tbuckley/cabot-search huggingface dataset:
Vascular dementia: From pathobiology to emerging perspectives
Authors: Amy Elizabeth Morgan, Mark Tomás Mc Auley
Journal: Ageing Research Reviews (2024)

Vascular dementia (VaD) is the second most common type of dementia. VaD is synonymous with ageing, and its symptoms place a significant burden on the health and wellbeing of older people. Despite the identification of a substantial number of risk factors for VaD, the pathological mechanisms underpinning this disease remain to be fully elucidated. Consequently, a biogerontological imperative exists to highlight the modifiable lifestyle factors which can mitigate against the risk of developing VaD. This review will critically examine some of the factors which have been revealed to modulate VaD risk. The survey commences by providing an overview of the putative mechanisms which are associated with the pathobiology of VaD. Next, the factors which influence the risk of developing VaD are examined. Finally, emerging treatment avenues including epigenetics, the gut microbiome, and pro-longevity pharmaceuticals are discussed. By drawing this key evidence together, it is our hope that it can be used to inform future experimental investigations in this field.
Dermatoscopic features and potential pitfalls of artificial intelligence–based analysis of benign acral pigmented lesions in Black patients: A multicenter observational study
Authors: Mariela Mitre, Sharif Hosein, Andia Mitri, Nicholas R. Kurtansky, Silvia E. Mancebo, Maira Fonseca, Ashley Keyes Jacobs, Veronica Rotemberg, Michael A. Marchetti
Journal: Journal of the American Academy of Dermatology (2024)
Landscape fire smoke airway exposure impairs respiratory and cardiac function and worsens experimental asthma
Authors: Henry M. Gomez, Tatt J. Haw, Dusan Ilic, Peter Robinson, Chantal Donovan, Amanda J. Croft, Kanth S. Vanka, Ellen Small, Olivia R. Carroll, Richard Y. Kim, Jemma R. Mayall, Tesfalidet Beyene, Thava Palanisami, Doan T.M. Ngo, Graeme R. Zosky, Elizabeth G. Holliday, Megan E. Jensen, Vanessa M. McDonald, Vanessa E. Murphy, Peter G. Gibson, Jay C. Horvat
Journal: Journal of Allergy and Clinical Immunology (2024)

Graphical abstractAbstractBackgroundMillions of people are exposed to landscape fire smoke (LFS) globally, and inhalation of LFS particulate matter (PM) is associated with poor respiratory and cardiovascular outcomes. However, how LFS affects respiratory and cardiovascular function is less well understood.ObjectiveWe aimed to characterize the pathophysiologic effects of representative LFS airway exposure on respiratory and cardiac function and on asthma outcomes.MethodsLFS was generated using a customized combustion chamber. In 8-week-old female BALB/c mice, low (25 μg/m3, 24-hour equivalent) or moderate (100 μg/m3, 24-hour equivalent) concentrations of LFS PM (10 μm and below [PM10]) were administered daily for 3 (short-term) and 14 (long-term) days in the presence and absence of experimental asthma. Lung inflammation, gene expression, structural changes, and lung function were assessed. In 8-week-old male C57BL/6 mice, low concentrations of LFS PM10 were administered for 3 days. Cardiac function and gene expression were assessed.ResultsShort- and long-term LFS PM10 airway exposure increased airway hyperresponsiveness and induced steroid insensitivity in experimental asthma, independent of significant changes in airway inflammation. Long-term LFS PM10 airway exposure also decreased gas diffusion. Short-term LFS PM10 airway exposure decreased cardiac function and expression of gene changes relating to oxidative stress and cardiovascular pathologies.ConclusionsWe characterized significant detrimental effects of physiologically relevant concentrations and durations of LFS PM10 airway exposure on lung and heart function. Our study provides a platform for assessment of mechanisms that underpin LFS PM10 airway exposure on respiratory and cardiovascular disease outcomes.
Lipid nanoparticles for RNA delivery: Self-assembling vs driven-assembling strategies
Authors: Valeria Nele, Virginia Campani, Seyedeh Alia Moosavian, Giuseppe De Rosa
Journal: Advanced Drug Delivery Reviews (2024)

Among non-viral vectors, lipid nanovectors are considered the gold standard for the delivery of RNA therapeutics. The success of lipid nanoparticles for RNA delivery, with three products approved for human use, has stimulated further investigation into RNA therapeutics for different pathologies. This requires decoding the pathological intracellular processes and tailoring the delivery system to the target tissue and cells. The complexity of the lipid nanovectors morphology originates from the assembling of the lipidic components, which can be elicited by various methods able to drive the formation of nanoparticles with the desired organization. In other cases, pre-formed nanoparticles can be mixed with RNA to induce self-assembly and structural reorganization into RNA-loaded nanoparticles. In this review, the most relevant lipid nanovectors and their potentialities for RNA delivery are described on the basis of the assembling mechanism and of the particle architecture.
Aging induces region-specific dysregulation of hormone synthesis in the primate adrenal gland
Authors: Qiaoran Wang, Xuebao Wang, Beibei Liu, Shuai Ma, Feng Zhang, Shuhui Sun, Yaobin Jing, Yanling Fan, Yingjie Ding, Muzhao Xiong, Jiaming Li, Qiaocheng Zhai, Yandong Zheng, Chengyu Liu, Gang Xu, Jiayin Yang, Si Wang, Jinlin Ye, Juan Carlos Izpisua Belmonte, Jing Qu, Guang-Hui Liu, Weiqi Zhang
Journal: Nature Aging (2024)
Towards a general-purpose foundation model for computational pathology
Authors: Richard J. Chen, Tong Ding, Ming Y. Lu, Drew F. K. Williamson, Guillaume Jaume, Andrew H. Song, Bowen Chen, Andrew Zhang, Daniel Shao, Muhammad Shaban, Mane Williams, Lukas Oldenburg, Luca L. Weishaupt, Judy J. Wang, Anurag Vaidya, Long Phi Le, Georg Gerber, Sharifa Sahai, Walt Williams, Faisal Mahmood
Journal: Nature Medicine (2024)
A visual-language foundation model for computational pathology
Authors: Ming Y. Lu, Bowen Chen, Drew F. K. Williamson, Richard J. Chen, Ivy Liang, Tong Ding, Guillaume Jaume, Igor Odintsov, Long Phi Le, Georg Gerber, Anil V. Parwani, Andrew Zhang, Faisal Mahmood
Journal: Nature Medicine (2024)
Key Performance Indicators and Metrics for the Implementation of an Oral Chemotherapy Adherence Program
Authors: Benyam Muluneh, James B. Collins, Brian Lam, Emily Mackler, Jennifer Elston Lafata
Journal: Journal of the National Comprehensive Cancer Network (2024)

Background: Oral anticancer agents (OAAs) transformed cancer care for patients, extending survival and delaying progression in certain cases. There are multiple pharmacy-driven models to improve patient knowledge and adherence to OAAs. However, a lack of measurable key performance indicators (KPIs) has limited the adoption, implementation, and maintenance of these models. The objective of this study was to identify a set of KPIs, their metrics, and the target values that indicated improved patient care through an OAA adherence program. Methods: A literature review was conducted to identify an initial list of defined KPIs, metrics of the KPIs, and targets for success. We assembled an advisory panel of clinicians (n=9), administrators (n=7), and patients (n=2) from across an academic and affiliated community cancer center to gauge agreement on identified KPIs for use within a structured adherence intervention. We used a Qualtrics survey consisting of questions measured using a 5-point Likert scale response that ranged from 1 (strongly disagree) to 5 (strongly agree) and a subsequent consensus-building discussion with the advisory panel to identify agreeability with the definitions, metrics, and targets of identified KPIs. Results: Eleven KPIs were identified: (1) time to intended OAA initiation; (2) adherence rate during active treatment; (3) adverse events; (4) medication-related financial toxicity; (5) patient satisfaction; (6) treatment-related emergency department visits; (7) treatment-related hospital admissions; (8) proportion of patients with adherence, toxicity, and financial barriers assessed; (9) proportion of patients referred to social work; (10) time spent by patient in each phase of care as defined by the intervention’s standard operating procedure; and (11) revenue generated by billing for service. Conclusions: This study identified 11 KPIs that can be used in evaluating the success of an OAA adherence program. Use of these KPIs will be piloted after formal implementation of the program in both academic and community cancer centers.
Expression of HIF1α in intestinal epithelium restricts arthritis inflammation by inhibiting RIPK3-induced cell death machinery
Authors: Pang Lyu, Jinming Wen, Wenshuo Zhang, Ning Liu, Iris Stolzer, Andreas Gießl, Yewei Jia, Daniele Mauro, Fulin Zhang, Francesco Ciccia, Didier Soulat, Claudia Günther, Georg Schett, Aline Bozec
Journal: Annals of the Rheumatic Diseases (2024)

To investigate the mechanism by which intestinal epithelial cell (IEC) death induces arthritis.
Efficacy and safety of pharmacological treatment of psoriatic arthritis: a systematic literature research informing the 2023 update of the EULAR recommendations for the management of psoriatic arthritis
Authors: Andreas Kerschbaumer, Josef S Smolen, Ricardo J O Ferreira, Heidi Bertheussen, Xenofon Baraliakos, Daniel Aletaha, Dennis G McGonagle, Désirée van der Heijde, Iain B McInnes, Bente Appel Esbensen, Kevin L Winthrop, Wolf-Henning Boehncke, Jan W Schoones, Laure Gossec
Journal: Annals of the Rheumatic Diseases (2024)

To obtain an overview of recent evidence on efficacy and safety of pharmacological treatments in psoriatic arthritis (PsA).
Algorithm Training and Testing for a Nonendoscopic Barrett’s Esophagus Detection Test in Prospective Multicenter Cohorts
Authors: Prasad G Iyer, Seth W Slettedahl, Douglas W Mahoney, Maria Giakoumopoulos, Marilyn C Olson, Martin Krockenberger, William R Taylor, Patrick Foote, Calise Berger, Cadman Leggett, Tsung-Teh Wu, Eduardo Antpack, Gary W Falk, Gregory G Ginsberg, Julian A Abrams, Charles J Lightdale, Francisco Ramirez, Allon Kahn, Herbert Wolfsen, Vani Konda, Arvind J Trindade, John B Kisiel
Journal: Clinical Gastroenterology and Hepatology (2024)

Background & AimsEndoscopic Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) detection is invasive and expensive. Nonendoscopic BE/EAC detection tools are guideline-endorsed alternatives. We previously described a 5-methylated DNA marker (MDM) panel assayed on encapsulated sponge cell collection device (CCD) specimens. We aimed to train a new algorithm using a 3-MDM panel and test its performance in an independent cohort.MethodsAlgorithm training and test samples were from 2 prospective multicenter cohorts. All BE cases had esophageal intestinal metaplasia (with or without dysplasia/EAC); control subjects had no endoscopic evidence of BE. The CCD procedure was followed by endoscopy. From CCD cell lysates, DNA was extracted, bisulfite treated, and MDMs were blindly assayed. The algorithm was set and locked using cross-validated logistic regression (training set) and its performance was assessed in an independent test set.ResultsTraining (N = 352) and test (N = 125) set clinical characteristics were comparable. The final panel included 3 MDMs (NDRG4, VAV3, ZNF682). Overall sensitivity was 82% (95% CI, 68%–94%) at 90% (79%–98%) specificity and 88% (78%–94%) sensitivity at 84% (70%–93%) specificity in training and test sets, respectively. Sensitivity was 90% and 68% for all long- and short-segment BE, respectively. Sensitivity for BE with high-grade dysplasia and EAC was 100% in training and test sets. Overall sensitivity for nondysplastic BE was 82%. Areas under the receiver operating characteristic curves for BE detection were 0.92 and 0.94 in the training and test sets, respectively.ConclusionsA locked 3-MDM panel algorithm for BE/EAC detection using a nonendoscopic CCD demonstrated excellent sensitivity for high-risk BE cases in independent validation samples. (Clinical trials.gov: NCT02560623, NCT03060642.)Graphical abstract
Endometriosis Is Associated with Higher Healthcare Utilization and Upper Gastrointestinal Symptoms
Authors: Madison Simons, Michael Cline, Ashley Gubbels, Cara King, Anthony Lembo, Stephen Lupe
Journal: Clinical Gastroenterology and Hepatology (2024)

Endometriosis is a chronic inflammatory disease affecting 10%-15% of women, with symptoms including abdominopelvic pain, dysmenorrhea, and menorrhagia. Up to 90% experience gastrointestinal (GI) symptoms including constipation, bloating, and nausea/vomiting.
RSV-related Community COPD Exacerbations and Novel Diagnostics: A Binational Prospective Cohort Study
Authors: Dexter J. Wiseman, Ryan S Thwaites, Andrew I Ritchie, Lydia Finney, Mairi Macleod, Faisal Kamal, Hassan Shahbakhti, Lisa H. van Smoorenburg, Huib A. Kerstjens, Joanne Wildenbeest, Deniz Öner, Jeroen Aerssens, Guy Berbers, Rutger Schepp, Ashley Uruchurtu, Benedikt Ditz, Louis Bont, James P. Allinson, Maarten van den Berge, Gavin C. Donaldson, Peter J. Openshaw, Jadwiga Wedzicha
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Respiratory syncytial virus (RSV) is a common global respiratory virus that is increasingly recognized as a major pathogen in frail older adults and as a cause of chronic obstructive pulmonary disease (COPD) exacerbations. There is no single test for RSV in adults that has acceptable diagnostic accuracy. Trials of RSV vaccines have recently shown excellent safety and efficacy against RSV in older adults; defining the frequency of RSV-related community infections and COPD exacerbations is important for vaccine deployment decisions.
WWP2 Regulates Renal Fibrosis and the Metabolic Reprogramming of Profibrotic Myofibroblasts
Authors: Huimei Chen, Ran You, Jing Guo, Wei Zhou, Gabriel Chew, Nithya Devapragash, Jui Zhi Loh, Loreto Gesualdo, Yanwei Li, Yuteng Jiang, Elisabeth Li Sa Tan, Shuang Chen, Paola Pontrelli, Francesco Pesce, Jacques Behmoaras, Aihua Zhang, Enrico Petretto
Journal: Journal of the American Society of Nephrology (2024)

Key Points WWP2 expression is elevated in the tubulointerstitium of fibrotic kidneys and contributes to CKD pathogenesis and progression. WWP2 uncouples the profibrotic activation and cell proliferation in renal myofibroblasts. WWP2 controls mitochondrial respiration in renal myofibroblasts through the metabolic regulator peroxisome proliferator-activated receptor gamma coactivator 1-alpha. Background Renal fibrosis is a common pathologic end point in CKD that is challenging to reverse, and myofibroblasts are responsible for the accumulation of a fibrillar collagen–rich extracellular matrix. Recent studies have unveiled myofibroblasts' diversity in proliferative and fibrotic characteristics, which are linked to different metabolic states. We previously demonstrated the regulation of extracellular matrix genes and tissue fibrosis by WWP2, a multifunctional E3 ubiquitin–protein ligase. Here, we investigate WWP2 in renal fibrosis and in the metabolic reprograming of myofibroblasts in CKD. Methods We used kidney samples from patients with CKD and WWP2 -null kidney disease mice models and leveraged single-cell RNA sequencing analysis to detail the cell-specific regulation of WWP2 in fibrotic kidneys. Experiments in primary cultured myofibroblasts by bulk-RNA sequencing, chromatin immunoprecipitation sequencing, metabolomics, and cellular metabolism assays were used to study the metabolic regulation of WWP2 and its downstream signaling. Results The tubulointerstitial expression of WWP2 was associated with fibrotic progression in patients with CKD and in murine kidney disease models. WWP2 deficiency promoted myofibroblast proliferation and halted profibrotic activation, reducing the severity of renal fibrosis in vivo . In renal myofibroblasts, WWP2 deficiency increased fatty acid oxidation and activated the pentose phosphate pathway, boosting mitochondrial respiration at the expense of glycolysis. WWP2 suppressed the transcription of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a metabolic mediator of fibrotic response, and pharmacologic inhibition of PGC-1 α partially abrogated the protective effects of WWP2 deficiency on myofibroblasts. Conclusions WWP2 regulates the metabolic reprogramming of profibrotic myofibroblasts by a WWP2-PGC-1 α axis, and WWP2 deficiency protects against renal fibrosis in CKD.
Pulmonary Hypertension in Idiopathic Interstitial Pneumonia Is Associated with Small Vessel Pruning
Authors: Eileen M. Harder, Fereidoun Abtin, Pietro Nardelli, Adam Brownstein, Richard N. Channick, George R. Washko, Jonathan Goldin, Raúl San José Estépar, Farbod N. Rahaghi, Rajan Saggar
Journal: American Journal of Respiratory and Critical Care Medicine (2024)
Increased incidence of thyroid, renal, lung, melanoma, bladder, and prostate cancers after diagnosis of primary cutaneous B-cell lymphoma: A Surveillance, Epidemiology, and End Results database analysis
Authors: Lauren Banner, Thomas Z. Rohan, Rachel Zachian, Tyler Gross, Henry Y. Yang, Daniel Joffe, Pierluigi Porcu, Neda Nikbakht
Journal: Journal of the American Academy of Dermatology (2024)
Gastroesophageal Adenocarcinomas With Defective Mismatch Repair: Current Knowledge and Clinical Management
Authors: Matthew R. Strickland, Eric M. Lander, Michael K. Gibson, David H. Ilson, Jaffer A. Ajani, Samuel J. Klempner
Journal: Journal of the National Comprehensive Cancer Network (2024)

Esophageal, gastroesophageal junction, and gastric adenocarcinomas, referred to collectively as gastroesophageal adenocarcinomas (GEAs), are a major cause of global cancer-related mortality. Our increasing molecular understanding has led to the addition of biomarker-directed approaches to defined subgroups and has improved survival in selected patients, such as those with HER2 and Claudin18.2 overexpression. Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer, including GEA, but biomarkers beyond PD-L1 expression are lacking. Mismatch repair deficiency and/or high microsatellite instability (dMMR/MSI-H) is observed in 8% to 22% of nonmetastatic GEA, and 3% to 5% of patients with metastatic disease. dMMR/MSI-H tumors are associated with more favorable prognosis and significant benefit from ICIs, although some heterogeneity exists. The activity of ICIs in advanced dMMR/MSI-H cancer is seen across lines of therapy and should be recommended in the frontline setting. In patients with nonmetastatic dMMR/MSI-H cancer, increasing evidence suggests that perioperative and adjuvant chemotherapy may not provide benefit to the dMMR/MSI-H subgroup. The activity of perioperative chemotherapy-free immune checkpoint regimens in patients with nonmetastatic dMMR/MSI-H cancer is highly promising and underscores the need to identify this unique subgroup. We recommend MMR/MSI testing for all patients with GEA at diagnosis, and review the key rationale and clinical management implications for patient with dMMR/MSI-H tumors across disease stages.
Risk of Cardiovascular Events after Acute Exacerbations of Chronic Obstructive Pulmonary Disease in Patients Receiving Long-Term Low-Dose Azithromycin
Authors: Tommaso Bucci, Dennis Wat, Dilip Nazareth, Sarah Sibley, Dan Wootton, Gregory Y. H. Lip, Freddy Frost
Journal: American Journal of Respiratory and Critical Care Medicine (2024)
CobB-mediated deacetylation of the chaperone CesA regulates <i>Escherichia coli</i> O157:H7 virulence
Authors: Linxing Li, Bin Yang, Jing Wang, Yi Wei, Binbin Xiang, Yutao Liu, Pan Wu, Wanwu Li, Yanling Wang, Xinyu Zhao, Jingliang Qin, Miaomiao Liu, Ruiying Liu, Guozhen Ma, Tian Fu, Min Wang, Bin Liu
Journal: Gut Microbes (2024)

Enterohemorrhagic Escherichia coli (EHEC) O157:H7 is a common food-borne pathogen that can cause acute diseases. Lysine acetylation is a post-translational modification (PTM) that occurs in various prokaryotes and is regulated by CobB, the only deacetylase found in bacteria. Here, we demonstrated that CobB plays an important role in the virulence of EHEC O157:H7 and that deletion of cobB significantly decreased the intestinal colonization ability of bacteria. Using acetylation proteomic studies, we systematically identified several proteins that could be regulated by CobB in EHEC O157:H7. Among these CobB substrates, we found that acetylation at the K44 site of CesA, a chaperone for the type-III secretion system (T3SS) translocator protein EspA, weakens its binding to EspA, thereby reducing the stability of this virulence factor; this PTM ultimately attenuating the virulence of EHEC O157:H7. Furthermore, we showed that deacetylation of the K44 site, which is deacetylated by CobB, promotes the interaction between CesA and EspA, thereby increasing bacterial virulence in vitro and in animal experiments. In summary, we showed that acetylation influences the virulence of EHEC O157:H7, and uncovered the mechanism by which CobB contributes to bacterial virulence based on the regulation of CesA deacetylation.
Drug-regulated CD33-targeted CAR T cells control AML using clinically optimized rapamycin dosing
Authors: Jacob Appelbaum, April E. Price, Kaori Oda, Joy Zhang, Wai-Hang Leung, Giacomo Tampella, Dong Xia, Pauline P.L. So, Sarah K. Hilton, Claudya Evandy, Semanti Sarkar, Unja Martin, Anne-Rachel Krostag, Marissa Leonardi, Daniel E. Zak, Rachael Logan, Paula Lewis, Secil Franke-Welch, Njabulo Ngwenyama, Michael Fitzgerald, Niklas Tulberg, Stephanie Rawlings-Rhea, Rebecca A. Gardner, Kyle Jones, Angelica Sanabria, William Crago, John Timmer, Andrew Hollands, Brendan Eckelman, Sanela Bilic, Jim Woodworth, Adam Lamble, Philip D. Gregory, Jordan Jarjour, Mark Pogson, Joshua A. Gustafson, Alexander Astrakhan, Michael C. Jensen
Journal: Journal of Clinical Investigation (2024)

Chimeric antigen receptor (CAR) designs that incorporate pharmacologic control are desirable, however designs suitable for clinical translation are needed. We designed a fully human, rapamycin-regulated, drug product for targeting CD33+ tumors called dimerization agent regulated immunoreceptor complex (DARIC33). T cell products demonstrated target specific and rapamycin-dependent cytokine release, transcriptional responses, cytotoxicity, and in vivo antileukemic activity in the presence of as little as 1nM rapamycin. Rapamycin withdrawal paused DARIC33-stimulated T cell effector functions, which were restored following re-exposure to rapamycin, demonstrating reversible effector function control. While rapamycin-regulated DARIC33 T cells were highly sensitive to target antigen, CD34+ stem cell colony forming capacity was not impacted. We benchmarked DARIC33 potency relative to CD19 CAR T cells to estimate a T cell dose for clinical testing. In addition, we integrated in vitro and preclinical in vivo drug concentration thresholds for OFF-ON state transitions, as well as murine and human rapamycin pharmacokinetics, to estimate a clinically applicable rapamycin dosing schedule. A phase 1 DARIC33 trial has been initiated (PLAT-08, NCT05105152), with initial evidence of rapamycin-regulated T cell activation and anti-tumor impact. Our findings provide evidence that the DARIC platform exhibits sensitive regulation and potency needed for clinical application to other important immunotherapy targets.
Xevinapant combined with pembrolizumab in patients with advanced, pretreated colorectal and pancreatic cancer: results of the phase 1b/2 CATRIPCA trial
Authors: Allison Voisin, Catherine Terret, Camille Schiffler, Anne-Sophie Bidaux, Hélène Vanacker, Marlène Perrin-Niquet, Maud Barbery, Armelle Vinceneux, Lauriane Eberst, Pierre Stéphan, Gwenaële Garin, Dany Spaggiari, David Pérol, Yenkel Grinberg-Bleyer, Philippe A. Cassier
Journal: Clinical Cancer Research (2024)

Xevinapant is an orally available inhibitor of apoptosis proteins (IAP) inhibitor. Preclinical data suggest that IAP antagonism may synergize with immune checkpoint blockers by modulating the NFκB pathway in immune cells.