tbuckley/cabot-search huggingface dataset:
A Manual for Genome and Transcriptome Engineering
Authors: Yesh Doctor, Milan Sanghvi, Prashant Mali
Journal: IEEE Reviews in Biomedical Engineering (2024)

Genome and transcriptome engineering have emerged as powerful tools in modern biotechnology, driving advancements in precision medicine and novel therapeutics. In this review, we provide a comprehensive overview of the current methodologies, applications, and future directions in genome and transcriptome engineering. Through this, we aim to provide a guide for tool selection, critically analyzing the strengths, weaknesses, and best use cases of these tools to provide context on their suitability for various applications. We explore standard and recent developments in genome engineering, such as base editors and prime editing, and provide insight into tool selection for change of function (knockout, deletion, insertion, substitution) and change of expression (repression, activation) contexts. Advancements in transcriptome engineering are also explored, focusing on established technologies like antisense oligonucleotides (ASOs) and RNA interference (RNAi), as well as recent developments such as CRISPR-Cas13 and adenosine deaminases acting on RNA (ADAR). This review offers a comparison of different approaches to achieve similar biological goals, and consideration of high-throughput applications that enable the probing of a variety of targets. This review elucidates the transformative impact of genome and transcriptome engineering on biological research and clinical applications that will pave the way for future innovations in the field.
Colonization resistance: the role of gut microbiota in preventing <i>Salmonella</i> invasion and infection
Authors: Lei Deng, Shaohui Wang
Journal: Gut Microbes (2024)

The human gastrointestinal tract is colonized by a complex microbial ecosystem, the gut microbiota, which is pivotal in maintaining host health and mediating resistance to diseases. This review delineates colonization resistance (CR), a critical defensive mechanism employed by the gut microbiota to safeguard against pathogenic bacterial invasions, notably by
Fluorescence Lifetime Imaging Enables In vivo Quantification of PD-L1 Expression and Inter-tumoral Heterogeneity
Authors: Rahul Pal, Murali Krishnamoorthy, Aya Matsui, Homan Kang, Satoru Morita, Hajime Taniguchi, Tatsuya Kobayashi, Atsuyo Morita, Hak Soo Choi, Dan G. Duda, Anand T.N. Kumar
Journal: Cancer Research (2024)

Patient selection for cancer immunotherapy requires precise, quantitative readouts of biomarker expression in intact tumors that can be reliably compared across multiple subjects over time. The current clinical standard biomarker for assessing immunotherapy response is programmed death-ligand-1 (PD-L1) expression, typically quantified using immunohistochemistry. This method, however, only provides snapshots of PD-L1 expression status in microscopic regions of ex vivo specimens. While various targeted probes have been investigated for in vivo imaging of PD-L1, non-specific probe accumulation within the tumor microenvironment (TME) has hindered accurate quantification, limiting the utility for preclinical and clinical studies. Here, we demonstrated that in vivo time-domain (TD) fluorescence imaging of an anti-PD-L1 antibody tagged with the near-infrared fluorophore IRDye 800CW (αPDL1-800) can yield quantitative estimates of baseline tumor PD-L1 heterogeneity across untreated mice, as well as variations in PD-L1 expression in mice undergoing clinically relevant anti-PD1 treatment. The fluorescence lifetime (FLT) of PD-L1 bound αPDL1-800 was significantly longer than the FLT of nonspecifically accumulated αPDL1-800 in the TME. This FLT contrast allowed quantification of PD-L1 expression across mice both in superficial breast tumors using planar FLT imaging and in deep-seated liver tumors (>5 mm depth) using the asymptotic TD algorithm for fluorescence tomography. These findings suggest that fluorescence lifetime imaging can accelerate the preclinical investigation and clinical translation of new immunotherapy treatments by enabling robust quantification of receptor expression across subjects.
CSTF2 Supports Hypoxia Tolerance in Hepatocellular Carcinoma by Enabling m6A Modification Evasion of PGK1 to Enhance Glycolysis
Authors: Qiangnu Zhang, Yusen Zhang, Chuli Fu, Xiaoyan He, Zuotian Huang, Geyan Wu, Teng Wei, Wen Jin, Lesen Yan, Meilong Wu, Gongze Peng, LinLan Fan, Mingyue Li, Yuehua Guo, Jiangang Bi, Yu Bai, Stephanie Roessler, Guang-Rong Yan, Liping Liu
Journal: Cancer Research (2024)

Cleavage stimulation factor subunit 2 (CSTF2) is a fundamental factor in the regulation of 3'-end cleavage and alternative polyadenylation of pre-mRNAs. Previous work has identified a tumor-promoting role of CSTF2, suggesting that it may represent a potential therapeutic target. Here, we aimed to elucidate the mechanistic function of CSTF2 in hepatocellular carcinoma (HCC). CSTF2 upregulation was frequent in HCC, and elevated levels of CSTF2 correlated with poor patient prognosis. While CSTF2 inhibition did not suppress HCC growth under non-stress conditions, it supported tolerance and survival of HCC cells under hypoxic conditions. Mechanistically, CSTF2 increased PGK1 protein production to enhance glycolysis, thereby sustaining the energy supply under hypoxic conditions. CSTF2 shortened the 3' untranslated region (3' UTR) of phosphoglycerate kinase 1 (PGK1) pre-mRNA by binding near the proximal polyadenylation site (pPAS). This shortening led to a loss of N6-methyladenosine (m6A) modification sites that are bound by YTH N6-methyladenosine RNA-binding protein F2 (YTHDF2) and increase degradation of PGK1 mRNA. Concurrently, hypoxia increased m6A modification of PGK1 mRNA near the pPAS that was recognized by the YTH N6-methyladenosine RNA-binding protein C1 (YTHDC1), which recruited CSTF2 to enhance the shortening of the PGK1 3'-UTR. A small molecule screen identified masitinib as an inhibitor of CSTF2. Masitinib counteracted PGK1 upregulation by CSTF2 and suppressed the growth of HCC xenograft and patient-derived organoid models. In conclusion, this study revealed a function of CSTF2 in supporting HCC survival under hypoxia conditions through m6A modification evasion and metabolic reprogramming, indicating inhibiting CSTF2 may overcome hypoxia tolerance in HCC.
Modeling Drug Responses and Evolutionary Dynamics using Patient-Derived Xenografts Reveals Precision Medicine Strategies for Triple Negative Breast Cancer
Authors: Abigail Shea, Yaniv Eyal-Lubling, Daniel Guerrero-Romero, Raquel Manzano Garcia, Wendy Greenwood, Martin O’Reilly, Dimitra Georgopoulou, Maurizio Callari, Giulia Lerda, Sophia Wix, Agnese Giovannetti, Riccardo Masina, Elham Esmaeilishirazifard, Wei Cope, Alistair G. Martin, Ai Nagano, Lisa Young, Steven Kupczak, Yi Cheng, Helen Bardwell, Elena Provenzano, Justine Kane, Jonny Lay, Louise Grybowicz, Karen McAdam, Carlos Caldas, Jean Abraham, Oscar M. Rueda, Alejandra Bruna
Journal: Cancer Research (2024)

The inter- and intra-tumor heterogeneity of triple negative breast cancers (TNBC), which is reflected in diverse drug responses, interplays with tumor evolution. Here, we developed a preclinical experimental and analytical framework using treatment-naive TNBC patient-derived tumor xenografts (PDTX) to test their predictive value in personalized cancer treatment approaches. Patients and their matched PDTX exhibited concordant drug responses to neoadjuvant therapy using two trial designs and dosing schedules. This platform enabled analysis of non-genetic mechanisms involved in relapse dynamics. Treatment resulted in permanent phenotypic changes with functional and therapeutic consequences. High throughput drug screening methods in ex vivo patient derived tumor xenograft cells (PDTCs) revealed patient-specific drug response changes dependent on first-line therapy. This was validated in vivo, as exemplified by a change in olaparib sensitivity in tumors previously treated with clinically relevant cycles of standard-of-care chemotherapy. In summary, PDTXs provide a robust tool to test patient drug responses and therapeutic regimens and to model evolutionary trajectories. However, high inter-model variability and permanent non-genomic transcriptional changes constrain their use for personalized cancer therapy. This work highlights important considerations associated with preclinical drug response modeling and potential uses of the platform to identify efficacious and preferential sequential therapeutic regimens.
Loss of CDKN2A Enhances the Efficacy of Immunotherapy in EGFR Mutant Non-Small Cell Lung Cancer
Authors: Simeng Wang, Jia-Cheng Lai, Yu Li, Chengfang Tang, Jiajia Lu, Min Han, Xianjiang Ye, Lina Jia, Wei Cui, Jingyu Yang, Chunfu Wu, Lihui Wang
Journal: Cancer Research (2024)

Mutant epidermal growth factor receptor (EGFR) is a common driver of non-small cell lung cancer (NSCLC). While mutant EGFR has been reported to limit the efficacy of immunotherapy, a subset of EGFR mutant NSCLC patients benefit from treatment with immune checkpoint inhibitors. A better understanding of how co-occurring genomic alterations in oncogenic driver genes impact immunotherapy efficacy may provide a more complete understanding of cancer heterogeneity and identify biomarkers of response. Here, we investigated the effects of frequent EGFR co-mutations in EGFR mutant lung cancer models and identified loss-of-function mutation of CDKN2A as a potential sensitizer to anti-PD-1 treatment in vitro and in vivo. Mechanistically, CDKN2A loss impacted the composition of the tumor immune microenvironment (TIME) by promoting the expression of PD-L2 through reduced ubiquitination of c-Myc, and mutant EGFR cooperated to upregulate c-Myc and PD-L2 by activating the MAPK pathway. Blocking PD-L2 induced anti-tumor immune responses mediated by CD8+ T cells in EGFR/CDKN2A co-mutated lung cancer. Importantly, a small-molecule PD-L2 inhibitor, zinc undecylenate, remodeled the TIME of EGFR/CDKN2A co-mutant tumors and enhanced the anti-tumor efficacy of EGFR-tyrosine kinase inhibitors. Collectively, these results identify EGFR/CDKN2A co-mutation as a distinct subtype of NSCLC that shows superior sensitivity to immune checkpoint blockade and reveals a potential combined therapeutic strategy for treating this NSCLC subtype.
Peritumoral Venous Vessels: Autobahn and Portal for T cells to Melanoma Brain Metastasis
Authors: Benjamin Izar, Minah Kim
Journal: Cancer Research (2024)

Melanoma brain metastasis is associated with high morbidity and mortality and remains a major clinical challenge. Despite recent successes with combination immune checkpoint inhibitors (ICI) in the treatment of affected patients, the mechanistic underpinnings of T cell entry and response to these drugs in brain metastasis are poorly understood. Using real-time intravital microscopy, Messmer and colleagues identified peritumoral venous vessels (PVVs) as critical sites for T cell entry into brain metastases, a process accelerated by ICI treatment. The expression of intercellular adhesion molecule 1 (ICAM-1) on PVVs was found to be important for T cell recruitment in pre-clinical models and associated with increased T cell infiltration in human brain metastatic lesions. This study highlights PVVs as key vascular entry points for T cells into brain metastases, laying the foundation for enhancing the efficacy of cancer immunotherapies.
Spatial and Single Cell Analyses Reveal Heterogeneity of DNAM-1 Receptor-Ligand Interactions that Instructs Intratumoral γδT-Cell Activity
Authors: Xiaolin Wang, Hui Wang, Zhengjing Lu, Xiangjun Liu, Wenjia Chai, Wei Wang, Jun Feng, Shen Yang, Wei Yang, Haiyan Cheng, Chenghao Chen, Shihan Zhang, Nian Sun, Qiaoyin Liu, Qiliang Li, Wenqi Song, Fang Jin, Qi Zeng, Shengcai Wang, Yan Su, Huanmin Wang, Xin Ni, Jingang Gui
Journal: Cancer Research (2024)

The dynamic interplay between tumor cells and γδT cells within the tumor microenvironment (TME) significantly influences disease progression and immunotherapy outcome. Here, we delved into the modulation of γδT-cell activation by tumor cell ligands CD112 and CD155, which interact with the activating receptor DNAM-1 on γδT cells. Spatial and single cell RNA sequencing (scRNA-seq), as well as spatial metabolome analysis, from neuroblastoma (NB) revealed that the expression levels and localization of CD112 and CD155 varied across and within tumors, correlating with differentiation status, metabolic pathways, and ultimately disease prognosis and patient survival. Both in vivo tumor xenograft experiments and in vitro co-culture experiments demonstrated that a high CD112/CD155 expression ratio in tumors enhanced γδT-cell-mediated cytotoxicity, while a low-ratio fostered tumor resistance. Mechanistically, CD112 sustained DNAM-1-mediated γδT-cell activation, whereas CD155 downregulated DNAM-1 expression via TRIM21-mediated ubiquitin proteasomal degradation. By interacting with tumor cells differentially expressing CD112 and CD155, intratumoral γδT cells exhibited varying degrees of activation and DNAM-1 expression, representing three major functional subsets. This study underscores the complexity of tumor-immune crosstalk, offering insights into how tumor heterogeneity shapes the immune landscape.
Adamts1 and Cyst Expansion in Polycystic Kidney Disease
Authors: Vijayakumar R. Kakade, Zafer Akman, Manga Motrapu, Marcelo F. Cassini, Leyuan Xu, Gilbert Moeckel, Stefan Somlo, Lloyd G. Cantley
Journal: Journal of the American Society of Nephrology (2024)

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by mutations in either the Pkd1 or Pkd2 genes leading to progressive cyst growth and often kidney failure. We have previously demonstrated that tubules can enlarge following loss of Pkd1 without an increase in tubular cell numbers, suggesting that tubular basement membrane remodeling is important for cystic dilation. RNA sequencing of Pkd1 null kidneys revealed increased expression of 17 metalloproteinases, of which A Disintegrin and Metalloproteinase with Thrombospondin Motif 1 (Adamts1) is the most highly expressed and upregulated.
Baseline Diastolic BP and BP-Lowering Effects on Cardiovascular Outcomes and All-Cause Mortality
Authors: Amara Sarwal, Robert E. Boucher, Sydney E. Hartsell, Guo Wei, Jincheng Shen, Glenn M. Chertow, Paul K. Whelton, Alfred K. Cheung, John William McEvoy, Tom Greene, Srinivasan Beddhu
Journal: Journal of the American Society of Nephrology (2024)

Lowering blood pressure (BP) in persons with low diastolic BP could be harmful. Hence, we examined whether baseline diastolic BP modifies the effects of BP lowering on clinical outcomes in a meta-analysis of five large BP lowering trials.
The COVID-19 Pandemic and Patient Expectations About Recovery From Acute Respiratory Failure
Authors: Diana C. Bouhassira, Victor D. Dinglas, Emma M. Lee, Sarah Beesley, Harris Carmichael, James C. Jackson, Mustafa Mir-Kasimov, Carla M. Sevin, Somnath Bose, Valerie Goodspeed, Ramona O. Hopkins, Samuel M. Brown, Dale M. Needham, Alison E. Turnbull, Krystal Capers, Julia Crane, Benjamin Hoenig, Maria Karamourtopoulos, Julia Larson, Andre De Souza Licht, Lauryn Tsai, Narges Akhlaghi, Omar Almaadawy, Toan Bui, Shihua Chen, Sai Phani Sree Cherukuri, Nicole Illesca, Ehizele Iyayi, Preethi Kadiri, Teja Kalva, Mounica Koneru, Mazin Ali Mahmoud, Albahi Malik, Roozbeh Nikooie, Darin Roberts, Bhavna Seth, Sriharsha Singu, Parvaneh Vaziri, Darrin Applegate, Valerie Aston, Katie Brown, Melissa Fergus, Ellie Hirshberg, Naresh Kumar, Jenna Lumpkin, Erna Serezlic, Rilee Smith, Craig High, Emily Beck, Rebecca Abel, Liza Frawley, Margaret Hays, Susan Mogan (in memoriam)
Journal: JAMA Network Open (2024)

This cohort study investigates the association of the COVID-19 pandemic with expectations about recovery among survivors of non–COVID-19 acute respiratory failure.
National Academies President on How to Use Generative AI Responsibly in Scientific Research
Authors: Kirsten Bibbins-Domingo, Yulin Hswen
Journal: JAMA (2024)

This Medical News article is an interview with National Academy of Sciences President Marcia McNutt, PhD, and JAMA Editor in Chief Kirsten Bibbins-Domingo, PhD, MD, MAS, about responsible use of generative AI for scientific research.
Cognitive and Behavioral Outcomes of Snoring Among Adolescents
Authors: Amal Isaiah, Sophia Uddin, Thomas Ernst, Christine Cloak, Dongdong Li, Linda Chang
Journal: JAMA Network Open (2024)

Snoring is central to sleep-disordered breathing (SDB), which arises from nocturnal upper airway resistance. Habitual snoring is associated with cognitive and behavioral problems in young children, but less is known about these associations in adolescents.
Symptom Shifting From Nonsuicidal Self-Injury to Substance Use and Borderline Personality Pathology
Authors: Annekatrin Steinhoff, Marialuisa Cavelti, Julian Koenig, Corinna Reichl, Michael Kaess
Journal: JAMA Network Open (2024)

A decline in nonsuicidal self-injury (NSSI) behavior is often viewed as an indication of mental health improvement when treating adolescents and young adults with borderline personality pathology. However, evidence shows that an initial decrease in NSSI behavior does not always signal recovery, and potential symptom shifting needs to be considered.
Perceived Mistreatment and Professional Identity of Medical Students in China
Authors: Xuanxuan Ma, Ziyue Shen, Ruilian Xiao, Hongbin Wu
Journal: JAMA Network Open (2024)

Mistreatment is a common experience among medical students, with various negative consequences of such perceived mistreatment reported. However, few large-scale studies have investigated the association between perceived mistreatment and the formation of medical students' professional identities.
Catastrophic Health Expenditures for In-State and Out-of-State Abortion Care
Authors: Ortal Wasser, Lauren J. Ralph, Shelly Kaller, M. Antonia Biggs
Journal: JAMA Network Open (2024)

Most US individuals who access abortion care pay out of pocket due to insurance coverage restrictions on abortion. More research is needed on the financial and psychological burdens of abortion seeking, particularly for those traveling across state lines for care.
Oral LPCN 1148 improves sarcopenia and hepatic encephalopathy in male patients with cirrhosis: A randomized, placebo-controlled phase 2 trial
Authors: Benjamin J. Bruno, Joshua C. Weavil, Jonathan Ogle, Nachiappan Chidambaram, Elizabeth J. Carey, Christopher J. Danford, Zarchary P. Fricker, Joseph S. Galati, William M. Lee, Parvez S. Mantry, Kirti Shetty, Anthony DelConte, Mahesh V. Patel, Jennifer C. Lai, Arun J. Sanyal
Journal: Hepatology (2024)

Sarcopenia is highly prevalent in patients with liver cirrhosis and is associated with adverse clinical outcomes including hepatic encephalopathy (HE). Androgen receptor agonists, ARAs, can address these conditions through multimodal mechanisms of action, however their safety and efficacy in patients with cirrhosis have not been well established.
Juvenile xanthogranuloma underneath a toenail: an unusual localization
Authors: Xiaoting Song, Hang Li, Shuxia Yang
Journal: British Journal of Dermatology (2024)

Various subungual tumours can cause nail deformities in children; however, juvenile xanthogranuloma (JXG) is rare. We show an image of a chronic subungual mass in a child, finally diagnosed with JXG according to the histopathology. The case warns us that if a nail deformity with a yellow discoloration is observed in a young child, subungual JXG should be considered as a differential diagnosis.
Tailoring Carrier-Free Nanoparticles based on Natural Small Molecule Assembly for Synergistic Anti-tumor Efficacy
Authors: Di Wu, Bin Zhou, Ying Liu, Xiao Zhu, Bin Li, Hongshan Liang
Journal: Asian Journal of Pharmaceutical Sciences (2024)

Interfacial modular assemblies of versatile polyphenols have attracted widespread interest in surface and materials engineering. In this study, natural polyphenol (tannic acid, TA) and nobiletin (NOB) can directly form binary carrier-free spherical nanoparticles (NT NPs) through synergistically driven by a variety of interactions (such as hydrogen bonding, oxidative reactions, etc.). The synthesis involves polyphenolic deposition on hydrophobic NOB nanoaggregates, followed by in situ oxidative self-polymerization. Interestingly, the assembled NT NPs exhibit controllable and dynamic changes in particle size during the initial stage. Ultimately, uniform and spherical NT NPs appear stable, with high loading capability, enabling incorporated NOB to preserve their function. Furthermore, in vitro evaluations demonstrate that the rational combination of polyphenol module and NOB can induce apoptosis and inhibit tumor metastasis for both lung cancer H1299 and human fibrosarcoma HT1080 cell lines. Notably, the optimized NT48 NPs were then verified in vivo experiments to achieve a promising synergistic anti-tumor efficacy. These findings not only provide new opportunities for the streamlined and sensible engineering of future polyphenol-based biomaterials, but also open up new prospects for the design of small-molecule nature phytochemicals.
The Rise of Cochlear Gene Therapy
Authors: Lukas D. Landegger, Ellen Reisinger, François Lallemend, Steffen R. Hage, Dirk Grimm, Christopher R. Cederroth
Journal: Molecular Therapy (2024)

Recent evidence provides strong support for the safe and effective use of gene therapy in humans with hearing loss. By means of a single local injection of a set of adeno-associated virus (AAV) vectors, hearing was partially restored in several children with neurosensory nonsyndromic autosomal recessive deafness 9 (DFNB9), harboring variants in the OTOF gene. Current research focuses on refining endoscopic and transmastoid injection procedures to reduce risks of side effects, as emerging evidence suggests bidirectional fluid exchanges between the ear and the brain. Moreover, gene editing approaches and novel AAV capsids are successfully tested in animal models and will likely lead to enhanced targeting of the cochlea. Here, we cover the recent advances in cochlear gene therapy, provide an overview of the translational potential of these new approaches for existing and future clinical trials, and highlight the translational implications that remain to be determined for their application in humans.Graphical abstract
Long-Term Safety and Efficacy of the Fully Human CAR-T Therapy CT103A in Relapsed/Refractory Multiple Myeloma
Authors: Qiuxia Yu, Di Wang, Zhe Li, Ning An, Chunhui Li, Yuhan Bao, Xinyu Wen, Xiaolu Long, Jue Wang, Lijun Jiang, Wei Mu, Peiling Zhang, Chang Shu, Huan Ye, Hongyu Gui, Songbai Cai, Guang Hu, Wen Wang, Aihua Du, Chunrui Li
Journal: Molecular Therapy (2024)