tbuckley/cabot-search huggingface dataset:
Effectiveness of conservative management versus laparoscopic cholecystectomy in the prevention of recurrent symptoms and complications in adults with uncomplicated symptomatic gallstone disease (C-GALL trial): pragmatic, multicentre randomised controlled trial
Authors: Irfan Ahmed, Jemma Hudson, Karen Innes, Rodolfo Hernández, Katie Gillies, Rebecca Bruce, Victoria Bell, Alison Avenell, Jane Blazeby, Miriam Brazzelli, Seonaidh Cotton, Bernard Croal, Mark Forrest, Graeme MacLennan, Peter Murchie, Samantha Wileman, Craig Ramsay
Journal: BMJ (2023)

Abstract Objective To assess the clinical and cost effectiveness of conservative management compared with laparoscopic cholecystectomy for the prevention of symptoms and complications in adults with uncomplicated symptomatic gallstone disease. Design Parallel group, pragmatic randomised, superiority trial. Setting 20 secondary care centres in the UK. Participants 434 adults (&gt;18 years) with uncomplicated symptomatic gallstone disease referred to secondary care, assessed for eligibility between August 2016 and November 2019, and randomly assigned (1:1) to receive conservative management or laparoscopic cholecystectomy. Interventions Conservative management or surgical removal of the gallbladder. Main outcome measures The primary patient outcome was quality of life, measured by area under the curve, over 18 months using the short form 36 (SF-36) bodily pain domain, with higher scores (range 0-100) indicating better quality of life. Other outcomes included costs to the NHS, quality adjusted life years (QALYs), and incremental cost effectiveness ratio. Results Of 2667 patients assessed for eligibility, 434 were randomised: 217 to the conservative management group and 217 to the laparoscopic cholecystectomy group. By 18 months, 54 (25%) participants in the conservative management arm and 146 (67%) in the cholecystectomy arm had received surgery. The mean SF-36 norm based bodily pain score was 49.4 (standard deviation 11.7) in the conservative management arm and 50.4 (11.6) in the cholecystectomy arm. The SF-36 bodily pain area under the curve up to 18 months did not differ (mean difference 0.0, 95% confidence interval −1.7 to 1.7; P=1.00). Conservative management was less costly (mean difference −£1033, (−$1334; −€1205), 95% credible interval −£1413 to −£632) and QALYs did not differ (mean difference −0.019, 95% credible interval −0.06 to 0.02). Conclusions In the short term (≤18 months), laparoscopic surgery is no more effective than conservative management for adults with uncomplicated symptomatic gallstone disease, and as such conservative management should be considered as an alternative to surgery. From an NHS perspective, conservative management may be cost effective for uncomplicated symptomatic gallstone disease. As costs, complications, and benefits will continue to be incurred in both groups beyond 18 months, future research should focus on longer term follow-up to establish effectiveness and lifetime cost effectiveness and to identify the cohort of patients who should be routinely offered surgery. Trial registration ISRCTN registry ISRCTN55215960 .
Inconsistent definitions of labour progress and over-medicalisation cause unnecessary harm during birth
Authors: Nanna Maaløe, Monica Lauridsen Kujabi, Nina Olsén Nathan, Morten Skovdal, Brenda Sequeira Dmello, Susan Wray, Thomas van den Akker, Natasha Housseine
Journal: BMJ (2023)

<b>Nanna Maaløe and colleagues</b> argue that resource challenges, unclear and outdated clinical practice guidelines, and lack of women's perspectives lead to overdiagnosis and overtreatment of prolonged labour
Differential requirements for CD4+ T cells in the efficacy of the anti-PD-1+LAG-3 and anti-PD-1+CTLA-4 combinations in melanoma flank and brain metastasis models
Authors: Manali S Phadke, Jiannong Li, Zhihua Chen, Paulo C Rodriguez, Jessica K Mandula, Lilit Karapetyan, Peter A Forsyth, Y Ann Chen, Keiran S M Smalley
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Although the anti-PD-1+LAG-3 and the anti-PD-1+CTLA-4 combinations are effective in advanced melanoma, it remains unclear whether their mechanisms of action overlap. Methods We used single cell (sc) RNA-seq, flow cytometry and IHC analysis of responding SM1, D4M-UV2 and B16 melanoma flank tumors and SM1 brain metastases to explore the mechanism of action of the anti-PD-1+LAG-3 and the anti-PD-1+CTLA-4 combination. CD4+ and CD8+ T cell depletion, tetramer binding assays and ELISPOT assays were used to demonstrate the unique role of CD4+T cell help in the antitumor effects of the anti-PD-1+LAG-3 combination. Results The anti-PD-1+CTLA-4 combination was associated with the infiltration of FOXP3+regulatory CD4+ cells (Tregs), fewer activated CD4+T cells and the accumulation of a subset of IFNγ secreting cytotoxic CD8+T cells, whereas the anti-PD-1+LAG-3 combination led to the accumulation of CD4+T helper cells that expressed CXCR4, TNFSF8, IL21R and a subset of CD8+T cells with reduced expression of cytotoxic markers. T cell depletion studies showed a requirement for CD4+T cells for the anti-PD-1+LAG-3 combination, but not the PD-1-CTLA-4 combination at both flank and brain tumor sites. In anti-PD-1+LAG-3 treated tumors, CD4+T cell depletion was associated with fewer activated (CD69+) CD8+T cells and impaired IFNγ release but, conversely, increased numbers of activated CD8+T cells and IFNγ release in anti-PD-1+CTLA-4 treated tumors. Conclusions Together these studies suggest that these two clinically relevant immune checkpoint inhibitor (ICI) combinations have differential effects on CD4+T cell polarization, which in turn, impacted cytotoxic CD8+T cell function. Further insights into the mechanisms of action/resistance of these clinically-relevant ICI combinations will allow therapy to be further personalized.
Targeting Tumor Heterogeneity with Neoantigen-Based Cancer Vaccines
Authors: Saranya Pounraj, Shuxiong Chen, Linlin Ma, Roberta Mazzieri, Riccardo Dolcetti, Bernd H.A. Rehm
Journal: Cancer Research (2023)

Abstract Neoantigen-based cancer vaccines have emerged as a promising immunotherapeutic approach to treat cancer. Nevertheless, the high degree of heterogeneity in tumors poses a significant hurdle for developing a vaccine that targets the therapeutically relevant neoantigens capable of effectively stimulating an immune response as each tumor contains numerous unique putative neoantigens. Understanding the complexities of tumor heterogeneity is crucial for the development of personalized neoantigen-based vaccines, which hold the potential to revolutionize cancer treatment and improve patient outcomes. In this review, we discuss recent advancements in the design of neoantigen-based cancer vaccines emphasizing the identification, validation, formulation, and targeting of neoantigens while addressing the challenges posed by tumor heterogeneity. The review highlights the application of cutting-edge approaches, such as single-cell sequencing and artificial intelligence to identify immunogenic neoantigens, while outlining current limitations and proposing future research directions to develop effective neoantigen-based vaccines.
Abstract 5868: Increased Expression Of Ectonucleotide Pyrophosphatase/phosphodiesterase-1 (enpp-1) In Aortic Stenosis: Implication For The Calcification Of The Aortic Valve
Authors: Andree Pepin, Yohan Bosse, Philippe Pibarot, Allain Charest, Patrick Mathieu
Journal: Circulation (2008)
Treatment of Severe Palmoplantar Pustular Psoriasis With Bimekizumab
Authors: Thierry Passeron, Jean-Luc Perrot, Denis Jullien, Catherine Goujon, Mireille Ruer, Thierry Boyé, Axel P. Villani, Nathalie Quiles Tsimaratos
Journal: JAMA Dermatology (2023)

Palmoplantar pustulosis (PPP) and palmoplantar plaque psoriasis with pustules remain challenging to treat. Studies suggest that an interleukin 17 or interleukin 36 loop acts synergistically in these diseases to induce palmoplantar pustules.
Publisher Correction: CD3ζ ITAMs enable ligand discrimination and antagonism by inhibiting TCR signaling in response to low-affinity peptides
Authors: Guillaume Gaud, Sooraj Achar, François X. P. Bourassa, John Davies, Teri Hatzihristidis, Seeyoung Choi, Taisuke Kondo, Selamawit Gossa, Jan Lee, Paul Juneau, Naomi Taylor, Christian S. Hinrichs, Dorian B. McGavern, Paul François, Grégoire Altan-Bonnet, Paul E. Love
Journal: Nature Immunology (2023)
Effect of baseline oestradiol serum concentration on the efficacy of anastrozole for preventing breast cancer in postmenopausal women at high risk: a case-control study of the IBIS-II prevention trial
Authors: Jack Cuzick, Kim Chu, Brian Keevil, Adam R Brentnall, Anthony Howell, Nicholas Zdenkowski, Bernardo Bonanni, Sibylle Loibl, Kaija Holli, D Gareth Evans, Steve Cummings, Mitch Dowsett
Journal: The Lancet Oncology (2023)

An increased risk of breast cancer is associated with high serum concentrations of oestradiol and testosterone in postmenopausal women, but little is known about how these hormones affect response to endocrine therapy for breast cancer prevention or treatment. We aimed to assess the effects of serum oestradiol and testosterone concentrations on the efficacy of the aromatase inhibitor anastrozole for the prevention of breast cancer in postmenopausal women at high risk.
Associations of Prenatal Per- and Polyfluoroalkyl Substance (PFAS) Exposures with Offspring Adiposity and Body Composition at 16–20 Years of Age: Project Viva
Authors: Mingyu Zhang, Sheryl L. Rifas-Shiman, Izzuddin M. Aris, Abby F. Fleisch, Pi-I Debby Lin, Amy R. Nichols, Emily Oken, Marie-France Hivert
Journal: Environmental Health Perspectives (2023)

Findings on the associations between prenatal PFAS exposures and offspring adiposity are inconsistent. Whether such associations may extend to adolescence is especially understudied.
The Effect of Pesticide Spray Season and Residential Proximity to Agriculture on Glyphosate Exposure among Pregnant People in Southern Idaho, 2021
Authors: Cynthia L. Curl, Carly Hyland, Meredith Spivak, Lianne Sheppard, Bruce Lanphear, Michael N. Antoniou, Maria Ospina, Antonia M. Calafat
Journal: Environmental Health Perspectives (2023)

Glyphosate is one of the most heavily used pesticides in the world, but little is known about sources of glyphosate exposure in pregnant people living in agricultural regions.
Genome and Transcriptome-Wide Association Study of Fibrotic Sarcoidosis in European Americans
Authors: Shu-Yi Liao, Lisa A. Maier, Tasha E. Fingerlin
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"Genome and Transcriptome-Wide Association Study of Fibrotic Sarcoidosis in European Americans." American Journal of Respiratory and Critical Care Medicine, 209(3), pp. 334–337
Intervertebral disc human nucleus pulposus cells associated with back pain trigger neurite outgrowth in vitro and pain behaviors in rats
Authors: Wensen Jiang, Juliane D. Glaeser, Giselle Kaneda, Julia Sheyn, Jacob T. Wechsler, Stephen Stephan, Khosrowdad Salehi, Julie L. Chan, Wafa Tawackoli, Pablo Avalos, Christopher Johnson, Chloe Castaneda, Linda E.A. Kanim, Teerachat Tanasansomboon, Joshua E. Burda, Oksana Shelest, Haneen Yameen, Tiffany G. Perry, Michael Kropf, Jason M. Cuellar, Dror Seliktar, Hyun W. Bae, Laura S. Stone, Dmitriy Sheyn
Journal: Science Translational Medicine (2023)

Low back pain (LBP) is often associated with the degeneration of human intervertebral discs (IVDs). However, the pain-inducing mechanism in degenerating discs remains to be elucidated. Here, we identified a subtype of locally residing human nucleus pulposus cells (NPCs), generated by certain conditions in degenerating discs, that was associated with the onset of discogenic back pain. Single-cell transcriptomic analysis of human tissues showed a strong correlation between a specific cell subtype and the pain condition associated with the human degenerated disc, suggesting that they are pain-triggering. The application of IVD degeneration-associated exogenous stimuli to healthy NPCs in vitro recreated a pain-associated phenotype. These stimulated NPCs activated functional human iPSC-derived sensory neuron responses in an in vitro organ-chip model. Injection of stimulated NPCs into the healthy rat IVD induced local inflammatory responses and increased cold sensitivity and mechanical hypersensitivity. Our findings reveal a previously uncharacterized pain-inducing mechanism mediated by NPCs in degenerating IVDs. These findings could aid in the development of NPC-targeted therapeutic strategies for the clinically unmet need to attenuate discogenic LBP.
Tobacco smoke exposure recruits inflammatory airspace monocytes that establish permissive lung niches for <i>Mycobacterium tuberculosis</i>
Authors: Björn Corleis, Constantine N. Tzouanas, Marc H. Wadsworth, Josalyn L. Cho, Alice H. Linder, Abigail E. Schiff, Björn Zessin, Fabian Stei, Anca Dorhoi, Amy K. Dickey, Benjamin D. Medoff, Alex K. Shalek, Douglas S. Kwon
Journal: Science Translational Medicine (2023)

Tobacco smoking doubles the risk of active tuberculosis (TB) and accounts for up to 20% of all active TB cases globally. How smoking promotes lung microenvironments permissive to Mycobacterium tuberculosis ( Mtb ) growth remains incompletely understood. We investigated primary bronchoalveolar lavage cells from current and never smokers by performing single-cell RNA sequencing (scRNA-seq), flow cytometry, and functional assays. We observed the enrichment of immature inflammatory monocytes in the lungs of smokers compared with nonsmokers. These monocytes exhibited phenotypes consistent with recent recruitment from blood, ongoing differentiation, increased activation, and states similar to those with chronic obstructive pulmonary disease. Using integrative scRNA-seq and flow cytometry, we identified CD93 as a marker for a subset of these newly recruited smoking-associated lung monocytes and further provided evidence that the recruitment of monocytes into the lung was mediated by CCR2-binding chemokines, including CCL11. We also show that these cells exhibit elevated inflammatory responses upon exposure to Mtb and accelerated intracellular growth of Mtb compared with mature macrophages. This elevated Mtb growth could be inhibited by anti-inflammatory small molecules, providing a connection between smoking-induced pro-inflammatory states and permissiveness to Mtb growth. Our findings suggest a model in which smoking leads to the recruitment of immature inflammatory monocytes from the periphery to the lung, which results in the accumulation of these Mtb -permissive cells in the airway. This work defines how smoking may lead to increased susceptibility to Mtb and identifies host-directed therapies to reduce the burden of TB among those who smoke.
USP2 inhibition prevents infection with ACE2-dependent coronaviruses in vitro and is protective against SARS-CoV-2 in mice
Authors: Fabin Dang, Lei Bai, Jiazhen Dong, Xiaoping Hu, Jingchao Wang, Joao A. Paulo, Yan Xiong, Xiaowei Liang, Yishuang Sun, Yuncai Chen, Ming Guo, Xin Wang, Zhixiang Huang, Hiroyuki Inuzuka, Li Chen, Chen Chu, Jianping Liu, Tao Zhang, Abdol-Hossein Rezaeian, Jing Liu, Husnu Ümit Kaniskan, Bo Zhong, Jinfang Zhang, Michael Letko, Jian Jin, Ke Lan, Wenyi Wei
Journal: Science Translational Medicine (2023)

Targeting angiotensin-converting enzyme 2 (ACE2) represents a promising and effective approach to combat not only the COVID-19 pandemic but also potential future pandemics arising from coronaviruses that depend on ACE2 for infection. Here, we report ubiquitin specific peptidase 2 (USP2) as a host-directed antiviral target; we further describe the development of MS102, an orally available USP2 inhibitor with viable antiviral activity against ACE2-dependent coronaviruses. Mechanistically, USP2 serves as a physiological deubiquitinase of ACE2, and targeted inhibition with specific small-molecule inhibitor ML364 leads to a marked and reversible reduction in ACE2 protein abundance, thereby blocking various ACE2-dependent coronaviruses tested. Using human ACE2 transgenic mouse models, we further demonstrate that ML364 efficiently controls disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as evidenced by reduced viral loads and ameliorated lung inflammation. Furthermore, we improved the in vivo performance of ML364 in terms of both pharmacokinetics and antiviral activity. The resulting lead compound, MS102, holds promise as an oral therapeutic option for treating infections with coronaviruses that are reliant on ACE2.
Genomic instability analysis in DNA from Papanicolaou test provides proof-of-principle early diagnosis of high-grade serous ovarian cancer
Authors: Lara Paracchini, Laura Mannarino, Chiara Romualdi, Riccardo Zadro, Luca Beltrame, Ilaria Fuso Nerini, Paolo Zola, Maria E. Laudani, Eva Pagano, Livia Giordano, Robert Fruscio, Fabio Landoni, Silvia Franceschi, Maria L. Dalessandro, Vincenzo Canzonieri, Luca Bocciolone, Domenica Lorusso, Cristina Bosetti, Francesco Raspagliesi, Isabella M. G. Garassino, Maurizio D’Incalci, Sergio Marchini
Journal: Science Translational Medicine (2023)

Late diagnosis and the lack of screening methods for early detection define high-grade serous ovarian cancer (HGSOC) as the gynecological malignancy with the highest mortality rate. In the work presented here, we investigated a retrospective and multicentric cohort of 250 archival Papanicolaou (Pap) test smears collected during routine gynecological screening. Samples were taken at different time points (from 1 month to 13.5 years before diagnosis) from 113 presymptomatic women who were subsequently diagnosed with HGSOC (pre-HGSOC) and from 77 healthy women. Genome instability was detected through low-pass whole-genome sequencing of DNA derived from Pap test samples in terms of copy number profile abnormality (CPA). CPA values of DNA extracted from Pap test samples from pre-HGSOC women were substantially higher than those in samples from healthy women. Consistently with the longitudinal analysis of clonal pathogenic TP53 mutations, this assay could detect HGSOC presence up to 9 years before diagnosis. This finding confirms the continual shedding of tumor cells from fimbriae toward the endocervical canal, suggesting a new path for the early diagnosis of HGSOC. We integrated the CPA score into the EVA (early ovarian cancer) test, the sensitivity of which was 75% (95% CI, 64.97 to 85.79), the specificity 96% (95% CI, 88.35 to 100.00), and the accuracy 81%. This proof-of-principle study indicates that the early diagnosis of HGSOC is feasible through the analysis of genomic alterations in DNA from endocervical smears.
DPA714 PET Imaging Shows That Inflammation of the Choroid Plexus Is Active in Chronic-Phase Intracerebral Hemorrhage
Authors: Shaobo Yao, Zhuyu Gao, Wenhua Fang, Ying Fu, Qianqian Xue, Tianmin Lai, Huangcheng Shangguan, Weiwei Sun, Yuanxiang Lin, Fuxin Lin, Dezhi Kang
Journal: Clinical Nuclear Medicine (2023)

Our aims were to investigate the presence of choroid plexus (CP) inflammation in chronic-phase intracerebral hemorrhage (ICH) patients and to characterize any inflammatory cells in the CP. An in vivo 18 F-DPA714 PET study was undertaken in 22 chronic-phase ICH patients who were admitted to the First Affiliated Hospital of Fujian Medical University or Tianjin Medical University General Hospital from April 2017 to June 2020. Ten control participants with nonhemorrhagic central nervous system diseases were included. Choroid plexus 18 F-DPA714 uptake was calculated as the average SUVR. To aid the interpretation of the 18 F-DPA714 uptake results at the CP level, Cy5-DPA714 in vivo imaging and immunofluorescence staining were used to show the presence of CP inflammation in an ICH mouse model during the chronic phase (14 weeks after ICH). Then immunofluorescence staining against translocator protein and other specific biomarkers was used to characterize the cells present in the inflamed CP of ICH mice in the chronic phase. PET imaging showed that CP DPA714 SUVRs in chronic-phase ICH patients were higher than in controls (mean CP SUVR ± SD; ICH group: 1.05 ± 0.35; control group: 0.81 ± 0.21; P = 0.006). Immunofluorescence staining of the CP in ICH model mice identified a population of CD45 + immune cells, peripheral monocyte-derived CD14 + cells, CD68 + phagocytes, and CD11b + resident microglia/macrophages expressing translocator protein, possibly contributing to the increased 18 F-DPA714 uptake. Our study shows that CP DPA714 uptake in chronic-phase ICH patients was higher than that of participants with nonhemorrhagic central nervous system diseases, which means that CP inflammation is still active in chronic-phase ICH patients.
A Prospective Comparative Study of 18F-FDOPA PET/CT Versus 123I-MIBG Scintigraphy With SPECT/CT for the Diagnosis of Pheochromocytoma and Paraganglioma
Authors: Changhwan Sung, Hyo Sang Lee, Dong Yun Lee, Yong-il Kim, Jae Eun Kim, Sang Ju Lee, Seung Jun Oh, Tae-Yon Sung, Yu-Mi Lee, Young Hoon Kim, Beom-Jun Kim, Jung-Min Koh, Seung Hun Lee, Jin-Sook Ryu
Journal: Clinical Nuclear Medicine (2023)

Purpose This study aimed to compare the diagnostic performances of 18 F-FDOPA PET/CT and 123 I-MIBG scintigraphy with SPECT/CT for detection of pheochromocytoma and paraganglioma (PPGL). Patients and Methods We conducted a prospective, single-institution comparative study. Patients suspected of having PPGL or those showing recurrence and/or distant metastasis of PPGL were enrolled. The primary objective was to affirm the noninferiority of 18 F-FDOPA PET/CT for diagnostic sensitivity. Both 123 I-MIBG scintigraphy with SPECT/CT (at 4 and 24 hours) and 18 F-FDOPA PET/CT (at 5 and 60 minutes after radiotracer administration) were performed. The final diagnosis was established either pathologically or via clinical follow-up. Nuclear physicians, unaware of the clinical data, undertook image analysis. Results Thirty-two patients were evaluated: 14 of 21 with an initial diagnosis and 9 of 11 with recurrence/metastasis had PPGLs in their final diagnoses. In patient-based analyses, 18 F-FDOPA PET/CT (95.7%) exhibited noninferior sensitivity compared with 123 I-MIBG SPECT/CT (91.3%), within the predetermined noninferiority margin of −12% by a 95% confidence interval lower limit of −10%. Both modalities showed no significant difference in specificity (88.9% vs 88.9%). In the region-based analysis for the recurrence/metastasis group, 18 F-FDOPA PET/CT demonstrated significantly higher sensitivity compared with 123 I-MIBG SPECT/CT (86.2% vs 65.5%, P = 0.031) and superior interobserver agreement (κ = 0.94 vs 0.85). The inclusion of an early phase in dual-phase 18 F-FDOPA PET/CT slightly improved diagnostic performance, albeit not to a statistically significant degree. Conclusions 18 F-FDOPA PET/CT demonstrated noninferior sensitivity and comparable specificity to 123 I-MIBG SPECT/CT in the diagnosing PPGL. Notably, in the assessment of PPGL recurrence and metastasis, 18 F-FDOPA PET/CT outperformed 123 I-MIBG SPECT/CT in terms of both sensitivity and interobserver agreement.