tbuckley/cabot-search huggingface dataset:
Natural killer cells are required for the recruitment of CD8+ T cells and the efficacy of immune checkpoint blockade in melanoma brain metastases
Authors: Christopher Fife, Jennifer Williams, Fiona James, Scott Gregory, Tereza Andreou, Ashley Sunderland, Clive McKimmie, Rebecca J Brownlie, Robert J Salmond, Samuel Heaton, Fiona Errington-Mais, Zarnaz Hadi, David R Westhead, Marlous Hall, Alexander Davie, Amber Emmett, Mihaela Lorger
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Brain metastases (BrM) affect up to 60% of patients with metastatic melanoma and are associated with poor prognosis. While combined immune checkpoint blockade of programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) demonstrates intracranial efficacy in a proportion of patients with melanoma, the responses are rarely durable, particularly in patients with symptomatic BrM. The brain is an immune-specialized organ and immune responses are regulated differently to the periphery. Methods Using our previously established two-site model of melanoma BrM with concomitant intracranial and extracranial tumors, in which clinically observed efficacy of the combined PD-1/CTLA-4 (PC) blockade can be reproduced, we here explored the role of natural killer (NK) cells in BrM, using functional studies, immunophenotyping and molecular profiling. Results We demonstrate that NK cells are required for the intracranial efficacy of PC blockade. While both perforin and interferon gamma were necessary for the PC blockade-dependent control of intracranial tumor growth, NK cells isolated from intracranial tumors demonstrated only a limited cancer cell killing ability, and PC blockade did not alter the abundance of NK cells within tumors. However, the depletion of NK cells in PC blockade-treated mice led to tumor molecular profiles reminiscent of those observed in intracranial tumors that failed to respond to therapy. Furthermore, the depletion of NK cells resulted in a strikingly reduced abundance of CD8+ T cells within intracranial tumors, while the abundance of other immune cell populations including CD4+ T cells, macrophages and microglia remained unaltered. Adoptive T cell transfer experiments demonstrated that PC blockade-induced trafficking of CD8+ T cells to intracranial tumors was chemokine-dependent. In line with this, PC blockade enhanced intratumoral expression of several T cell-attracting chemokines and we observed high expression levels of cognate chemokine receptors on BrM-infiltrating CD8+ T cells in mice, as well as in human BrM. Importantly, the depletion of NK cells strikingly reduced the intratumoral expression levels of T cell attracting chemokines and vascular T cell entry receptors that were upregulated following PC blockade. Conclusion Our data demonstrate that NK cells underpin the efficacy of PC blockade in BrM by orchestrating the "responder" molecular profile in tumors, and by controlling the intratumoral abundance of CD8+ T cells through regulation of multiple key molecular mediators of T cell trafficking.
Morphine treatment restricts response to immunotherapy in oral squamous cell carcinoma
Authors: Lisa A McIlvried, Andre A Martel Matos, Mona M Yuan, Megan A Atherton, Fendi Obuekwe, Marci L Nilsen, Amin Reza Nikpoor, Sebastien Talbot, Tullia C Bruno, David N Taggart, Lorin K Johnson, Robert L Ferris, Dan P Zandberg, Nicole N Scheff
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Immune checkpoint inhibitors (ICIs) are becoming the standard of care for recurrent and metastatic cancer. Opioids, the primary treatment for cancer-related pain, are immunosuppressive raising concerns about their potential to interfere with the efficacy of ICIs. We hypothesize that exogenous opioids given for analgesia suppress antitumor immunity via T cell-mediated mu opioid receptor 1 (OPRM1) signaling. Methods In silico bioinformatics were used to assess OPRM1 receptor expression on tumor-infiltrating immune cells in patients with head and neck squamous cell carcinoma (HNSCC) and across different cancer types. A syngeneic orthotopic mouse model of oral squamous cell carcinoma was used to study the impact of morphine and OPRM1 antagonism on tumor-infiltrating immune cells, tumor growth and antitumor efficacy of anti-Programmed cell death protein 1 (PD-1) monoclonal antibody treatment. Results In patients with HNSCC, OPRM1 expression was most abundant in CD8+ T cells, particularly in patients who had not been prescribed opioids prior to resection and exhibited increased expression of exhaustion markers. Exogenous morphine treatment in tumor-bearing mice reduced CD4+ and CD8+ T-cell infiltration and subsequently anti-PD1 ICI efficacy. Peripherally acting mu opioid receptor antagonism, when administered in the adjunctive setting, was able to block morphine-induced immunosuppression and recover the antitumor efficacy of anti-PD1. Conclusions These findings suggest that morphine acts via a peripheral OPRM1-mediated mechanism to suppress CD8+ T cells, thereby fostering a pro-tumor-impaired immune response. Importantly, peripherally-restricted OPRM1 antagonism can effectively block this morphine-induced immunosuppression while still allowing for centrally-mediated analgesia, indicating a potential therapeutic strategy for mitigating the adverse effects of opioid pain relief in cancer treatment.
Comparison of CAR T-cell and bispecific antibody as third-line or later-line treatments for multiple myeloma: a meta-analysis
Authors: Xiaojie Liang, Yufan Wang, Baiwei Luo, Bingyu Lin, WeiXiang Lu, Shengyu Tian, Dan Liu, Liang Wang
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background CAR-T-cell therapy and bispecific antibody have revolutionized the treatment landscape for multiple myeloma. However, there is currently a lack of studies comparing the efficacy and safety of these two approaches. This meta-analysis assesses the efficacy and safety of B-cell maturation antigen (BCMA)-directed CAR-T-cell therapies and BCMA×CD3 bispecific antibodies as third-line or later interventions for relapsed/refractory multiple myeloma (RRMM). Methods We searched PubMed, Embase, Web of Science, and Cochrane databases up to May 31, 2024, identifying 11 eligible studies encompassing 1269 participants. Random-effects models evaluated the primary (complete response (CR) rate) and secondary (overall response rate (ORR)) outcomes, while meta-regression analyses adjusted for relevant covariates. Results CAR-T-cell therapy achieved significantly higher pooled CR rate (0.54 (95% CI 0.42–0.69) vs bispecific antibodies 0.35 (0.30–0.41), p&lt;0.01) and pooled ORR (0.83 (0.76–0.90) vs 0.65 (0.59–0.71), p&lt;0.01). However, CAR-T therapy had a higher incidence of adverse events, particularly cytokine release syndrome (CRS 0.83 (0.70–0.97) vs bispecific antibodies 0.59 (0.43–0.74), p&lt;0.05). Severe CRS (grade ≥3) occurred at a rate of 0.07 (0.03–0.14) in the CAR-T cell group, contrasting with a negligible rate of 0.01 (0.00–0.02) in the bispecific antibody group (p&lt;0.01). Hematologic adverse events, including neutropenia (grade ≥3; 0.88 (0.81–0.95) vs 0.48 (0.30–0.67), p&lt;0.01) and anemia (grade≥3; 0.55 (0.47–0.62) vs 0.34 (0.28 to 0.40), p&lt;0.01), were also more frequent in the CAR-T-cell group. Furthermore, differences in efficacy were observed among various CAR-T products, with ciltacabtagene autoleucel showing greater efficacy in CR rate (0.77 (0.71–0.84) vs 0.37 (0.32–0.41), p&lt;0.01) and ORR (0.91 (0.83–0.99) vs 0.73 (0.68–0.77), p&lt;0.01) compared with idecabtagene vicleucel. Conclusion CAR-T-cell therapy demonstrated superior CR rates compared with bispecific antibodies, although with an increase in severe adverse events.
Why mental health should be embedded across climate and health discussions at COP29
Authors: Alessandro Massazza, Naro Alonzo, Jura Augustinavicius, Claudia Selin Batz, Jess Beagley, Luiz Roberto Carvalho, Mercian Daniel, Juliana Fleury, Narmin Guluzade, Zeinab Hijazi, Emma L Lawrance, Omnia El Omrani, Saad Uakkas, Victor Ugo, Harshita Umesh
Journal: The Lancet Psychiatry (2024)
Phase 1 Study of AAV9.LAMP2B Gene Therapy in Danon Disease
Authors: Barry Greenberg, Matthew Taylor, Eric Adler, Steven Colan, David Ricks, Paul Yarabe, Pavan Battiprolu, Gaurav Shah, Kinnari Patel, Matthew Coggins, Susanna Carou-Keenan, Jonathan D Schwartz, Joseph W Rossano
Journal: New England Journal of Medicine (2024)

Danon disease is a rare, X-linked, monogenic cardiomyopathy caused by mutations in the lysosomal-associated membrane 2 gene (LAMP2), which encodes the LAMP2 protein. In male patients, the predominant phenotype is progressive cardiac hypertrophy, cardiac dysfunction, and early death. There are no directed therapies for the disease. In this phase 1 study, we evaluated the safety and efficacy of a single infusion of RP-A501, a recombinant adeno-associated virus serotype 9 containing the transgene LAMP2B, which encodes an isoform of LAMP2. The primary outcomes were the safety and toxic effects of RP-A501, myocardial LAMP2 transduction and protein expression, stabilization of or reduction in heart-failure symptoms, and stabilization of or improvement in cardiac structure and function. Key secondary outcomes were sustained reduction in or stabilization of symptoms, immunologic response to RP-A501, end-stage heart failure, and overall survival. Exploratory outcomes included improvement in serologic markers of cardiac disease, patient-reported outcomes, and quality-of-life assessments. RP-A501 infusion was administered to seven male patients with Danon disease: five who were 15 years of age or older and two who were between 11 and 14 years of age. All the patients received a transient immunomodulatory regimen of prednisone, tacrolimus or sirolimus, and rituximab. Phase 1 data over 24 to 54 months, including interim data from a long-term follow-up study, are reported here. One patient had complement-mediated thrombotic microangiopathy (grade 4) with thrombocytopenia and acute kidney injury. Three patients had glucocorticoid-related exacerbation (grade 3) of Danon disease-related skeletal myopathy. One patient with left ventricular systolic dysfunction at baseline had progressive heart failure and underwent transplantation 5 months after infusion. In the six patients with normal left ventricular ejection fraction at baseline, we observed cardiac LAMP2 protein expression and a reduction from baseline in or stabilization of the left ventricular mass index, preservation of left ventricular ejection fraction, and reduction in or stabilization of the levels of cardiac troponin I and N-terminal pro-B-type natriuretic peptide. At 24 to 54 months, all the patients were alive, with complete resolution of side effects. A single infusion of RP-A501 appeared to be safe and was associated with cardiac LAMP2 expression and evidence of clinical improvement over a period of 24 to 54 months. (Funded by Rocket Pharmaceuticals; ClinicalTrials.gov number, NCT03882437.).
Nondigestible stachyose binds membranous HSP90β on small intestinal epithelium to regulate the exosomal miRNAs: A new function and mechanism
Authors: Ting Li, Yueyue Liu, Tianchi Duan, Chao Guo, Bin Liu, Xiuqiong Fu, Lu Wang, Xiaoyuan Wang, Xinyue Dong, Chennan Wang, Yalong Lu, Yu Wang, Lin Shi, Honglei Tian, Xingbin Yang
Journal: Cell Metabolism (2024)
Human genetics identify convergent signals in mitochondrial LACTB-mediated lipid metabolism in cardiovascular-kidney-metabolic syndrome
Authors: Shen Li, Hongbo Liu, Hailong Hu, Eunji Ha, Praveena Prasad, Brenita C Jenkins, Ujjalkumar Subhash Das, Sarmistha Mukherjee, Kyosuke Shishikura, Renming Hu, Daniel J Rader, Liming Pei, Joseph A Baur, Megan L Matthews, Garret A FitzGerald, Melanie R McReynolds, Katalin Susztak
Journal: Cell Metabolism (2024)
Targeting the aminopeptidase ERAP enhances antitumor immunity by disrupting the NKG2A-HLA-E inhibitory checkpoint
Authors: Hsiao-Wei Tsao, Seth Anderson, Kenneth J Finn, Jonathan J Perera, Lomax F Pass, Emily M Schneider, Aiping Jiang, Rachel Fetterman, Cun Lan Chuong, Kaiya Kozuma, Marcia M Stickler, Marc Creixell, Susan Klaeger, Kshiti Meera Phulphagar, Suzanna Rachimi, Eva K Verzani, Niclas Olsson, Juan Dubrot, Matthew F Pech, Whitney Silkworth, Sarah Kate Lane-Reticker, Peter M Allen, Kyrellos Ibrahim, Nelson H Knudsen, Andrew Y Cheng, Adrienne H Long, Hakimeh Ebrahimi-Nik, Sarah Y Kim, Peter P Du, Arvin Iracheta-Vellve, Emily J Robitschek, Juliette S M T Suermondt, Thomas G R Davis, Clara H Wolfe, Trisha Atluri, Kira E Olander, Jason S Rush, Thomas B Sundberg, Fiona E McAllister, Jennifer G Abelin, Ari Firestone, David Stokoe, Steven A Carr, Fiona A Harding, Kathleen B Yates, Robert T Manguso
Journal: Immunity (2024)
ACSS2 acts as a lactyl-CoA synthetase and couples KAT2A to function as a lactyltransferase for histone lactylation and tumor immune evasion
Authors: Rongxuan Zhu, Xianglai Ye, Xiaotong Lu, Liwei Xiao, Ming Yuan, Hong Zhao, Dong Guo, Ying Meng, Hongkuan Han, Shudi Luo, Qingang Wu, Xiaoming Jiang, Jun Xu, Zhonghui Tang, Yizhi Jane Tao, Zhimin Lu
Journal: Cell Metabolism (2024)
A trivalent mucosal vaccine encoding phylogenetically inferred ancestral RBD sequences confers pan-Sarbecovirus protection in mice
Authors: James Brett Case, Shilpa Sanapala, Carly Dillen, Victoria Rhodes, Christian Zmasek, Taras M Chicz, Charlotte E Switzer, Suzanne M Scheaffer, George Georgiev, Catherine Jacob-Dolan, Blake M Hauser, Déborah Carolina Carvalho Dos Anjos, Lucas J Adams, Nadia Soudani, Chieh-Yu Liang, Baoling Ying, Ryan P McNamara, Richard H Scheuermann, Adrianus C M Boon, Daved H Fremont, Sean P J Whelan, Aaron G Schmidt, Alessandro Sette, Alba Grifoni, Matthew B Frieman, Michael S Diamond
Journal: Cell Host & Microbe (2024)
C-C motif chemokine receptor-2 blockade ameliorates pulmonary hypertension in rats and synergizes with a pulmonary vasodilator
Authors: Naoki Tsuboya, Hirofumi Sawada, Yoshihide Mitani, Hironori Oshita, Kazunobu Ohya, Mami Takeoka, Jane Chanda Kabwe, Yoshiki Miyasaka, Hiromasa Ito, Noriko Yodoya, Hiroyuki Ohashi, Junko Maruyama, Ryuji Okamoto, Tomoji Mashimo, Kaoru Dohi, Yuhei Nishimura, Kazuo Maruyama, Masahiro Hirayama
Journal: Cardiovascular Research (2024)

We investigated whether the disruption of C-C motif chemokine receptor (CCR) 2 may attenuate the development of pulmonary arterial hypertension (PAH) in any rat models with the reversal of the associated pro-inflammatory state and vascular dysfunction, and synergize with a conventional pulmonary vasodilator.
Long-Term Efficacy and Safety of Acoramidis in ATTR-CM: Initial Report From the Open-Label Extension of the ATTRibute-CM Trial
Authors: Daniel P. Judge, Julian D. Gillmore, Kevin M. Alexander, Amrut V. Ambardekar, Francesco Cappelli, Marianna Fontana, Pablo García-Pavía, Justin L. Grodin, Martha Grogan, Mazen Hanna, Ahmad Masri, Jose Nativi-Nicolau, Laura Obici, Steen Hvitfeldt Poulsen, Nitasha Sarswat, Keyur Shah, Prem Soman, Ted Lystig, Xiaofan Cao, Kevin Wang, Maria Lucia Pecoraro, Jean-François Tamby, Leonid Katz, Uma Sinha, Jonathan C. Fox, Mathew S. Maurer
Journal: Circulation (2024)

Background: In the phase 3 randomized controlled study, ATTRibute-CM, acoramidis, a transthyretin (TTR) stabilizer, demonstrated significant efficacy on the primary endpoint. Participants with transthyretin amyloid cardiomyopathy (ATTR-CM) who completed ATTRibute-CM were invited to enroll in an open-label extension study (OLE). We report efficacy and safety data of acoramidis in participants who completed ATTRibute-CM and enrolled in the ongoing OLE. Methods: Participants who previously received acoramidis through Month 30 (M30) in ATTRibute-CM continued to receive it (continuous acoramidis), and those who received placebo through M30 were switched to acoramidis (placebo to acoramidis). Participants who received concomitant tafamidis in ATTRibute-CM were required to discontinue it to be eligible to enroll in the OLE. Clinical efficacy outcomes analyzed through Month 42 (M42) included time to event for all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH), ACM alone, first CVH alone, ACM or recurrent CVH, change from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP), 6-minute walk distance (6MWD), serum TTR, and the Kansas City Cardiomyopathy Questionnaire Overall Summary score (KCCQ-OS). Safety outcomes were analyzed through M42. Results: Overall, 438 of 632 participants in ATTRibute-CM completed treatment and 389 enrolled in the ongoing OLE (263 continuous acoramidis, 126 placebo to acoramidis). The hazard ratio (HR) (95% CI) for ACM or first CVH was 0.57 (0.46, 0.72) at M42 based on a stratified Cox proportional hazards model ( P -value &lt; 0.0001) favoring continuous acoramidis. Similar analyses were performed on ACM alone and first CVH alone, with HRs (95% CI) of 0.64 (0.47, 0.88) and 0.53 (0.41, 0.69), respectively, at M42. Treatment effects for NT-proBNP and 6MWD also favored continuous acoramidis. Upon initiation of open-label acoramidis in the placebo-to-acoramidis arm there was a prompt increase in serum TTR. Quality of life assessed by KCCQ-OS was well preserved in continuous acoramidis participants compared with the placebo to acoramidis participants. No new clinically important safety issues were identified in this long-term evaluation. Conclusions: Early initiation and continuous use of acoramidis in the ATTRibute-CM study through M42 of the ongoing OLE study was associated with sustained clinical benefits in a contemporary ATTR-CM cohort, with no clinically important safety issues newly identified.
Deriving and validating a risk prediction model for long COVID: a population-based, retrospective cohort study in Scotland
Authors: Karen Jeffrey, Vicky Hammersley, Rishma Maini, Anna Crawford, Lana Woolford, Ashleigh Batchelor, David Weatherill, Chris White, Tristan Millington, Robin Kerr, Siddharth Basetti, Calum Macdonald, Jennifer K Quint, Steven Kerr, Syed Ahmar Shah, Amanj Kurdi, Colin R Simpson, Srinivasa Vittal Katikireddi, Igor Rudan, Chris Robertson, Lewis Ritchie, Aziz Sheikh, Luke Daines
Journal: Journal of the Royal Society of Medicine (2024)

Objectives Using electronic health records, we derived and internally validated a prediction model to estimate risk factors for long COVID and predict individual risk of developing long COVID. Design Population-based, retrospective cohort study. Setting Scotland. Participants Adults (≥18 years) with a positive COVID-19 test, registered with a general medical practice between 1 March 2020 and 20 October 2022. Main outcome measures Adjusted odds ratios (aORs) with 95% confidence intervals (CIs) for predictors of long COVID, and patients’ predicted probabilities of developing long COVID. Results A total of 68,486 (5.6%) patients were identified as having long COVID. Predictors of long COVID were increasing age (aOR: 3.84; 95% CI: 3.66–4.03 and aOR: 3.66; 95% CI: 3.27–4.09 in first and second splines), increasing body mass index (BMI) (aOR: 3.17; 95% CI: 2.78–3.61 and aOR: 3.09; 95% CI: 2.13–4.49 in first and second splines), severe COVID-19 (aOR: 1.78; 95% CI: 1.72–1.84); female sex (aOR: 1.56; 95% CI: 1.53–1.60), deprivation (most versus least deprived quintile, aOR: 1.40; 95% CI: 1.36–1.44), several existing health conditions. Predictors associated with reduced long COVID risk were testing positive while Delta or Omicron variants were dominant, relative to when the Wild-type variant was dominant (aOR: 0.85; 95% CI: 0.81–0.88 and aOR: 0.64; 95% CI: 0.61–0.67, respectively) having received one or two doses of COVID-19 vaccination, relative to unvaccinated (aOR: 0.90; 95% CI: 0.86–0.95 and aOR: 0.96; 95% CI: 0.93–1.00). Conclusions Older age, higher BMI, severe COVID-19 infection, female sex, deprivation and comorbidities were predictors of long COVID. Vaccination against COVID-19 and testing positive while Delta or Omicron variants were dominant predicted reduced risk.
Pharmaceutical industry payments to healthcare professional organisations in the United Kingdom: a seven-year cross-sectional analysis of the Disclosure UK database from 2015 to 2021
Authors: Anju Murayama, Alice Fabbri, Hannah Scholfield, Piotr Ozieranski
Journal: Journal of the Royal Society of Medicine (2024)

Objectives This study aimed to examine the size and trends in payments from the pharmaceutical industry to healthcare professional organisations (HPOs) in the United Kingdom (UK), and to characterise the conflict of interest (COI) management plans by HPOs who received large payments. Design Cross-sectional analysis of non-research payments disclosed in the Disclosure UK database from 2015 to 2021. Setting United Kingdom. Participants 148 pharmaceutical companies disclosing payment data and HPOs receiving the largest payments. Main outcome measures Total value and median of payments per HPO; existence and content of COI policies among HPOs receiving the largest payments. Results A total of 898 HPOs received non-research payments worth £99.9 million (17.4% of non-research payments to all healthcare organisations). The median seven-year payment per HPO was £4509 (interquartile range: £943–£30,360). The annual payments nearly doubled from £9.3 million in 2015 to £17.6 million in 2021. Event payments constituted the largest share (£68.2 million, 68.2%). HPOs representing physicians received over 91.5% (£91.5 million) of all payments, while those related to endocrinology and diabetology – 16.3% (£16.3 million). Over 59.9% (£59.9 million) went to the 30 top-funded HPOs, of which only 17 (56.7%) had a publicly accessible COI policy. However, just 6 (35.3%) of these policies included provisions for payments from external organisations. Conclusions HPOs received nearly one-fifth of pharmaceutical company payments to the UK healthcare sector. These payments were concentrated among a small number of HPOs, which often lacked effective policies for management of COI and payments from the industry.