tbuckley/cabot-search huggingface dataset:
Tumor necrosis factor α promotes clonal dominance of <i>KIT</i> D816V+ cells in mastocytosis: role of survivin and impact on prognosis
Authors: Georg Greiner, Nadine Witzeneder, Klara Klein, Simone Tangermann, Petra Kodajova, Eva Jaeger, Franz Ratzinger, Marlene C. Gerner, Mohamad Jawhar, Sigrid Baumgartner, Karin Fruehwirth, Klaus G. Schmetterer, Johannes Zuber, Karoline V. Gleixner, Matthias Mayerhofer, Ilse Schwarzinger, Ingrid Simonitsch-Klupp, Harald Esterbauer, Constance Baer, Wencke Walter, Manja Meggendorfer, Robert Strassl, Torsten Haferlach, Karin Hartmann, Lukas Kenner, Wolfgang R. Sperr, Andreas Reiter, Veronika Sexl, Michel Arock, Peter Valent, Gregor Hoermann
Journal: Blood (2023)
Tackling Esophageal Squamous Cell Carcinoma with ITFn‐Pt(IV): A Novel Fusion of PD‐L1 Blockade, Chemotherapy, and T‐cell Activation
Authors: Qi Xin, Daji Wang, Shenghui Wang, Lirong Zhang, Qian Liang, Xiyun Yan, Kelong Fan, Bing Jiang
Journal: Advanced Healthcare Materials (2023)

PD-1/PD-L1 blockade immunotherapy has gained approval for the treatment of a diverse range of tumors; however, its efficacy is constrained by the insufficient infiltration of T lymphocytes into the tumor microenvironment, resulting in suboptimal patient responses. Here, a pioneering immunotherapy ferritin nanodrug delivery system denoted as ITFn-Pt(IV) is introduced. This system orchestrates a synergistic fusion of PD-L1 blockade, chemotherapy, and T-cell activation, aiming to augment the efficacy of tumor immunotherapy. Leveraging genetic engineering approach and temperature-regulated channel-based drug loading techniques, the architecture of this intelligent responsive system is refined. It is adept at facilitating the precise release of T-cell activating peptide Tα1 in the tumor milieu, leading to an elevation in T-cell proliferation and activation. The integration of PD-L1 nanobody KN035 ensures targeted engagement with tumor cells and mediates the intracellular delivery of the encapsulated Pt(IV) drugs, culminating in immunogenic cell death and the subsequent dendritic cell maturation. Employing esophageal squamous cell carcinoma (ESCC) as tumor model, the potent antitumor efficacy of ITFn-Pt(IV) is elucidated, underscored by augmented T-cell infiltration devoid of systemic adverse effects. These findings accentuate the potential of ITFn-Pt(IV) for ESCC treatment and its applicability to other malignancies resistant to established PD-1/PD-L1 blockade therapies.
Experimental structure based drug design (SBDD) applications for anti‐leishmanial drugs: A paradigm shift?
Authors: Miguel Marín, Marta López, Laura Gallego‐Yerga, Raquel Álvarez, Rafael Peláez
Journal: Medicinal Research Reviews (2023)

Leishmaniasis is a group of neglected tropical diseases caused by at least 20 species of Leishmania protozoa, which are spread by the bite of infected sandflies. There are three main forms of the disease: cutaneous leishmaniasis (CL, the most common), visceral leishmaniasis (VL, also known as kala-azar, the most serious), and mucocutaneous leishmaniasis. One billion people live in areas endemic to leishmaniasis, with an annual estimation of 30,000 new cases of VL and more than 1 million of CL. New treatments for leishmaniasis are an urgent need, as the existing ones are inefficient, toxic, and/or expensive. We have revised the experimental structure-based drug design (SBDD) efforts applied to the discovery of new drugs against leishmaniasis. We have grouped the explored targets according to the metabolic pathways they belong to, and the key achieved advances are highlighted and evaluated. In most cases, SBDD studies follow high-throughput screening campaigns and are secondary to pharmacokinetic optimization, due to the majoritarian belief that there are few validated targets for SBDD in leishmaniasis. However, some SBDD strategies have significantly contributed to new drug candidates against leishmaniasis and a bigger number holds promise for future development.
Reversible Intracellular Gelation of MCF10A Cells Enables Programmable Control Over 3D Spheroid Growth
Authors: Delaney L. McNally, Laura J. Macdougall, Bruce E. Kirkpatrick, Chima V. Maduka, Timothy E. Hoffman, Benjamin D. Fairbanks, Christopher N. Bowman, Sabrina L. Spencer, Kristi S. Anseth
Journal: Advanced Healthcare Materials (2023)

Abstract In nature, some organisms survive extreme environments by inducing a biostatic state wherein cellular contents are effectively vitrified. Recently, a synthetic biostatic state in mammalian cells is achieved via intracellular network formation using bio‐orthogonal strain‐promoted azide‐alkyne cycloaddition (SPAAC) reactions between functionalized poly(ethylene glycol) (PEG) macromers. In this work, the effects of intracellular network formation on a 3D epithelial MCF10A spheroid model are explored. Macromer‐transfected cells are encapsulated in Matrigel, and spheroid area is reduced by ≈50% compared to controls. The intracellular hydrogel network increases the quiescent cell population, as indicated by increased p21 expression. Additionally, bioenergetics (ATP/ADP ratio) and functional metabolic rates are reduced. To enable reversibility of the biostasis effect, a photosensitive nitrobenzyl‐containing macromer is incorporated into the PEG network, allowing for light‐induced degradation. Following light exposure, cell state, and proliferation return to control levels, while SPAAC‐treated spheroids without light exposure (i.e., containing intact intracellular networks) remain smaller and less proliferative through this same period. These results demonstrate that photodegradable intracellular hydrogels can induce a reversible slow‐growing state in 3D spheroid culture.
<i>Enteromorpha Prolifera</i> Polysaccharide‐Derived Injectable Hydrogel for Fast Intraoperative Hemostasis and Accelerated Postsurgical Wound Healing Following Tumor Resection
Authors: Fei Jiang, Luxi Li, Yu Tian, Yun Su, Tiange Zhao, Ruyi Ren, Zhe Chi, Chenguang Liu
Journal: Advanced Healthcare Materials (2023)

Intraoperative bleeding and delayed postsurgical wound healing caused by persistent inflammation can increase the risk of tumor recurrence after surgical resection. To address these issues, Enteromorpha prolifera polysaccharide (PEP) with intrinsic potentials for hemostasis and wound healing, is chemically modified into aldehyde-PEP and hydrazine-PEP. Thereby, an injectable double-network hydrogel (OPAB) is developed via forming dual dynamic bonding of acylhydrazone bonds between the decorated aldehyde and hydrazine groups and hydrogen bonds between hydroxyl groups between boric acid and PEP skeletons. The OPAB exhibits controllable shape-adaptive gelation (35.0 s), suitable mechanical properties, nonstimulating self-healing (60 s), good wet tissue adhesion (30.9 kPa), and pH-responsive biodegradability. For in vivo models, owing to these properties, OPAB can achieve rapid hemostasis within 30 s for the liver hemorrhage, and readily loading of curcumin nanoparticles to remarkably accelerate surgical wound closure by alleviating inflammation, re-epithelialization, granulation tissue formation, and collagen deposition. Overall, this multifunctional injectable hydrogel is a promising material that facilitates simultaneous intraoperative hemorrhage and postsurgical wound repair, holding significant potential in the clinical managements of bleeding and surgical wounds for tumor resection.
Injectable Radiopaque Hyaluronic Acid Granular Hydrogels for Intervertebral Disc Repair
Authors: Victoria G. Muir, Matthew Fainor, Brianna S. Orozco, Rachel L. Hilliard, Madeline Boyes, Harvey E. Smith, Robert L. Mauck, Thomas P. Schaer, Jason A. Burdick, Sarah E. Gullbrand
Journal: Advanced Healthcare Materials (2023)

Injectable hydrogels offer minimally-invasive treatment options for degenerative disc disease, a prevalent condition affecting millions annually. Many hydrogels explored for intervertebral disc (IVD) repair suffer from weak mechanical integrity, migration issues, and expulsion. To overcome these limitations, an injectable and radiopaque hyaluronic acid granular hydrogel is developed. The granular structure provides easy injectability and low extrusion forces, while the radiopacity enables direct visualization during injection into the disc and non-invasive monitoring after injection. The radiopaque granular hydrogel is injected into rabbit disc explants to investigate restoration of healthy disc mechanics following needle puncture injury ex vivo and then delivered in a minimally-invasive manner into the intradiscal space in a clinically-relevant in vivo large animal goat model of IVD degeneration initiated through degradation by chondroitinase. The radiopaque granular hydrogel successfully halted loss of disc height due to degeneration. Further, the hydrogel not only enhanced proteoglycan content and reduced collagen content in the nucleus pulposus (NP) region compared to degenerative discs, but also helped to maintain the structural integrity of the disc and promote healthy segregation of the NP and annulus fibrosus regions. Overall, this study demonstrates the great potential of an injectable radiopaque granular hydrogel for treatment of degenerative disc disease.
Performance of Topology Tests under Extreme Selection Bias
Authors: Etai Markowski, Edward Susko
Journal: Molecular Biology and Evolution (2023)

Abstract Tree tests like the Kishino–Hasegawa (KH) test and chi-square test suffer a selection bias that tests like the Shimodaira–Hasegawa (SH) test and approximately unbiased test were intended to correct. We investigate tree-testing performance in the presence of severe selection bias. The SH test is found to be very conservative and, surprisingly, its uncorrected analog, the KH test has low Type I error even in the presence of extreme selection bias, leading to a recommendation that the SH test be abandoned. A chi-square test is found to usually behave well and but to require correction in extreme cases. We show how topology testing procedures can be used to get support values for splits and compare the likelihood-based support values to the approximate likelihood ratio test (aLRT) support values. We find that the aLRT support values are reasonable even in settings with severe selection bias that they were not designed for. We also show how they can be used to construct tests of topologies and, in doing so, point out a multiple comparisons issue that should be considered when looking at support values for splits.
Treatment outcomes of complement protein C5 inhibition in 509 UK patients with paroxysmal nocturnal hemoglobinuria
Authors: Richard J. Kelly, Matthew Holt, Jennifer Vidler, Louise M. Arnold, Joanna Large, Briony Forrest, Catherine Barnfield, Alexandra Pike, Morag Griffin, Talha Munir, Petra Muus, Sateesh K. Nagumantry, Abraham Varghese, John R. Davies, Roochi Trikha, Austin G. Kulasekararaj, Lindsay Mitchell, Shreyans Gandhi
Journal: Blood (2023)
Type 1 VWD classification revisited: novel insights from combined analysis of the LoVIC and WiN studies
Authors: Ferdows Atiq, Robin Blok, Calvin B. van Kwawegen, Dearbhla Doherty, Michelle Lavin, Johanna G. van der Bom, Niamh M. O'Connell, Joke de Meris, Kevin Ryan, Saskia E. M. Schols, Mary Byrne, Floor C. J. I. Heubel-Moenen, Karin P. M. van Galen, Roger J. S. Preston, Marjon H. Cnossen, Karin Fijnvandraat, Ross I. Baker, Karina Meijer, Paula James, Jorge Di Paola, Jeroen Eikenboom, Frank W. G. Leebeek, James S. O'Donnell
Journal: Blood (2023)

Abstract There is significant ongoing debate regarding type 1 von Willebrand disease (VWD) defintion. Previous guidelines recommended patients with von Willebrand factor (VWF) levels &amp;lt;30 IU/dL be diagnosed type 1 VWD, whereas patients with significant bleeding and VWF levels from 30 to 50 IU/dL be diagnosed with low VWF. To elucidate the relationship between type 1 VWD and low VWF in the context of age-induced increases in VWF levels, we combined data sets from 2 national cohort studies: 162 patients with low VWF from the Low VWF in Ireland Cohort (LoVIC) and 403 patients with type 1 VWD from the Willebrand in The Netherlands (WiN) studies. In 47% of type 1 VWD participants, VWF levels remained &amp;lt;30 IU/dL despite increasing age. Conversely, VWF levels increased to the low VWF range (30-50 IU/dL) in 30% and normalized (&amp;gt;50 IU/dL) in 23% of type 1 VWD cases. Crucially, absolute VWF antigen (VWF:Ag) levels and increase of VWF:Ag per year overlapped between low VWF and normalized type 1 VWD participants. Moreover, multiple regression analysis demonstrated that VWF:Ag levels in low VWF and normalized type 1 VWD patients would not have been different had they been diagnosed at the same age (β = 0.00; 95% confidence interval, −0.03 to 0.04). Consistently, no difference was found in the prevalence of VWF sequence variants; factor VIII activity/VWF:Ag or VWF propeptide/VWF:Ag ratios; or desmopressin responses between low VWF and normalized type 1 VWD patients. In conclusion, our findings demonstrate that low VWF does not constitute a discrete clinical or pathological entity. Rather, it is part of an age-dependent type 1 VWD evolving phenotype. Collectively, these data have important implications for future VWD classification criteria.
Venous thromboembolism risk is lower in patients with atopic dermatitis than other immune-mediated inflammatory diseases: A retrospective, observational, comparative cohort study using US claims data
Authors: Joseph F. Merola, Brennan Ertmer, Huifang Liang, Xiaomeng Yue, Sarah Ofori, Whitney Krueger
Journal: Journal of the American Academy of Dermatology (2023)

Background Certain immune-mediated inflammatory diseases (IMIDs) may increase patients' risk for venous thromboembolisms (VTEs), yet how atopic dermatitis (AD) influences VTE risk remains unclear. Objective Describe VTE incidence in patients with AD compared with other IMIDs and unaffected, AD-matched controls. Methods This retrospective, observational, comparative cohort study used Optum® Clinformatics® United States claims data (2010–2019) of adults with AD, rheumatoid arthritis (RA), Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PsO), psoriatic arthritis (PsA), or ankylosing spondylitis (AS). Unaffected control patients were matched 1:1 with patients with AD. Results Of 2,061,222 patients with IMIDs, 1,098,633 had AD. Patients with AD had a higher VTE incidence (95% CI) than did unaffected, AD-matched controls (0.73 [0.72–0.74] vs 0.59 [0.58–0.60] cases/100 person-years). When controlling for baseline VTE risk factors, however, AD was not associated with increased VTE risk (HR 0.96 [0.90–1.02]). VTE risk was lower in patients with AD versus RA, UC, CD, AS, or PsA; VTE risk was similar to patients with PsO. Limitations Disease activity and severity were not accounted for. Conclusion AD did not increase VTE risk when accounting for underlying risk factors. AD was associated with lower VTE risk compared with several rheumatologic and gastrointestinal IMIDs.
Dual-crosslinking immunostimulatory hydrogel synchronously suppresses pancreatic fistula and pancreatic cancer relapse post-resection
Authors: Ruizhi Zhao, Qiuqun Xiao, Yuanyuan Wu, Weiqi Zhang, Jiale Liu, Yinghua Zeng, Jie Zhan, Yanbin Cai, Chihua Fang
Journal: Biomaterials (2023)
Systematic analysis of Mendelian disease-associated gene variants reveals new classes of cancer-predisposing genes
Authors: Seulki Song, Youngil Koh, Seokhyeon Kim, Sang Mi Lee, Hyun Uk Kim, Jung Min Ko, Se-Hoon Lee, Sung-Soo Yoon, Solip Park
Journal: Genome Medicine (2023)

Abstract Background Despite the acceleration of somatic driver gene discovery facilitated by recent large-scale tumor sequencing data, the contribution of inherited variants remains largely unexplored, primarily focusing on previously known cancer predisposition genes (CPGs) due to the low statistical power associated with detecting rare pathogenic variant-phenotype associations. Methods Here, we introduce a generalized log-regression model to measure the excess of pathogenic variants within genes in cancer patients compared to control samples. It aims to measure gene-level cancer risk enrichment by collapsing rare pathogenic variants after controlling the population differences across samples. Results In this study, we investigate whether pathogenic variants in Mendelian disease-associated genes (OMIM genes) are enriched in cancer patients compared to controls. Utilizing data from PCAWG and the 1,000 Genomes Project, we identify 103 OMIM genes demonstrating significant enrichment of pathogenic variants in cancer samples (FDR 20%). Through an integrative approach considering three distinct properties, we classify these CPG-like OMIM genes into four clusters, indicating potential diverse mechanisms underlying tumor progression. Further, we explore the function of PAH (a key metabolic enzyme associated with Phenylketonuria), the gene exhibiting the highest prevalence of pathogenic variants in a pan-cancer (1.8%) compared to controls (0.6%). Conclusions Our findings suggest a possible cancer progression mechanism through metabolic profile alterations. Overall, our data indicates that pathogenic OMIM gene variants contribute to cancer progression and introduces new CPG classifications potentially underpinning diverse tumorigenesis mechanisms.
Multiomics analysis reveals metabolic subtypes and identifies diacylglycerol kinase α (DGKA) as a potential therapeutic target for intrahepatic cholangiocarcinoma
Authors: Weiren Liu, Huqiang Wang, Qianfu Zhao, Chenyang Tao, Weifeng Qu, Yushan Hou, Run Huang, Zimei Sun, Guiqi Zhu, Xifei Jiang, Yuan Fang, Jun Gao, Xiaoling Wu, Zhixiang Yang, Rongyu Ping, Jiafeng Chen, Rui Yang, Tianhao Chu, Jian Zhou, Jia Fan, Zheng Tang, Dong Yang, Yinghong Shi
Journal: Cancer Communications (2023)

Abstract Background Intrahepatic cholangiocarcinoma (iCCA) is a highly heterogeneous and lethal hepatobiliary tumor with few therapeutic strategies. The metabolic reprogramming of tumor cells plays an essential role in the development of tumors, while the metabolic molecular classification of iCCA is largely unknown. Here, we performed an integrated multiomics analysis and metabolic classification to depict differences in metabolic characteristics of iCCA patients, hoping to provide a novel perspective to understand and treat iCCA. Methods We performed integrated multiomics analysis in 116 iCCA samples, including whole‐exome sequencing, bulk RNA‐sequencing and proteome analysis. Based on the non‐negative matrix factorization method and the protein abundance of metabolic genes in human genome‐scale metabolic models, the metabolic subtype of iCCA was determined. Survival and prognostic gene analyses were used to compare overall survival (OS) differences between metabolic subtypes. Cell proliferation analysis, 5‐ethynyl‐2'‐deoxyuridine (EdU) assay, colony formation assay, RNA‐sequencing and Western blotting were performed to investigate the molecular mechanisms of diacylglycerol kinase α (DGKA) in iCCA cells. Results Three metabolic subtypes (S1‐S3) with subtype‐specific biomarkers of iCCA were identified. These metabolic subtypes presented with distinct prognoses, metabolic features, immune microenvironments, and genetic alterations. The S2 subtype with the worst survival showed the activation of some special metabolic processes, immune‐suppressed microenvironment and Kirsten rat sarcoma viral oncogene homolog ( KRAS )/AT‐rich interactive domain 1A ( ARID1A ) mutations. Among the S2 subtype‐specific upregulated proteins, DGKA was further identified as a potential drug target for iCCA, which promoted cell proliferation by enhancing phosphatidic acid (PA) metabolism and activating mitogen‐activated protein kinase (MAPK) signaling. Conclusion Via multiomics analyses, we identified three metabolic subtypes of iCCA, revealing that the S2 subtype exhibited the poorest survival outcomes. We further identified DGKA as a potential target for the S2 subtype.
Antitumor efficacy and safety of unedited autologous CD5.CAR T cells in relapsed/refractory mature T-cell lymphomas
Authors: LaQuisa C. Hill, Rayne H. Rouce, Mengfen J. Wu, Tao Wang, Royce Ma, Huimin Zhang, Birju Mehta, Natalia Lapteva, Zhuyong Mei, Tyler S. Smith, Lina Yang, Madhuwanti Srinivasan, Phillip M. Burkhardt, Carlos A. Ramos, Premal Lulla, Martha Arredondo, Bambi Grilley, Helen E. Heslop, Malcolm K. Brenner, Maksim Mamonkin
Journal: Blood (2023)
Toric Monofocal Intraocular Lenses for the Correction of Astigmatism during Cataract Surgery
Authors: Zaina Al-Mohtaseb, W. Allan Steigleman, Seth M. Pantanelli, Charles C. Lin, Kathryn M. Hatch, Jennifer R. Rose-Nussbaumer, Marcony R. Santhiago, Timothy W. Olsen, Stephen J. Kim, Julie M. Schallhorn
Journal: Ophthalmology (2023)
Ensuring Equitable Access to Participation in the Electoral Process: A Policy Brief From the American College of Physicians
Authors: Katelan Cline, David Hilden, Micah Beachy, Jan Carney, Haidn Foster, Austin Hoeg, Matthew Hollon, Cynthia Jumper, Selvam Mascarenhas, Jenny Silberger, Ankita Sagar, Jamar Slocum, Michael Tan, Elham Yousef
Journal: Annals of Internal Medicine (2023)

During the past 2 decades, voter turnout in U.S. presidential elections has ranged from 51.7% to 66.9% of the eligible population. Low voter turnout rates and inequitable electoral institutions, such as gerrymandered districts, can skew policy decisions toward the preferences of a smaller group and further exclude individuals and communities who have been historically marginalized and excluded from decision-making processes. Voting and health are directly connected through the institution of policies by ballot initiative and the election of officials who incorporate health into their platforms. They are also indirectly connected, as civic participation connects persons to their community and empowers them with agency in decision making. In this position paper, the American College of Physicians seeks to inform physicians, medical students, and other health care professionals on the links between electoral processes and health; encourage civic participation; and offer policy recommendations to support safe and equitable access to electoral participation to advance health equity for both patients and health care professionals.
Annals Graphic Medicine - The Heart Tells Its Story
Authors: Naveed Shah
Journal: Annals of Internal Medicine (2023)

Web Exclusives26 December 2023Annals Graphic Medicine - The Heart Tells Its StoryFREENaveed ShahNaveed ShahUniversity of Toledo College of Medicine and Life Sciences, Toledo, Ohio (N.S.)Author, Article, and Disclosure Informationhttps://doi.org/10.7326/G22-0072 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Author, Article, and Disclosure InformationAuthors: Naveed ShahAffiliations: University of Toledo College of Medicine and Life Sciences, Toledo, Ohio (N.S.)Disclosures: The author has reported no disclosures of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G22-0072.Author/Illustrator Information: Naveed Shah is a medical student at the University of Toledo College of Medicine and Life Sciences (e-mail, naveedshah@mail.adelphi.edu).This article was published at Annals.org on 26 December 2023. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics January 2024Volume 177, Issue 1 ePublished: 26 December 2023 Issue Published: January 2024 Copyright & PermissionsCopyright © 2023 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Adoption of Internal Medicine Milestone Ratings and Changes in Bias Against Black, Latino, and Asian Internal Medicine Residents
Authors: Bradley M. Gray, Rebecca S. Lipner, Robert O. Roswell, Alicia Fernandez, Jonathan L. Vandergrift, Marcella Alsan
Journal: Annals of Internal Medicine (2023)

The 2014 adoption of the Milestone ratings system may have affected evaluation bias against minoritized groups.