tbuckley/cabot-search huggingface dataset:
There is a role for physician associates in the NHS
Authors: Sarah Clarke
Journal: BMJ (2024)

There is a role for physician associates in the NHS The upcoming extraordinary general meeting at the Royal College of Physicians is an opportunity to contribute constructively to the debate around the future of physician associates Sarah Clarke PresidentWe are in the midst of a political and professional storm over the role of the Royal College of Physicians (RCP) in supporting physician associates (PAs). 1 Concerns around the profession's scope of practice, supervision, and regulation have come to the fore in recent months.The NHS has changed beyond recognition since I qualified as a doctor almost 40 years ago and I genuinely believe that the development of multidisciplinary team (MDT) working has improved access to services, evidence-based care, and continuity of care.On 13 March 2024, the RCP will hold an extraordinary general meeting (EGM) to discuss these concerns and, whatever its outcome, we must use it as an important opportunity to further the conversation about how these multidisciplinary teams-including PAs-can work together safely to provide the best care possible for patients.
Promoting Diabetic Wound Healing through a Hydrogel‐Based Cascade Regulation Strategy of Fibroblast‐Macrophage
Authors: Nuo Jin, Zilin Wang, Xi Tang, Nianqiang Jin, Xiaohong Wang
Journal: Advanced Healthcare Materials (2024)

Abstract The management of diabetic wounds (DWs) continues to pose a significant challenge in the field of medicine. DWs are primarily prevented from healing due to damage to macrophage efferocytosis and fibroblast dysfunction. Consequently, a treatment strategy that involves both immunoregulation and the promotion of extracellular matrix (ECM) formation holds promise for healing DWs. Nevertheless, existing treatment methods necessitate complex interventions and are associated with increased costs, for example, the use of cytokines and cell therapy, both of which have limited effectiveness. In this study, a new type of ruthenium (IV) oxide nanoparticles (RNPs)‐laden hybrid hydrogel dressing with a double network of Pluronic F127 and F68 has been developed. Notably, the hybrid hydrogel demonstrates remarkable thermosensitivity, injectability, immunoregulatory characteristics, and healing capability. RNPs in hydrogel effectively regulate both fibroblasts and macrophages in a cascade manner, stimulating fibroblast differentiation while synergistically enhancing the efferocytosis of macrophage. The immunoregulatory character of the hydrogel aids in restoring the intrinsic stability of the immune microenvironment in the wound and facilitates essential remodeling of the ECM. This hydrogel therefore offers a novel approach for treating DWs through intercellular communication.
rhIL-7-hyFc and hIL-2/TCB2c combination promotes an immune-stimulatory tumor microenvironment that improves antitumor efficacy of checkpoint inhibitors
Authors: Minji Lee, Sun-Kyoung Im, Seungtae Baek, Mankyu Ji, Miyoung Kim, Eun Ju Lee, Seung Taek Ji, Sara Ferrando-Martinez, Alexandra Wolfarth, Jun-Young Lee, Daeun Kim, Donghoon Choi
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Recombinant human interleukin (rhIL)-7-hyFc (efineptakin alfa; NT-I7) is a potent T-cell amplifier, with two IL-7 molecules fused to IgD/IgG4 elements. rhIL-7-hyFc promotes extensive infiltration of CD8 + T cells into the tumor, concurrently increasing the numbers of intratumoral PD-1 + CD8 + T cells. The hIL-2/TCB2 complex (SLC-3010) inhibits tumor growth by preferential activation of CD122 (IL-2Rβ) high CD8 + T cells and natural killer cells, over regulatory T cells (Tregs). We investigated the underlying mechanisms of rhIL-7-hyFc and hIL-2/TCB2c antitumor activity and the potential synergistic efficacy, specifically focusing on tumor-specific CD8 + cells within the tumor and the tumor-draining lymph nodes (tdLN). Methods MC38 and CT26 tumor-bearing mice were administered with 10 mg/kg rhIL-7-hyFc intramuscularly and 0.9 mg/kg hIL-2/TCB2c intravenously. Anti-PD-1 monoclonal antibody was administered intraperitoneally three times at 3-day intervals at a dose of 5 mg/kg. Tumor volume was measured to assess efficacy. To compare the composition of immune cells between each monotherapy and the combination therapy, we analyzed tumors and tdLNs by flow cytometry. Results Our data demonstrate that the combination of rhIL-7-hyFc and hIL-2/TCB2c increases efficacy and generates an immune-stimulatory tumor microenvironment (TME). The TME is characterized by an increased infiltration of tumor-specific CD8 + T cells, and a decreased frequency of CD39 high TIM-3 + Treg cells. Most importantly, rhIL-7-hyFc increases infiltration of a CD62L + Ly108 + early progenitor population of exhausted CD8 + T cells (T PEX ), which may retain long-term proliferation capacity and replenish functional effector CD8 + T cells. hIL-2/TCB2c induces differentiation of CD62L + Ly108 + T PEX rapidly into CD101 + terminally differentiated subsets (terminally exhausted T cell (T EX term )). Our study also demonstrates that rhIL-7-hyFc significantly enhances the proliferation rate of T PEX in the tdLNs, positively correlating with their abundance within the tumor. Moreover, rhIL-7-hyFc and hIL-2/TCB2c can overcome the limited therapeutic effectiveness of PD-1 blockade, culminating in the complete regression of tumors. Conclusions rhIL-7-hyFc can expand and maintain the progenitor pool of exhausted CD8 + T cells, whereas hIL-2/TCB2c promotes their differentiation into T EX term . Together, this induces an immune-stimulatory TME that improves the efficacy of checkpoint blockade.
ASF1A-dependent P300-mediated histone H3 lysine 18 lactylation promotes atherosclerosis by regulating EndMT
Authors: Mengdie Dong, Yunjia Zhang, Minghong Chen, Yongkang Tan, Jiao Min, Xian He, Fuhao Liu, Jiaming Gu, Hong Jiang, Longbin Zheng, Jiajing Chen, Quanwen Yin, Xuesong Li, Xiang Chen, Yongfeng Shao, Yong Ji, Hongshan Chen
Journal: Acta Pharmaceutica Sinica B (2024)

Endothelial-to-mesenchymal transition (EndMT) is a key driver of atherosclerosis. Aerobic glycolysis is increased in the endothelium of atheroprone areas, accompanied by elevated lactate levels. Histone lactylation, mediated by lactate, can regulate gene expression and participate in disease regulation. However, whether histone lactylation is involved in atherosclerosis remains unknown. Here, we report that lipid peroxidation could lead to EndMT-induced atherosclerosis by increasing lactate-dependent histone H3 lysine 18 lactylation (H3K18la) in vitro and in vivo, as well as in atherosclerotic patients' arteries. Mechanistically, the histone chaperone ASF1A was first identified as a cofactor of P300, which precisely regulated the enrichment of H3K18la at the promoter of SNAI1, thereby activating SNAI1 transcription and promoting EndMT. We found that deletion of ASF1A inhibited EndMT and improved endothelial dysfunction. Functional analysis based on ApoeKOAsf1aECKO mice in the atherosclerosis model confirmed the involvement of H3K18la in atherosclerosis and found that endothelium-specific ASF1A deficiency inhibited EndMT and alleviated atherosclerosis development. Inhibition of glycolysis by pharmacologic inhibition and advanced PROTAC attenuated H3K18la, SNAI1 transcription, and EndMT-induced atherosclerosis. This study illustrates precise crosstalk between metabolism and epigenetics via H3K18la by the P300/ASF1A molecular complex during EndMT-induced atherogenesis, which provides emerging therapies for atherosclerosis.
Ciclopirox inhibits SARS-CoV-2 replication by promoting the degradation of the nucleocapsid protein
Authors: Xiafei Wei, Yuzheng Zhou, Xiaotong Shen, Lujie Fan, Donglan Liu, Xiang Gao, Jian Zhou, Yezi Wu, Yunfei Li, Wei Feng, Zheng Zhang
Journal: Acta Pharmaceutica Sinica B (2024)

The nucleocapsid protein (NP) plays a crucial role in SARS-CoV-2 replication and is the most abundant structural protein with a long half-life. Despite its vital role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) assembly and host inflammatory response, it remains an unexplored target for drug development. In this study, we identified a small-molecule compound (ciclopirox) that promotes NP degradation using an FDA-approved library and a drug-screening cell model. Ciclopirox significantly inhibited SARS-CoV-2 replication both in vitro and in vivo by inducing NP degradation. Ciclopirox induced abnormal NP aggregation through indirect interaction, leading to the formation of condensates with higher viscosity and lower mobility. These condensates were subsequently degraded via the autophagy-lysosomal pathway, ultimately resulting in a shortened NP half-life and reduced NP expression. Our results suggest that NP is a potential drug target, and that ciclopirox holds substantial promise for further development to combat SARS-CoV-2 replication.
High response rate with extended dosing of cemiplimab in advanced cutaneous squamous cell carcinoma
Authors: Danny Rischin, Brett G M Hughes, Nicole Basset-Séguin, Dirk Schadendorf, Samantha Bowyer, Sabiha Trabelsi Messai, Friedegund Meier, Thomas K Eigentler, Victoria Casado Echarren, Brian Stein, Marie Beylot-Barry, Sophie Dalac, Brigitte Dréno, Michael R Migden, Axel Hauschild, Chrysalyne D Schmults, Annette M Lim, Suk-Young Yoo, Anne J Paccaly, Apostolos Papachristos, Jenny-Hoa Nguyen, Emmanuel Okoye, Frank Seebach, Jocelyn Booth, Israel Lowy, Matthew G Fury, Alexander Guminski
Journal: Journal for ImmunoTherapy of Cancer (2024)

Cemiplimab (Libtayo®), a human monoclonal immunoglobulin G4 antibody to the programmed cell death-1 receptor, is approved for the treatment of patients with advanced cutaneous squamous cell carcinoma (CSCC), who are not candidates for curative surgery or curative radiation, using an every-3-weeks (Q3W) dosing interval. Pharmacokinetic modeling indicated that Ctrough of extended intravenous dosing of 600 mg every 4 weeks (Q4W) would be comparable to the approved intravenous dosage of 350 mg Q3W. We examined the efficacy, pharmacokinetics, and safety of cemiplimab dosed Q4W. In this open-label, phase II trial (ClinicalTrials.gov identifier NCT02760498), the cohort of patients ≥18 years old with advanced CSCC received cemiplimab 600 mg intravenously Q4W for up to 48 weeks. Tumor measurements were recorded every 8 weeks. The primary endpoint was objective response rate by independent central review. Sixty-three patients with advanced CSCC were treated with cemiplimab. The median duration of follow-up was 22.4 months (range: 1.0-39.8). An objective response was observed in 39 patients (62%; 95% CI: 48.8% to 73.9%), with 22% of patients (n=14) achieving complete response and 40% (n=25) achieving partial response. The most common treatment-emergent adverse events were diarrhea, pruritus, and fatigue. Extended dosing of cemiplimab 600 mg intravenously Q4W exhibited substantial antitumor activity, rapid and durable responses, and an acceptable safety profile in patients with advanced CSCC. These results confirm that cemiplimab is a highly active therapy for advanced CSCC. Additional data would help ascertain the benefit-risk profile for the 600 mg intravenous dosing regimen compared with the approved regimen.
Mefloquine enhances the efficacy of anti-PD-1 immunotherapy via IFN-γ-STAT1-IRF1-LPCAT3-induced ferroptosis in tumors
Authors: Qian Tao, Nian Liu, Jie Wu, Jing Chen, Xiang Chen, Cong Peng
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Ferroptosis plays an important role in enhancing the efficacy of anti-programmed cell death 1 (PD-1) immunotherapy; however, the molecular mechanisms by which tumor ferroptosis sensitizes melanoma and lung cancer to anti-PD-1 immunotherapy have not been elucidated. Methods Cytotoxicity assays, colony formation assays, flow cytometry and animal experiments were used to evaluate the effects of mefloquine (Mef) on survival and ferroptosis in melanoma and lung cancer. RNA sequencing, Real-time quantitative PCR (qRT-PCR), western blotting, chromatin immunoprecipitation-qPCR and flow cytometry were used to determine the molecular mechanisms by which Mef regulates lysophosphatidylcholine acyltransferase 3 (LPCAT3). The relationship between LPCAT3 and the efficacy of anti-PD-1 immunotherapy was verified via a clinical database and single-cell RNA sequencing (ScRNA-Seq). Results In this study, we discovered that Mef induces ferroptosis. Furthermore, treatment with Mef in combination with T-cell-derived interferon-γ (IFN-γ) enhanced tumor ferroptosis and sensitized melanoma and lung cancer cells to anti-PD-1 immunotherapy. Mechanistically, Mef upregulated the expression of LPCAT3, a key gene involved in lipid peroxidation, by activating IFN-γ-induced STAT1-IRF1 signaling, and knocking down LPCAT3 impaired the induction of ferroptosis by Mef+IFN-γ. Clinically, analysis of the transcriptome and single-cell sequencing results in patients with melanoma showed that LPCAT3 expression was significantly lower in patients with melanoma than in control individuals, and LPCAT3 expression was positively correlated with the efficacy of anti-PD-1 immunotherapy. Conclusions In conclusion, our study demonstrated a novel mechanism by which LPCAT3 is regulated, and demonstrated that Mef is a highly promising new target that can be utilized to enhance the efficacy of anti-PD-1 immunotherapy.
iPSC-derived models for anorexia nervosa research
Authors: Gilles Maussion, Cecilia Rocha, Nicolas Ramoz
Journal: Trends in Molecular Medicine (2024)

Anorexia nervosa (AN) is a complex neuropsychiatric disorder with genetic and epigenetic components that results in reduced food intake combined with alterations in the reward-processing network. While studies of patient cohorts and mouse models have uncovered genes and epigenetic changes associated with the disease, neuronal networks and brain areas preferentially activated and metabolic changes associated with reduced food intake, the underlying molecular and cellular mechanisms remain unknown. The use of both 2D in vitro cultures and 3D models, namely organoids and spheroids, derived from either human embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs), would allow identification of cell type-specific changes associated with AN and comorbid diseases, to study preferential connections between brain areas and organs, and the development of therapeutic strategies.
Hepatic mitochondrial reductive stress in the pathogenesis and treatment of steatotic liver disease
Authors: Mari J. Jokinen, Panu K. Luukkonen
Journal: Trends in Pharmacological Sciences (2024)

Steatotic liver diseases (SLDs) affect one-third of the population, but the pathogenesis underlying these diseases is not well understood, limiting the available treatments. A common factor in SLDs is increased hepatic mitochondrial reductive stress, which occurs as a result of excessive lipid and alcohol metabolism. Recent research has also shown that genetic risk factors contribute to this stress. This review aims to explore how these risk factors increase hepatic mitochondrial reductive stress and how it disrupts hepatic metabolism, leading to SLDs. Additionally, the review will discuss the latest clinical studies on pharmaceutical treatments for SLDs, specifically peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists, thyroid hormone receptor (THR) agonists, acetyl-CoA carboxylase (ACC) inhibitors, and mitochondrial uncouplers. These treatments have a common effect of decreasing hepatic mitochondrial reductive stress, which has been largely overlooked.
Sodium–glucose cotransporter 2 inhibitors influence skeletal muscle pathology in patients with heart failure and reduced ejection fraction
Authors: Nathanael Wood, Sam Straw, Chew W. Cheng, Yu Hirata, Marcelo G. Pereira, Harrison Gallagher, Stuart Egginton, Wataru Ogawa, Stephen B. Wheatcroft, Klaus K. Witte, Lee D. Roberts, T. Scott Bowen
Journal: European Journal of Heart Failure (2024)

Abstract Aims Patients with heart failure and reduced ejection fraction (HFrEF) exhibit skeletal muscle pathology, which contributes to symptoms and decreased quality of life. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) improve clinical outcomes in HFrEF but their mechanism of action remains poorly understood. We aimed, therefore, to determine whether SGLT2i influence skeletal muscle pathology in patients with HFrEF. Methods and results Muscle biopsies from 28 male patients with HFrEF (New York Heart association class I–III) treated with SGLT2i (&gt;12 months) or without SGLT2i were compared. Comprehensive analyses of muscle structure (immunohistochemistry), transcriptome (RNA sequencing), and metabolome (liquid chromatography‐mass spectrometry) were performed, and serum inflammatory profiling (ELISA). Experiments in mice ( n = 16) treated with SGLT2i were also performed. Myofiber atrophy was ~20% less in patients taking SGLT2i ( p = 0.07). Transcriptomics and follow‐up measures identified a unique signature in patients taking SGLT2i related to beneficial effects on atrophy, metabolism, and inflammation. Metabolomics identified influenced tryptophan metabolism in patients taking SGLT2i: kynurenic acid was 24% higher and kynurenine was 32% lower ( p &lt; 0.001). Serum profiling identified that SGLT2i treatment was associated with lower ( p &lt; 0.05) pro‐inflammatory cytokines by 26–64% alongside downstream muscle interleukin (IL)‐6‐JAK/STAT3 signalling ( p = 008 and 0.09). Serum IL‐6 and muscle kynurenine were correlated ( R = 0.65; p &lt; 0.05). Muscle pathology was lower in mice treated with SGLT2i indicative of a conserved mammalian response to treatment. Conclusions Treatment with SGLT2i influenced skeletal muscle pathology in patients with HFrEF and was associated with anti‐atrophic, anti‐inflammatory, and pro‐metabolic effects. These changes may be regulated via IL‐6–kynurenine signalling. Together, clinical improvements following SGLT2i treatment in patients with HFrEF may be partly explained by their positive effects on skeletal muscle pathology.
Diagnostic Performance of Perfusion-Only SPECT/CT for Chronic Thromboembolic Pulmonary Hypertension in Comparison With Ventilation-Perfusion Planar, SPECT, and SPECT/CT Imaging
Authors: Changhwan Sung, Sangwon Han, Soyoon Yoon, Shin Ae Han, Do-Yoon Kang, Dae-Hee Kim, Duk-Woo Park, Jong-Min Song, Jae Seung Lee, Jin-Sook Ryu, Dae Hyuk Moon
Journal: Clinical Nuclear Medicine (2024)

Purpose The aim of this study was to assess the diagnostic performance of perfusion-only SPECT/CT (Q SPECT/CT) in comparison with that of ventilation/perfusion planar scintigraphy (V/Q planar), perfusion SPECT with ventilation scan (V/Q SPECT), and perfusion SPECT/CT with ventilation scan (V/Q SPECT/CT) in chronic thromboembolic pulmonary hypertension (CTEPH). Patients and Methods Patients with pulmonary hypertension who underwent ventilation-perfusion planar and SPECT/CT were retrospectively recruited. Two nuclear medicine physicians interpreted V/Q planar, V/Q SPECT, V/Q SPECT/CT, and Q SPECT/CT according to the European Association of Nuclear Medicine criteria. The diagnostic accuracy of these modalities for CTEPH was compared using a composite reference standard of pulmonary angiography, imaging test, cardiorespiratory assessment, and follow-up. Results A total of 192 patients were enrolled, including 85 with CTEPH. The sensitivity of Q SPECT/CT was 98.8%, which similar to that of V/Q planar (97.6%), V/Q SPECT (96.5%), or V/Q SPECT/CT (100.0%). In contrast, Q SPECT/CT exhibited significantly lower specificity (73.8%) compared with V/Q planar (86.9%, P = 0.001), V/Q SPECT (87.9%, P &lt; 0.001), and V/Q SPECT/CT (88.8%, P &lt; 0.001). The significantly lower specificity of Q SPECT/CT, compared with the 3 others, was observed in the subgroup aged ≥50 years ( P &lt; 0.001 for all), but not in those &lt;50 years. Conclusions Q SPECT/CT exhibited lower specificity compared with V/Q planar, V/Q SPECT, and V/Q SPECT/CT in diagnosing CTEPH. It might underscore the essential role of a ventilation scan in patients with PH, even with the introduction of SPECT/CT.
Targeting ABCA1 via Extracellular Vesicle‐Encapsulated Staurosporine as a Therapeutic Strategy to Enhance Radiosensitivity
Authors: Qi Yang, Wenyan Gao, Xinyue Li, Xin Li, Xuantong Zhou, Wenxin Li, Changchun Zhou, Aiping Luo, Zhihua Liu
Journal: Advanced Healthcare Materials (2024)

Abstract Cancer stem cells (CSCs) are essential for tumor initiation, recurrence, metastasis, and resistance. However, targeting CSCs as a therapeutic approach remains challenging. Here, a stemness signature based on 22‐gene is developed to predict prognosis in esophageal squamous cell carcinoma (ESCC). Staurosporine (STS) is identified as a radioresistance suppressor by high‐throughput screening of a library of 2131 natural compounds, leading to dramatically improved radiotherapy efficacy in subcutaneous tumor models. Mechanistically, STS inhibits cell proliferation through the mTOR/AKT signaling pathway and suppressed stemness by targeting ATP‐binding cassette A1 (ABCA1), which is transcriptionally regulated by liver X receptor alpha (LXRα). STS can selectively bind to the nucleotide‐binding domain (NBD) of ABCA1 and compete for ATP, blocking ABCA1‐mediated drug efflux and facilitating intracellular accumulation of STS. Considering the cytotoxicity of STS, an extracellular vesicle‐encapsulated STS system (EV‐STS) is established for effective STS delivery. EV‐STS shows remarkable tumor growth inhibition, even at half the dose of STS, with superior safety and efficacy. These findings indicate that ABCA1 may serve as a predictor of response to neoadjuvant chemotherapy and/or radiotherapy in ESCC patients. EV‐STS has shown improved antitumor efficacy and low systemic toxicity, offering a promising therapeutic approach for ESCC.
Journals must expand access to peer review data
Authors: Olivia M. Smith, Kayla L. Davis, Robin Waterman, Riley B. Pizza, Caitlin Mack, Emily E. Conway, Kara C. Dobson, Brianna Foster, Ani E. Hristova, Julie C. Jarvey, Nan Nourn, Courtney L. Davis
Journal: Trends in Ecology & Evolution (2024)