Chisholm, Murat Alp Oztek, Mike LaLoggia, Anupam Verma, Haneen Shalabi, Alexandra E Kovach, Brent L Wood, Adam Lamble, Ilan Kirsch, Kasey Leger, Nirali N Shah
Journal: Journal for ImmunoTherapy of Cancer (2024)

Lineage switch (LS) refers to the immunophenotypic transformation of one leukemia lineage to another (ie, lymphoid to myeloid) with retention of baseline genetics. This phenomenon was originally observed in infants with B-lymphoblastic leukemia (B-ALL) with
Inhibitory Fcγ receptor deletion enhances CD8 T cell stemness increasing anti-PD-1 therapy responsiveness against glioblastoma
Authors: Keun Bon Ku, Chae Won Kim, Yumin Kim, Byeong Hoon Kang, Jeongwoo La, In Kang, Won Hyung Park, Stephen Ahn, Sung Ki Lee, Heung Kyu Lee
Journal: Journal for ImmunoTherapy of Cancer (2024)

Certain cancers present challenges for treatment because they are resistant to immune checkpoint blockade (ICB), attributed to low tumor mutational burden and the absence of T cell-inflamed features. Among these, glioblastoma (GBM) is notoriously resistant to ICB. To overcome this resistance, the identification of T cells with heightened stemness marked by T-cell factor 1 (TCF1) expression has gained attention. Several studies have explored ways to preserve stem-like T cells and prevent terminal exhaustion. In this study, we investigate a target that triggers stem-like properties in CD8 T cells to enhance the response to ICB in a murine GBM model.
Dendritic cell-intrinsic PTPN22 negatively regulates antitumor immunity and impacts anti-PD-L1 efficacy
Authors: Santiago Acero-Bedoya, Emily F Higgs, Anna C Martinez, Ruxandra Tonea, Thomas F Gajewski
Journal: Journal for ImmunoTherapy of Cancer (2024)

Individuals with a loss-of-function single-nucleotide polymorphism in the gene encoding PTPN22 have an increased risk for autoimmune diseases, and patients with cancer with such alleles may respond better to checkpoint blockade immunotherapy. Studies in PTPN22 knockout (KO) mice have established it as a negative regulator of T cell responses in cancer models. However, the role of PTPN22 in distinct immune cell compartments, such as dendritic cells (DCs), remains undefined.
Ten challenges and opportunities in computational immuno-oncology
Authors: Riyue Bao, Alan Hutson, Anant Madabhushi, Vanessa D Jonsson, Spencer R Rosario, Jill S Barnholtz-Sloan, Elana J Fertig, Himangi Marathe, Lyndsay Harris, Jennifer Altreuter, Qingrong Chen, James Dignam, Andrew J Gentles, Edgar Gonzalez-Kozlova, Sacha Gnjatic, Erika Kim, Mark Long, Martin Morgan, Eytan Ruppin, David Van Valen, Hong Zhang, Natalie Vokes, Daoud Meerzaman, Song Liu, Eliezer M Van Allen, Yi Xing
Journal: Journal for ImmunoTherapy of Cancer (2024)

Immuno-oncology has transformed the treatment of cancer, with several immunotherapies becoming the standard treatment across histologies. Despite these advancements, the majority of patients do not experience durable clinical benefits, highlighting the imperative for ongoing advancement in immuno-oncology. Computational immuno-oncology emerges as a forefront discipline that draws on biomedical data science and intersects with oncology, immunology, and clinical research, with the overarching goal to accelerate the development of effective and safe immuno-oncology treatments from the laboratory to the clinic. In this review, we outline 10 critical challenges and opportunities in computational immuno-oncology, emphasizing the importance of robust computational strategies and interdisciplinary collaborations amid the constantly evolving interplay between clinical needs and technological innovation.
Community-based approaches to improve tuberculosis services: observations from preintervention and postintervention surveys in a high TB burden disadvantaged community in India
Authors: Jyothi Bhat, Ravendra Kumar Sharma, Rajiv Yadav, M Muniyandi, Prashant Mishra, Samridhi Nigam, Mercy Aparna Latha Lingala, Vikas Gangadhar Rao
Journal: Thorax (2024)

An alarmingly high prevalence of tuberculosis (TB) was reported among the Saharia tribe in Madhya Pradesh, India. A community-based intervention study was undertaken to improve TB case finding during 2018-2021. The interventions mainly comprised active case detection through village TB volunteers using advocacy, communication and social mobilisation activities. A preintervention and postintervention survey design was adopted to assess the impact of intervention. The prevalence declined from 1357 (95% CI 1206 to 1527) to 752 (95% CI 646 to 875) per 100 000 population (p<0.001). The study findings highlight the importance of innovative community-based approaches in controlling TB in high burden areas.
TGF-β trap of AdAPT-001 turns up the heat on tumors and turns down checkpoint blocker resistance
Authors: Tony R Reid, Bryan Oronsky, Jeannie Williams, Scott Caroen, Anthony Conley
Journal: Journal for ImmunoTherapy of Cancer (2024)

At the ASCO 2024 meeting, Anthony P Conley, coauthor on this editorial, presented promising data from the phase 1/2 clinical trial called BETA PRIME (ClinicalTrials.gov NCT04673942) with AdAPT-001 plus a checkpoint inhibitor (CI). All participants gave informed consent to participate in BETA PRIME before taking part. AdAPT-001 is an oncolytic adenovirus that expresses a transforming growth factor beta (TGF-β) trap to neutralize active TGF-β. This editorial proposes that the TGF-β trap of AdAPT-001 reverses the immunosuppressive environment of tumor cells, and thus makes these tumors susceptible to CIs like the anti-PD-1 agent, nivolumab, and potentially other therapies as well.
Impact of race, ethnicity, and social determinants on outcomes following immune checkpoint therapy
Authors: Rahul K Nayak, Meili Aiello, Laneisha Marielis Maldonado, Tarralyn Y Clark, Zachary S Buchwald, Andres Chang
Journal: Journal for ImmunoTherapy of Cancer (2024)

Immune checkpoint blockade (ICB) therapies are one of the greatest advances in the history of cancer care and are now commonly used in the management of many different malignancies. However, much remains unknown about the factors that affect the efficacy and side effect profile of these agents. This review delves into the published literature that evaluates the intricate interplay between race, age, gender, and social determinants in shaping outcomes following ICB across solid tumors and hematologic malignancies. We examine the pivotal phase 2 and 3 trials to evaluate the demographics of participants and outcomes based on these variables, if reported. Most, but not all, trials reported some basic demographic information like age, sex, race, ethnicity, and/or geographic area for enrollment. Clinically relevant biological markers that could affect ICB outcomes such as obesity or markers of social determinants of health were largely not reported. Trials were generally representative for men and women based on expected prevalence for a given malignancy, but often under-represented non-white participants and rarely enrolled patients from the global south. Subgroup analyses were conducted in many ICB trials for solid malignancies, but rarely conducted for hematologic malignancies. These analyses largely showed similar qualitative benefit across subgroups, but adverse events were rarely reported by subgroup. This review adds to our understanding of the populations that these clinical trials have studied and highlight the urgent need to redouble our efforts at increasing the diversity of the population in future ICB trials.
Zebrafish arterial valve development occurs through direct differentiation of second heart field progenitors
Authors: Christopher J Derrick, Lorraine Eley, Ahlam Alqahtani, Deborah J Henderson, Bill Chaudhry
Journal: Cardiovascular Research (2024)

Bicuspid Aortic Valve (BAV) is the most common congenital heart defect, affecting at least 2% of the population. The embryonic origins of BAV remain poorly understood, with few assays for validating patient variants, limiting the identification of causative genes for BAV. In both human and mouse, the left and right leaflets of the arterial valves arise from the outflow tract cushions, with interstitial cells originating from neural crest cells and the overlying endocardium through endothelial-to-mesenchymal transition (EndoMT). In contrast, an EndoMT-independent mechanism of direct differentiation of cardiac progenitors from the second heart field (SHF) is responsible for the formation of the anterior and posterior leaflets. Defects in either of these developmental mechanisms can result in BAV. Although zebrafish have been suggested as a model for human variant testing, their naturally bicuspid arterial valve has not been considered suitable for understanding human arterial valve development. Here, we have set out to investigate to what extent the processes involved in arterial valve development are conserved in zebrafish and ultimately, whether functional testing of BAV variants could be carried out.
Clinically applicable optimized periprosthetic joint infection diagnosis via AI based pathology
Authors: Ye Tao, Yazhi Luo, Hanwen Hu, Wei Wang, Ying Zhao, Shuhao Wang, Qingyuan Zheng, Tianwei Zhang, Guoqiang Zhang, Jie Li, Ming Ni
Journal: npj Digital Medicine (2024)

Periprosthetic joint infection (PJI) is a severe complication after joint replacement surgery that demands precise diagnosis for effective treatment. We enhanced PJI diagnostic accuracy through three steps: (1) developing a self-supervised PJI model with DINO v2 to create a large dataset; (2) comparing multiple intelligent models to identify the best one; and (3) using the optimal model for visual analysis to refine diagnostic practices. The self-supervised model generated 27,724 training samples and achieved a perfect AUC of 1, indicating flawless case differentiation. EfficientNet v2-S outperformed CAMEL2 at the image level, while CAMEL2 was superior at the patient level. By using the weakly supervised PJI model to adjust diagnostic criteria, we reduced the required high-power field diagnoses per slide from five to three. These findings demonstrate AI's potential to improve the accuracy and standardization of PJI pathology and have significant implications for infectious disease diagnostics.
Tree sequences as a general-purpose tool for population genetic inference
Authors: Logan S Whitehouse, Dylan Ray, Daniel R Schrider
Journal: Molecular Biology and Evolution (2024)

As population genetics data increases in size new methods have been developed to store genetic information in efficient ways, such as tree sequences. These data structures are computationally and storage efficient, but are not interchangeable with existing data structures used for many population genetic inference methodologies such as the use of convolutional neural networks (CNNs) applied to population genetic alignments. To better utilize these new data structures we propose and implement a graph convolutional network (GCN) to directly learn from tree sequence topology and node data, allowing for the use of neural network applications without an intermediate step of converting tree sequences to population genetic alignment format. We then compare our approach to standard CNN approaches on a set of previously defined benchmarking tasks including recombination rate estimation, positive selection detection, introgression detection, and demographic model parameter inference. We show that tree sequences can be directly learned from using a GCN approach and can be used to perform well on these common population genetics inference tasks with accuracies roughly matching or even exceeding that of a CNN-based method. As tree sequences become more widely used in population genetics research we foresee developments and optimizations of this work to provide a foundation for population genetics inference moving forward.
<i>APOL1</i> Bi- and Monoallelic Variants and Chronic Kidney Disease in West Africans
Authors: Rasheed A. Gbadegesin, Ifeoma Ulasi, Samuel Ajayi, Yemi Raji, Timothy Olanrewaju, Charlotte Osafo, Adebowale D. Ademola, Adanze Asinobi, Cheryl A. Winkler, David Burke, Fatiu Arogundade, Ivy Ekem, Jacob Plange-Rhule, Manmak Mamven, Michael Matekole, Olukemi Amodu, Richard Cooper, Sampson Antwi, Adebowale A. Adeyemo, Titilayo O. Ilori, Victoria Adabayeri, Alexander Nyarko, Anita Ghansah, Toyin Amira, Adaobi Solarin, Olugbenga Awobusuyi, Paul L. Kimmel, Frank Chip Brosius, Muhammad Makusidi, Uzoma Odenigbo, Matthias Kretzler, Jeffrey B. Hodgin, Martin R. Pollak, Vincent Boima, Barry I. Freedman, Nicholette D. Palmer, Bernard Collins, Milind Phadnis, Jill Smith, Celia I. Agwai, Ogochukwu Okoye, Aliyu Abdu, Jillian Wilson, Winfred Williams, Babatunde L. Salako, Rulan S. Parekh, Bamidele Tayo, Dwomoa Adu, Akinlolu Ojo
Journal: New England Journal of Medicine (2024)

Apolipoprotein L1 gene (
Adjuvant Modified FOLFIRINOX for Resected Pancreatic Adenocarcinoma (PDAC): Clinical Insights and Genomic Features from a Large Contemporary Cohort
Authors: Fergus Keane, Catherine O’Connor, Drew Moss, Joanne F Chou, Maria A Perry, Fionnuala Crowley, Parima Saxena, Amelia Chan, Joshua D Schoenfeld, Anupriya Singhal, Wungki Park, Darren Cowzer, Emily Harrold, Anna M Varghese, Imane El Dika, Christopher Crane, James J Harding, Ghassan K Abou-Alfa, T Peter Kingham, Alice C Wei, Kenneth H Yu, Michael I D’Angelica, Vinod P Balachandran, Jeffrey Drebin, William R Jarnagin, Chaitanya Bandlamudi, David Kelsen, Marinela Capanu, Kevin C Soares, Fiyinfolu Balogun, Eileen M O’Reilly
Journal: JNCI Journal of the National Cancer Institute (2024)

Adjuvant mFOLFIRINOX (mFFX) is standard of care for fit individuals with resected pancreatic ductal adenocarcinoma (PDAC). There are limited data on adjuvant mFFX outcomes outside clinical trials.
Nintedanib for patients with lymphangioleiomyomatosis: a phase 2, open-label, single-arm study
Authors: Sergio Harari, Davide Elia, Antonella Caminati, Jens Geginat, Francesca Luisi, Giuseppe Pelosi, Claudia Specchia, Olga Torre, Roberta Trevisan, Chiara Vasco, Maurizio Zompatori, Roberto Cassandro
Journal: The Lancet Respiratory Medicine (2024)
Serotype-specific epidemiological patterns of inapparent versus symptomatic primary dengue virus infections: a 17-year cohort study in Nicaragua
Authors: Sandra Bos, José Victor Zambrana, Elias Duarte, Aaron L Graber, Julia Huffaker, Carlos Montenegro, Lakshmanane Premkumar, Aubree Gordon, Guillermina Kuan, Angel Balmaseda, Eva Harris
Journal: The Lancet Infectious Diseases (2024)
Publisher Correction: Development and assessment of a machine learning tool for predicting emergency admission in Scotland
Authors: James Liley, Gergo Bohner, Samuel R. Emerson, Bilal A. Mateen, Katie Borland, David Carr, Scott Heald, Samuel D. Oduro, Jill Ireland, Keith Moffat, Rachel Porteous, Stephen Riddell, Simon Rogers, Ioanna Thoma, Nathan Cunningham, Chris Holmes, Katrina Payne, Sebastian J. Vollmer, Catalina A. Vallejos, Louis J. M. Aslett
Journal: npj Digital Medicine (2024)
Advancing Two‐Photon Photodynamic Therapy Over NIR‐II Excitable Conjugated Microporous Polymer with NIR‐I Emission
Authors: Bo Li, Xinlei Yu, Xin Lu, Xianshun Sun, Yuanzhong Kai, Longjiu Cheng, Hongping Zhou, Yupeng Tian, Dandan Li
Journal: Advanced Healthcare Materials (2024)

Abstract The availability of second near‐infrared (NIR‐II) excitable two‐photon photosensitizers with NIR‐I emission for efficient photodynamic therapy (PDT) is limited by challenges in molecular design. In this study, a NIR‐II light‐excitable two‐photon conjugated microporous polymer ( Tph‐Dbd ) with emission in the NIR‐I region is developed. The large conjugated system and delocalized electronic structures endow Tph‐Dbd with a large two‐photon absorption cross‐section under NIR‐II light excitation. Moreover, the efficient electron acceptor and donor units within the π‐conjugated backbones result in NIR‐I emission for high signal‐to‐background ratio imaging, as well as separated highest occupied molecular orbital and lowest unoccupied molecular orbital distributions for excellent singlet oxygen generation ability. The excellent NIR‐II excitable two‐photon absorption activity, NIR‐I emission, good biocompatibility, and high photostability allow Tph‐Dbd to be used for efficient in vitro fluorescence imaging guided PDT. Moreover, the impressive photothermal effect of Tph‐Dbd can overcome the limitations of PDT in the treatment of hypoxic tumors. This study highlights a strategy for designing NIR‐II excitable two‐photon photosensitizers for advanced PDT.
MOF‐Enhanced Phototherapeutic Wound Dressings Against Drug‐Resistant Bacteria
Authors: Zhihao Yu, Xiali Fu, Theotim Lucas, Heng Zhao, Changchong Chen, Iharilalao Dubail, Yong Chen, Gilles Patriarche, Jérôme Gateau, Florence Gazeau, Anne Jamet, Mathilde Lepoitevin, Christian Serre
Journal: Advanced Healthcare Materials (2024)

Phototherapy is a low-risk alternative to traditional antibiotics against drug-resistant bacterial infections. However, optimizing phototherapy agents, refining treatment conditions, and addressing misuse of agents, remain a formidable challenge. This study introduces a novel concept leveraging the unique customizability of metal-organic frameworks (MOFs) to house size-matched dye molecules in "single rooms". The mesoporous iron(III) carboxylate nanoMOF, MIL-100(Fe), and the hydrophobic heptamethine cyanine photothermal dye (Cy7), IR775, are selected as model systems. Their combination is predicted to minimize dye-dye interactions, leading to exceptional photostability and efficient light-to-heat conversion. Furthermore, MIL-100(Fe) preserves the antimicrobial nature of hydrophobic IR775, enabling it to disrupt bacterial cell envelopes. Through electrospinning, MIL-100(Fe)@IR775 nanoparticles are shaped into a gelatin-based film dressing for the treatment of skin wounds infected by Methicillin-resistant Staphylococcus aureus (MRSA). Activation of the dressing requires only a portable near-infrared light-emitting diode (NIR LED) and induces both low-dose photodynamic therapy (LPDT) and mild-temperature photothermal therapy (MPTT). Combined with the antimicrobial properties of IR775 and ferroptosis-like lipid peroxidation induced by MIL-100(Fe), the photoactive dressing eradicates MRSA and the healing is as quick as the uninfected wounds. This safe, cost-effective, and multifunctional therapeutic wound dressing offers a promising solution to overcome the current bottleneck in phototherapy.