tbuckley/cabot-search huggingface dataset:
Electronic Patient-Reported Symptoms After Ambulatory Cancer Surgery
Authors: Jennifer R. Cracchiolo, Amy L. Tin, Melissa Assel, Taylor M. McCready, Cara Stabile, Brett Simon, Sigrid V. Carlsson, Andrew J. Vickers, Vincent Laudone
Journal: JAMA Surgery (2024)

Importance Complex cancer procedures are now performed in the ambulatory surgery setting. Remote symptom monitoring (RSM) with electronic patient-reported outcomes (ePROs) can identify patients at risk for acute hospital encounters. Defining normal recovery is needed to set patient expectations and optimize clinical team responses to manage evolving problems in real time. Objective To describe the patterns of postoperative recovery among patients undergoing ambulatory cancer surgery with RSM using an ePRO platform—the Recovery Tracker. Design, Setting, and Participants In this retrospective cohort study, patients who underwent 1 of 5 of the most common procedures (prostatectomy, nephrectomy, mastectomy, hysterectomy, or thyroidectomy) at the Josie Robertson Surgery Center at Memorial Sloan Kettering Cancer Center from September 2016 to June 2022. Patients completed the Recovery Tracker, a brief ePRO platform assessing symptoms for 10 days after surgery. Data were analyzed from September 2022 to May 2023. Main Outcomes and Measures Symptom severity and interference were estimated by postoperative day and procedure. Results A total of 12 433 patients were assigned 110 936 surveys. Of these patients, 7874 (63%) were female, and the median (IQR) age at surgery was 57 (47-65) years. The survey response rate was 87% (10 814 patients responding to at least 1 of 10 daily surveys). Among patients who submitted at least 1 survey, the median (IQR) number of surveys submitted was 7 (4-8), and each assessment took a median (IQR) of 1.7 (1.2-2.5) minutes to complete. Symptom burden was modest in this population, with the highest severity on postoperative days 1 to 3. Pain was moderate initially and steadily improved. Fatigue was reported by 6120 patients (57%) but was rarely severe. Maximum pain and fatigue responses (very severe) were reported by 324 of 10 814 patients (3%) and 106 of 10 814 patients (1%), respectively. The maximum pain severity (severe or very severe) was highest after nephrectomy (92 of 332 [28%]), followed by mastectomy with reconstruction (817 of 3322 [25%]) and prostatectomy (744 of 3543 [21%]). Nausea (occasionally, frequently, or almost constantly) was common and experienced on multiple days by 1485 of 9300 patients (16%), but vomiting was less common (139 of 10 812 [1%]). Temperature higher than 38 °C was reported by 740 of 10 812 (7%). Severe or very severe shortness of breath was reported by 125 of 10 813 (1%). Conclusions and Relevance Defining detailed postoperative symptom burden through this analysis provides valuable data to inform further implementation and maintenance of RSM programs in surgical oncology patients. These data can enhance patient education, set expectations, and support research to allow iterative improvement of clinical care based on the patient-reported experience after discharge.
What’s VAT All About—The Clue Is in the Genetics
Authors: Sharlene M. Day
Journal: JAMA Cardiology (2024)

White adipose tissue (WAT) is responsible for energy storage. WAT is subdivided into subcutaneous adipose tissue (SAT, approximately 80%-90% of total AT) and visceral adipose tissue (VAT), the latter of which includes both ectopic thoracic and abdominal depots.
Primary osteoarthritis chondrocyte map of chromatin conformation reveals novel candidate effector genes
Authors: Norbert Bittner, Chenfu Shi, Danyun Zhao, James Ding, Lorraine Southam, Diane Swift, Peter Kreitmaier, Mauro Tutino, Odysseas Stergiou, Jackson T S Cheung, Georgia Katsoula, Jenny Hankinson, Jeremy Mark Wilkinson, Gisela Orozco, Eleftheria Zeggini
Journal: Annals of the Rheumatic Diseases (2024)

Osteoarthritis is a complex disease with a huge public health burden. Genome-wide association studies (GWAS) have identified hundreds of osteoarthritis-associated sequence variants, but the effector genes underpinning these signals remain largely elusive. Understanding chromosome organisation in three-dimensional (3D) space is essential for identifying long-range contacts between distant genomic features (e.g., between genes and regulatory elements), in a tissue-specific manner. Here, we generate the first whole genome chromosome conformation analysis (Hi-C) map of primary osteoarthritis chondrocytes and identify novel candidate effector genes for the disease.
Prevalence and Patient Characteristics of Ectodermal Dysplasias in Denmark
Authors: Laura Krogh Herlin, Sigrun A. J. Schmidt, Xenia Buus Hermann, Kirsten Rønholt, Anette Bygum, Annette Schuster, Ulrikke Lei, Mette Mogensen, Gabrielle R. Vinding, Malene Djursby, Hanne Hove, Jenny Blechingberg, Lise Graversen, Trine H. Mogensen, Hans Gjørup, Sinéad M. Langan, Mette Sommerlund
Journal: JAMA Dermatology (2024)

Ectodermal dysplasias constitute a group of rare genetic disorders of the skin and skin appendages with hypodontia, hypotrichosis, and hypohidrosis as cardinal features. There is a lack of population-based research into the epidemiology of ectodermal dysplasias.
John Launer: Troubled by trolls
Authors: John Launer
Journal: BMJ (2024)

Trolls are imaginary creatures in Scandinavian folklore who are dim witted, live far from human company, and are generally unpleasant when encountered.In modern slang the word refers to individuals who make themselves disagreeable on social media by persistently responding to other people's posts in negative ways, ranging from discourtesy to threats and intimidation.If you write for the medical press and try to maintain a social media presence it's almost impossible to avoid trolls.Some topics are guaranteed to bring them out in battalions.
COVID-19 Rebound After VV116 vs Nirmatrelvir-Ritonavir Treatment
Authors: Zhitao Yang, Yu Xu, Ruizhi Zheng, Lei Ye, Gang Lv, Zhujun Cao, Rulai Han, Mian Li, Yuanyue Zhu, Qiuyu Cao, Yi Ding, Jiqiu Wang, Yun Tan, Feng Liu, Dong Wei, Wei Tan, Weiwei Jiang, Jing Sun, Shouyue Sun, Jie Shao, Yang Deng, Weiyi Gao, Weiqing Wang, Ren Zhao, Liping Qiu, Erzhen Chen, Xinxin Zhang, Shengyue Wang, Guang Ning, Yiping Xu, Yufang Bi
Journal: JAMA Network Open (2024)

Importance With the widespread use of anti–SARS-CoV-2 drugs, accumulating data have revealed potential viral load rebound after treatment. Objective To compare COVID-19 rebound after a standard 5-day course of antiviral treatment with VV116 vs nirmatrelvir-ritonavir. Design, Setting, and Participants This is a single-center, investigator-blinded, randomized clinical trial conducted in Shanghai, China. Adult patients with mild-to-moderate COVID-19 and within 5 days of SARS-CoV-2 infection were enrolled between December 20, 2022, and January 19, 2023, and randomly allocated to receive either VV116 or nirmatrelvir-ritonavir. Interventions Participants in the VV116 treatment group received oral 600-mg VV116 tablets every 12 hours on day 1 and 300 mg every 12 hours on days 2 through 5. Participants in the nirmatrelvir-ritonavir treatment group received oral nirmatrelvir-ritonavir tablets with 300 mg of nirmatrelvir plus 100 mg of ritonavir every 12 hours for 5 days. Participants were followed up every other day until day 28 and every week until day 60. Main Outcomes and Measures The primary outcome was viral load rebound (VLR), defined as a half-log increase in viral RNA copies per milliliter compared with treatment completion. Secondary outcomes included a reduction in the cycle threshold value of 1.5 or more, time until VLR, and symptom rebound, defined as an increase of more than 2 points in symptom score compared with treatment completion. The primary outcome and secondary outcomes were analyzed using the full analysis set. Sensitivity analyses were conducted using the per protocol set. Adverse events were analyzed using the safety analysis set. Results The full analysis set included 345 participants (mean [SD] age, 53.2 [16.8] years; 175 [50.7%] were men) who received VV116 (n = 165) or nirmatrelvir-ritonavir (n = 180). Viral load rebound occurred in 33 patients (20.0%) in the VV116 group and 39 patients (21.7%) in the nirmatrelvir-ritonavir group ( P = .70). Symptom rebound occurred in 41 of 160 patients (25.6%) in the VV116 group and 40 of 163 patients (24.5%) in the nirmatrelvir-ritonavir group ( P = .82). Viral whole-genome sequencing of 24 rebound cases revealed the same lineage at baseline and at viral load rebound in each case. Conclusions and Relevance In this randomized clinical trial of patients with mild-to-moderate COVID-19, viral load rebound and symptom rebound were both common after a standard 5-day course of treatment with either VV116 or nirmatrelvir-ritonavir. Prolongation of treatment duration might be investigated to reduce COVID-19 rebound. Trial Registration Chinese Clinical Trial Registry Identifier: ChiCTR2200066811
Hepatic danger signaling triggers TREM2 <sup>+</sup> macrophage induction and drives steatohepatitis via MS4A7-dependent inflammasome activation
Authors: Linkang Zhou, Xiaoxue Qiu, Ziyi Meng, Tongyu Liu, Zhimin Chen, Peng Zhang, Henry Kuang, Tong Pan, You Lu, Ling Qi, David P. Olson, X. Z. Shawn Xu, Y. Eugene Chen, Siming Li, Jiandie D. Lin
Journal: Science Translational Medicine (2024)

Metabolic dysfunction–associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), is an advanced stage of metabolic fatty liver disease. The pathogenic mechanisms of MASH center on hepatocyte injury and the ensuing immune response within the liver microenvironment. Recent work has implicated TREM2 + macrophages in various disease conditions, and substantial induction of TREM2 + NASH-associated macrophages (NAMs) serves as a hallmark of metabolic liver disease. Despite this, the mechanisms through which NAMs contribute to MASH pathogenesis remain poorly understood. Here, we identify membrane-spanning 4-domains a7 (MS4A7) as a NAM-specific pathogenic factor that exacerbates MASH progression in mice. Hepatic MS4A7 expression was strongly induced in mouse and human MASH and associated with the severity of liver injury. Whole-body and myeloid-specific ablation of Ms4a7 alleviated diet-induced MASH pathologies in male mice. We demonstrate that exposure to lipid droplets (LDs), released upon injury of steatotic hepatocytes, triggered NAM induction and exacerbated MASH-associated liver injury in an MS4A7-dependent manner. Mechanistically, MS4A7 drove NLRP3 inflammasome activation via direct physical interaction and shaped disease-associated cell states within the liver microenvironment. This work reveals the LD-MS4A7-NLRP3 inflammasome axis as a pathogenic driver of MASH progression and provides insights into the role of TREM2 + macrophages in disease pathogenesis.
An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations
Authors: Michael Westberg, Yichi Su, Xinzhi Zou, Pinghan Huang, Arjun Rustagi, Jaishree Garhyan, Puja Bhavesh Patel, Daniel Fernandez, Yan Wu, Chenzhou Hao, Chieh-Wen Lo, Marwah Karim, Lin Ning, Aimee Beck, Panatda Saenkham-Huntsinger, Vivian Tat, Aleksandra Drelich, Bi-Hung Peng, Shirit Einav, Chien-Te K. Tseng, Catherine Blish, Michael Z. Lin
Journal: Science Translational Medicine (2024)

Inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M pro ) such as nirmatrelvir (NTV) and ensitrelvir (ETV) have proven effective in reducing the severity of COVID-19, but the presence of resistance-conferring mutations in sequenced viral genomes raises concerns about future drug resistance. Second-generation oral drugs that retain function against these mutants are thus urgently needed. We hypothesized that the covalent hepatitis C virus protease inhibitor boceprevir (BPV) could serve as the basis for orally bioavailable drugs that inhibit SARS-CoV-2 M pro more efficiently than existing drugs. Performing structure-guided modifications of BPV, we developed a picomolar-affinity inhibitor, ML2006a4, with antiviral activity, oral pharmacokinetics, and therapeutic efficacy similar or superior to those of NTV. A crucial feature of ML2006a4 is a derivatization of the ketoamide reactive group that improves cell permeability and oral bioavailability. Last, ML2006a4 was found to be less sensitive to several mutations that cause resistance to NTV or ETV and occur in the natural SARS-CoV-2 population. Thus, anticipatory design can preemptively address potential resistance mechanisms to expand future treatment options against coronavirus variants.
Cortical hyperexcitability in mouse models and patients with amyotrophic lateral sclerosis is linked to noradrenaline deficiency
Authors: Jelena Scekic-Zahirovic, Cristina Benetton, Aurore Brunet, XiaoQian Ye, Evgeny Logunov, Vincent Douchamps, Salim Megat, Virginie Andry, Vanessa Wing Yin Kan, Geoffrey Stuart-Lopez, Johan Gilet, Simon J. Guillot, Sylvie Dirrig-Grosch, Charlotte Gorin, Margaux Trombini, Stéphane Dieterle, Jérôme Sinniger, Mathieu Fischer, Frédérique René, Zeynep Gunes, Pascal Kessler, Luc Dupuis, Pierre-François Pradat, Yannick Goumon, Romain Goutagny, Véronique Marchand-Pauvert, Sabine Liebscher, Caroline Rouaux
Journal: Science Translational Medicine (2024)

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by the death of upper (UMN) and lower motor neurons (LMN) in the motor cortex, brainstem, and spinal cord. Despite decades of research, ALS remains incurable, challenging to diagnose, and of extremely rapid progression. A unifying feature of sporadic and familial forms of ALS is cortical hyperexcitability, which precedes symptom onset, negatively correlates with survival, and is sufficient to trigger neurodegeneration in rodents. Using electrocorticography in the Sod1 G86R and Fus Δ NLS/+ ALS mouse models and standard electroencephalography recordings in patients with sporadic ALS, we demonstrate a deficit in theta-gamma phase-amplitude coupling (PAC) in ALS. In mice, PAC deficits started before symptom onset, and in patients, PAC deficits correlated with the rate of disease progression. Using mass spectrometry analyses of CNS neuropeptides, we identified a presymptomatic reduction of noradrenaline (NA) in the motor cortex of ALS mouse models, further validated by in vivo two-photon imaging in behaving SOD1 G93A and Fus Δ NLS/+ mice, that revealed pronounced reduction of locomotion-associated NA release. NA deficits were also detected in postmortem tissues from patients with ALS, along with transcriptomic alterations of noradrenergic signaling pathways. Pharmacological ablation of noradrenergic neurons with DSP-4 reduced theta-gamma PAC in wild-type mice and administration of a synthetic precursor of NA augmented theta-gamma PAC in ALS mice. Our findings suggest theta-gamma PAC as means to assess and monitor cortical dysfunction in ALS and warrant further investigation of the NA system as a potential therapeutic target.
Lumasiran, Isolated Kidney Transplantation, and Continued Vigilance
Authors: Justine Bacchetta, Stéphanie Clavé, Peggy Perrin, Sandrine Lemoine, Anne-Laure Sellier-Leclerc, Lisa J Deesker
Journal: New England Journal of Medicine (2024)

Although lumasiran targets glycolate oxidase and decreases hepatic oxalate synthesis, systemic oxalate release continues after single-organ kidney transplantation, requiring close follow-up with rigorous hyperhydration.
Identification of transcriptomic signatures associated with glioblastoma recurrence
Authors: Sean E Lawler
Journal: Neuro-Oncology (2024)

Journal Article Corrected proof Identification of transcriptomic signatures associated with glioblastoma recurrence Get access Sean E Lawler Sean E Lawler Department of Pathology and Laboratory Medicine, Legorreta Cancer Center, Brown University, Providence, Rhode Island, USA Corresponding Author: Sean Lawler, PhD, Department of Pathology and Laboratory Medicine, Legorreta Cancer Center, Brown University, Providence, RI 02903, USA (sean_lawler@brown.edu). https://orcid.org/0000-0002-1633-2339 Search for other works by this author on: Oxford Academic PubMed Google Scholar Neuro-Oncology, noae044, https://doi.org/10.1093/neuonc/noae044 Published: 12 March 2024 Article history Published: 12 March 2024 Corrected and typeset: 31 March 2024
Disruption of cyclin D1 degradation leads to the development of mantle cell lymphoma
Authors: Ke Lu, Ming Zhang, Hongyu Qin, Siyu Shen, Haiqing Song, Hua Jiang, Chunxiang Zhang, Guozhi Xiao, Liping Tong, Qing Jiang, Di Chen
Journal: Acta Pharmaceutica Sinica B (2024)

Cyclin D1 has been recognized as an oncogene due to its abnormal upregulation in different types of cancers. Here, we demonstrated that cyclin D1 is SUMOylated, and we identified Itch as a specific E3 ligase recognizing SUMOylated cyclin D1 and mediating SUMO-induced ubiquitination and proteasome degradation of cyclin D1. We generated cyclin D1 mutant mice with mutations in the SUMOylation site, phosphorylation site, or both sites of cyclin D1, and found that double mutant mice developed a Mantle cell lymphoma (MCL)-like phenotype. We showed that arsenic trioxide (ATO) enhances cyclin D1 SUMOylation-mediated degradation through inhibition of cyclin D1 deSUMOylation enzymes, leading to MCL cell apoptosis. Treatment of severe combined immunodeficiency (SCID) mice grafted with MCL cells with ATO resulted in a significant reduction in tumor growth. In this study, we provide novel insights into the mechanisms of MCL tumor development and cyclin D1 regulation and discover a new strategy for MCL treatment.
Glucagon-like peptide-1 receptor agonists rescued diabetic vascular endothelial damage through suppression of aberrant STING signaling
Authors: Xuemin He, Siying Wen, Xixiang Tang, Zheyao Wen, Rui Zhang, Shasha Li, Rong Gao, Jin Wang, Yanhua Zhu, Dong Fang, Ting Li, Ruiping Peng, Zhaotian Zhang, Shiyi Wen, Li Zhou, Heying Ai, Yan Lu, Shaochong Zhang, Guojun Shi, Yanming Chen
Journal: Acta Pharmaceutica Sinica B (2024)

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) protect against diabetic cardiovascular diseases and nephropathy. However, their activity in diabetic retinopathy (DR) remains unclear. Our retrospective cohort study involving 1626 T2DM patients revealed superior efficacy of GLP-1 RAs in controlling DR compared to other glucose-lowering medications, suggesting their advantage in DR treatment. By single-cell RNA-sequencing analysis and immunostaining, we observed a high expression of GLP-1R in retinal endothelial cells, which was down-regulated under diabetic conditions. Treatment of GLP-1 RAs significantly restored the receptor expression, resulting in an improvement in retinal degeneration, vascular tortuosity, avascular vessels, and vascular integrity in diabetic mice. GO and GSEA analyses further implicated enhanced mitochondrial gene translation and mitochondrial functions by GLP-1 RAs. Additionally, the treatment attenuated STING signaling activation in retinal endothelial cells, which is typically activated by leaked mitochondrial DNA. Expression of STING mRNA was positively correlated to the levels of angiogenic and inflammatory factors in the endothelial cells of human fibrovascular membranes. Further investigation revealed that the cAMP-responsive element binding protein played a role in the GLP-1R signaling pathway on suppression of STING signaling. This study demonstrates a novel role of GLP-1 RAs in the protection of diabetic retinal vasculature by inhibiting STING-elicited inflammatory signals.
Pharmacokinetic enhancement of oncolytic virus M1 by inhibiting JAK‒STAT pathway
Authors: Jingyi Tan, Jiayu Zhang, Cheng Hu, Gongwei Wang, Qianyao Ren, Chaoqun Wang, Jia Dan, Zexin Zeng, Jun Hu, Wenbo Zhu, Jiankai Liang, Jing Cai, Ying Liu, Guangmei Yan, Yuan Lin
Journal: Acta Pharmaceutica Sinica B (2024)

Oncolytic viruses (OVs), a group of replication-competent viruses that can selectively infect and kill cancer cells while leaving healthy cells intact, are emerging as promising living anticancer agents. Unlike traditional drugs composed of non-replicating compounds or biomolecules, the replicative nature of viruses confer unique pharmacokinetic properties that require further studies. Despite some pharmacokinetics studies of OVs, mechanistic insights into the connection between OV pharmacokinetics and antitumor efficacy remain vague. Here, we characterized the pharmacokinetic profile of oncolytic virus M1 (OVM) in immunocompetent mouse tumor models and identified the JAK‒STAT pathway as a key modulator of OVM pharmacokinetics. By suppressing the JAK‒STAT pathway, early OVM pharmacokinetics are ameliorated, leading to enhanced tumor-specific viral accumulation, increased AUC and Cmax, and improved antitumor efficacy. Rather than compromising antitumor immunity after JAK‒STAT inhibition, the improved pharmacokinetics of OVM promotes T cell recruitment and activation in the tumor microenvironment, providing an optimal opportunity for the therapeutic outcome of immune checkpoint blockade, such as anti-PD-L1. Taken together, this study advances our understanding of the pharmacokinetic-pharmacodynamic relationship in OV therapy.
An antibiotic-free platform for eliminating persistent Helicobacter pylori infection without disrupting gut microbiota
Authors: Yongkang Lai, Tinglin Zhang, Xiaojing Yin, Chunping Zhu, Yiqi Du, Zhaoshen Li, Jie Gao
Journal: Acta Pharmaceutica Sinica B (2024)

Helicobacter pylori (H. pylori) infection remains the leading cause of gastric adenocarcinoma, and its eradication primarily relies on the prolonged and intensive use of two antibiotics. However, antibiotic resistance has become a compelling health issue, leading to H. pylori eradication treatment failure worldwide. Additionally, the powerlessness of antibiotics against biofilms, as well as intracellular H. pylori and the long-term damage of antibiotics to the intestinal microbiota, have also created an urgent demand for antibiotic-free approaches. Herein, we describe an antibiotic-free, multifunctional copper-organic framework (HKUST-1) platform encased in a lipid layer comprising phosphatidic acid (PA), rhamnolipid (RHL), and cholesterol (CHOL), enveloped in chitosan (CS), and loaded in an ascorbyl palmitate (AP) hydrogel: AP@CS@Lip@HKUST-1. This platform targets inflammatory sites where H. pylori aggregates through electrostatic attraction. Then, hydrolysis by matrix metalloproteinases (MMPs) releases CS-encased nanoparticles, disrupting bacterial urease activity and membrane integrity. Additionally, RHL disperses biofilms, while PA promotes lysosomal acidification and activates host autophagy, enabling clearance of intracellular H. pylori. Furthermore, AP@CS@Lip@HKUST-1 alleviates inflammation and enhances mucosal repair through delayed Cu2+ release while preserving the intestinal microbiota. Collectively, this platform presents an advanced therapeutic strategy for eradicating persistent H. pylori infection without inducing drug resistance.