tbuckley/cabot-search huggingface dataset:
Pneumococcal pneumonia trends in adults hospitalised with community-acquired pneumonia over 10 years (2013–2023) and the role of serotype 3
Authors: Louise Lansbury, Tricia M McKeever, Hannah Lawrence, Harry Pick, Vadsala Baskaran, Rochelle Edwards-Pritchard, Laura Matthews, Helen Bailey, Deborah Ashton, Lesley Bendall, Chamira Rodrigo, Priya Daniel, David Litt, Seyi Eletu, Hanshi Parmar, Carmen Sheppard, Shamez N Ladhani, Caroline Trotter, Wei Shen Lim
Journal: Thorax (2024)

With higher valency pneumococcal vaccines on the horizon and new adult immunisation strategies under discussion, we aimed to evaluate the contribution of individual pneumococcal serotypes to the burden of pneumococcal community-acquired pneumonia (CAP). Over 10 years, trends in pneumococcal pneumonia epidemiology in adults hospitalised with CAP were assessed. The risk factors and severity associated with serotype 3 were examined.
Hepatic TM6SF2 activates antitumour immunity to suppress metabolic dysfunction-associated steatotic liver disease-related hepatocellular carcinoma and boosts immunotherapy
Authors: Yating Zhang, Mingxu Xie, Jun Wen, Cong Liang, Qian Song, Weixin Liu, Yali Liu, Yang Song, Harry Cheuk Hay Lau, Alvin Ho-Kwan Cheung, Kwan Man, Jun Yu, Xiang Zhang
Journal: Gut (2024)

Background Transmembrane 6 superfamily member 2 (TM6SF2) has a protective role against metabolic dysfunction-associated steatotic liver disease (MASLD). Objective We aim to investigate the mechanistic role and therapeutic potential of hepatic TM6SF2 in MASLD-related hepatocellular carcinoma (HCC). Design Hepatocyte-specific Tm6sf2 knockout ( Tm6sf2 ∆hep ) mice were fed with high-fat/high-cholesterol (HFHC) diet or diethylnitrosamine plus HFHC diet to induce MASLD-HCC. TM6SF2 function was also evaluated in orthotopic MASLD-HCC mice. Human MASLD-HCC specimens were included to evaluate clinical significance. Results TM6SF2 was downregulated in tumours compared with adjacent normal tissues from MASLD-HCC patients. Hepatocyte-specific Tm6sf2 knockout exacerbated tumour formation in mice with diet-induced or diet-induced and carcinogen-induced MASLD-HCC. The tumour-promoting effect of Tm6sf2 knockout was verified in orthotopic MASLD-HCC mice, while mice bearing Tm6sf2 -overexpressing tumours had opposite phenotypes. We observed the reduction of interferon-gamma (IFN-γ) + CD8 + T cells in the tumours of Tm6sf2 ∆hep mice and orthotopic Tm6sf2 knockout mice, while the tumour-suppressive effect of Tm6sf2 was abolished after depleting CD8 + T cells. The correlation between TM6SF2 and CD8 + T cells was confirmed in human MASLD-HCC tissues, inferring that TM6SF2 could promote antitumour immunity. Mechanistically, TM6SF2 directly bound to IKKβ and inhibited NF-κB signalling pathway to reduce interleukin (IL)-6 secretion, thereby activating cytotoxic CD8 + T cells. IL-6 neutralisation abolished the tumour-promoting and immunosuppressive effects of Tm6sf2 knockout in mice. Moreover, introducing Tm6sf2 by adenovirus improved immunotherapy response against MASLD-HCC in mice. Conclusion Hepatic TM6SF2 protects against MASLD-HCC and activates cytotoxic CD8 + T cells via NF-κB-IL-6 axis. TM6SF2 is a promising strategy for sensitising MASLD-HCC to immunotherapy.
Early tumour necrosis factor antagonist treatment prevents perianal fistula development in children with Crohn’s disease: post hoc analysis of the RISK study
Authors: Jeremy Adler, Samir Gadepalli, Moshiur Rahman, Sandra Kim
Journal: Gut (2024)

One in three children with Crohn's disease develop perianal fistula complications (PFCs), among the most disturbing and difficult-to-treat disease-related complications. Retrospective evidence suggests PFCs may be preventable.
A deformable SIS/HA composite hydrogel coaxial scaffold promotes alveolar bone regeneration after tooth extraction
Authors: Shiqing Ma, Yumeng Li, Shiyu Yao, Yucheng Shang, Rui Li, Lijuan Ling, Wei Fu, Pengfei Wei, Bo Zhao, Xuesong Zhang, Jiayin Deng
Journal: Bioactive Materials (2024)
The Microbiota and Evolution of Obesity
Authors: Mario J A Saad, Andrey Santos
Journal: Endocrine Reviews (2024)

Abstract Obesity is a major global concern and is generally attributed to a combination of genetic and environmental factors. Several hypotheses have been proposed to explain the evolutionary origins of obesity epidemic, including thrifty and drifty genotypes, and changes in thermogenesis. Here, we put forward the hypothesis of metaflammation, which proposes that due to intense selection pressures exerted by environmental pathogens, specific genes that help develop a robust defense mechanism against infectious diseases have had evolutionary advantages and that this may contribute to obesity in modern times due to connections between the immune and energy storage systems. Indeed, incorporating the genetic variations of gut microbiota into the complex genetic framework of obesity makes it more polygenic than previously believed. Thus, uncovering the evolutionary origins of obesity requires a multifaceted approach that considers the complexity of human history, the unique genetic makeup of different populations, and the influence of gut microbiome on host genetics.
The rich evolutionary history of the Reactive Oxygen Species metabolic arsenal shapes its mechanistic plasticity at the onset of metazoan regeneration
Authors: Aurore Vullien, Aldine R Amiel, Loeiza Baduel, Dilara Diken, Cécile Renaud, Gabriel Krasovec, Michel Vervoort, Eric Röttinger, Eve Gazave
Journal: Molecular Biology and Evolution (2024)

Abstract Regeneration, the ability to restore body parts after injury, is widespread in metazoans; however, the underlying molecular and cellular mechanisms involved in this process remain largely unknown, and its evolutionary history is consequently unresolved. Recently, reactive oxygen species (ROS) have been shown in several metazoan models to be triggers of apoptosis and cell proliferation that drive regenerative success. However, it is not known whether the contribution of ROS to regeneration relies on conserved mechanisms. Here we performed a comparative genomic analysis of ROS metabolism actors across metazoans, and carried out a comparative study of the deployment and roles of ROS during regeneration in two different metazoan models: the annelid Platynereis dumerilii and the cnidarian Nematostella vectensis. We established that the vast majority of metazoans encode a core redox kit allowing for the production and detoxification of ROS, and overall regulation of ROS levels. However, the precise composition of the redox arsenal can vary significantly from species to species, suggesting that evolutionary constraints apply to ROS metabolism functions rather than precise actors. We found that while ROS are necessary for regeneration in both Platynereis and Nematostella, the two species deploy different enzymatic activities controlling ROS dynamics, and display distinct effects of ROS signaling on injury-induced apoptosis and cell proliferation. We conclude that, while ROS are a common feature of metazoan regeneration, their production and contribution to this phenomenon may depend on different molecular mechanisms highlighting the overall plasticity of the machinery.
Dupilumab as an Adjunct to Oral Immunotherapy in Pediatric Patients With Peanut Allergy
Authors: R. Sharon Chinthrajah, Sayantani B. Sindher, Kari C. Nadeau, Jeffrey G. Leflein, Jonathan M. Spergel, Daniel H. Petroni, Stacie M. Jones, Thomas B. Casale, Julie Wang, Warner W. Carr, Wayne G. Shreffler, Robert A. Wood, Erik Wambre, Jinzhong Liu, Bolanle Akinlade, Amanda Atanasio, Jamie M. Orengo, Jennifer D. Hamilton, Mohamed A. Kamal, Andrea T. Hooper, Kiran Patel, Elizabeth Laws, Leda P. Mannent, Daniel C. Adelman, Anoshie Ratnayake, Allen R. Radin
Journal: Allergy (2024)

Peanut allergy is a common, life-threatening food allergy in children. We evaluated whether dupilumab, which blocks the activity of interleukin (IL)-4/IL-13, enhances the efficacy of oral immunotherapy (OIT) AR101 in pediatric patients with peanut allergy.
Early Reduction of <scp>FeNO</scp> on Anti‐<scp>IL5</scp> Biologics Is Associated With Clinical Remission of Severe Asthma
Authors: Marianne Baastrup Soendergaard, Susanne Hansen, Kjell Erik Julius Håkansson, Anna von Bülow, Anne‐Sofie Bjerrum, Johannes Martin Schmid, Sofie Lock Johansson, Linda Makowska Rasmussen, Claus Rikard Johnsen, Barbara Bonnesen Bertelsen, Niels Steen Krogh, Ole Hilberg, Charlotte Suppli Ulrik, Celeste Porsbjerg
Journal: Allergy (2024)

In patients with severe asthma, treatment with anti-interleukin-5 (IL-5) biologics can lead to a reduction in fractional exhaled nitric oxide (FeNO) in some patients. The clinical implications of varying FeNO responses to anti-IL-5 biologics remain unclear. This study aims to categorise patients based on their FeNO response to anti-IL-5 biologics and evaluate the association of these categories with clinical outcomes.
Efficacy and Safety of Dupilumab in Children With Peanut Allergy: A Multicenter, Open‐Label, Phase <scp>II</scp> Study
Authors: Sayantani B. Sindher, Kari C. Nadeau, R. Sharon Chinthrajah, Jeffrey G. Leflein, Philippe Bégin, Jason A. Ohayon, Punita Ponda, Erik Wambre, Jinzhong Liu, Faisal A. Khokhar, Bolanle Akinlade, Jennifer Maloney, Jamie M. Orengo, Jennifer D. Hamilton, Mohamed A. Kamal, Andrea T. Hooper, Naimish Patel, Kiran Patel, Elizabeth Laws, Leda P. Mannent, Allen R. Radin
Journal: Allergy (2024)

ABSTRACT Background Peanut allergy is a potentially life‐threatening food allergy in children. This study explored whether dupilumab, a human monoclonal immunoglobulin (Ig)G4 antibody that blocks the activity of interleukin (IL)‐4/IL‐13, improved safety and desensitization to peanut exposure in children with peanut allergy. Methods A Phase II, 24‐week, multicenter, single‐arm, open‐label, proof‐of‐concept study was conducted in the USA and Canada (NCT03793608). Children/adolescents with peanut allergy received subcutaneous dupilumab 300 mg (≥ 60 kg) or 200 mg (≥ 20 to &lt; 60 kg) every 2 weeks. The primary endpoint was the proportion of participants who passed a double‐blind placebo‐controlled food challenge (DBPCFC) with ≥ 444 mg (cumulative) of peanut protein at week 24. Secondary endpoints included safety measures (Consortium of Food Allergy Research grading system) and change from baseline in peanut‐specific (ps)‐IgG4, total IgE, and ps‐IgE. Results Twenty‐four participants enrolled and received dupilumab: 75.0% were male, 79.2% were white, mean (standard deviation) age was 11.7 (3.3) years. Most (95.8%) participants had not received allergen immunotherapy. Two participants (8.3%) achieved the primary endpoint and passed the DBPCFC at week 24. Fifteen participants (62.5%) reported 66 treatment‐emergent adverse events, all being mild or in moderate intensity. At the week 24 DBPCFC, 8 participants (33.3%) had a grade 2 allergic reaction (no grade 3 or above); 10 (41.7%) used adrenaline as a rescue medication. Dupilumab treatment resulted in a median reduction of total and ps‐IgE of −54% and −49%, respectively, and a 0% change in ps‐IgG4. Conclusions Dupilumab monotherapy treatment for 24 weeks did not improve desensitization to peanut exposure after food challenge.
Genome‐Wide Association Study Reveals a Causal Relationship Between Allergic Rhinitis and Hazelnut Allergy
Authors: Yidan Sun, Judith M. Vonk, Elin T. G. Kersten, Cancan Qi, Aline B. Sprikkelman, Gerard H. Koppelman
Journal: Allergy (2024)

ABSTRACT Background Little is known about the genetics of food allergy (FA) to various allergens and the heterogeneity of FA in adults. Objective We aimed to investigate genetic susceptibility to FA in an adult population and to assess the association between secondary FA and allergic rhinitis (AR). Methods FA and allergen‐specific FA were defined based on in‐depth questionnaires and a previously published FA algorithm in the Lifelines. We performed a series of genome‐wide association studies (GWAS) on FA and nine allergen‐specific (e.g., hazelnut) FA in 21,353 adults in Lifelines. Single nucleotide polymorphisms (SNPs) ( p &lt; 1E‐5) were replicated in a second independent set of 15,518 adults participating in the Lifelines followed by meta‐analysis of the results of the two datasets. We subsequently investigated the causal relationship of AR to FA using Mendelian randomization (MR) analysis. Results We observed co‐occurrence of tree nuts and apple FA, with over 80% of this group also reporting AR. After meta‐analysis, we identified one genome‐wide significant locus near HLA‐DPA1 associated with self‐reported hazelnut allergy (hazelnutFA), of which the top SNP is rs5025825 ( p = 2.51E‐9, OR = 1.43). Two‐sample MR indicated that AR is a significant causal risk factor for hazelnutFA ( p ‐IVW = 5.27E‐10, β = 5.90, p ‐pleiotropy = 0.46). Conclusion Our questionnaire enabled a large GWAS on self‐reported FA in Dutch adults. We report one novel locus in the human leukocyte antigens (HLA) region associated with hazelnutFA, implying an association with antigen recognition. Our findings genetically link secondary FA to AR in adults.
Comparison of Double‐Blind and Open Food Challenges for the Diagnosis of Food Allergy in Childhood: The <scp>ALDORADO</scp> Study
Authors: Wouter W. de Weger, Aline. B. Sprikkelman, Catherina. E. M. Herpertz, Gerbrich N. van der Meulen, Judith. M. Vonk, Gerard. H. Koppelman, Arvid. W. A. Kamps
Journal: Allergy (2024)

ABSTRACT Background Double‐blind placebo‐controlled food challenge (DBPCFC) is widely regarded as the “gold standard” to diagnose food allergy. Maximum efforts are made to reduce bias, yet DBPCFCs are costly, time‐, and resource‐intensive. Less demanding open food challenges are increasingly used in clinical practice. However, recommendations regarding the use of these challenges are based on low certainty of evidence, and no comparative studies have been performed using the most recent international food challenge guidelines. We hypothesised that the open food challenge is non‐inferior to DBPCFC in children suspected of allergy to cashew nuts, hazelnuts or peanuts. Methods A total of 63 children, aged 4 years and older, were included if referred for suspected IgE‐mediated allergy to cashew nut, hazelnut, or peanut. All study participants underwent DBPCFC first, followed by an open food challenge for the same food. Challenge outcomes were assessed by predefined criteria into positive, negative, or inconclusive. Results DBPCFC and open food challenge outcomes were the same for 36/41 (87.8%) patients. Sensitivity and specificity of the open food challenge were 0.91 (95% CI 0.79, 1.03) and 0.83 (95% CI 0.63, 1.01), respectively, with an AUC value of 0.87. Eliciting and stop doses were not significantly different between both food challenges. Conclusion The Diagnostic accuracy of open food challenge is non‐inferior to that of DBPCFC. This finding implies less demanding open food challenges can be implemented for children from the age of 4 years suspected to be cashew nut, hazelnut, or peanut allergic. Further research is necessary to validate our findings and to investigate the diagnostic accuracy for other major food allergens.
T Cells Induce Prolonged Downregulation of Barrier Molecules in a Mouse Model of Allergic Contact Dermatitis
Authors: Helen Vaher, Anne‐Sofie Ø. Gadsbøll, Alexandra T. Seibel, Martin Kongsbak‐Wismann, Rebecca K. D. Lohmann, Veronika Mraz, Anders B. Funch, Mia H. Jee, Niels Ødum, Anders Woetmann, Carsten Geisler, Charlotte M. Bonefeld
Journal: Allergy (2024)

Dysfunction of the skin barrier is regarded as a key event in the initiation and progression of inflammatory skin diseases. In many cases of allergic contact dermatitis (ACD), epidermal-resident memory CD8
Tralokinumab Treatment in Adult Atopic Dermatitis Patients: 28‐Week Evaluation of Clinical Effectiveness, Safety, Serum Proteins and Total <scp>IgE</scp> Levels
Authors: Coco Dekkers, Nicolaas Zuithoff, Daphne Bakker, Edward Knol, Anne Wevers, Wouter Touwslager, Wianda Christoffers, Petra Prosje, Anneke van Lynden‐van Nes, Paula van Lümig, Marijke Kamsteeg, Albert Jan Oosting, Marie L. A. Schuttelaar, Inge Haeck, Marlies de Graaf, Femke van Wijk, Marjolein de Bruin‐Weller
Journal: Allergy (2024)

ABSTRACT Introduction and Objectives Tralokinumab—a biological that specifically targets interleukin‐13—is one of the newer advanced systemic treatments for patients with moderate‐to‐severe atopic dermatitis (AD). Although safety and efficacy have been shown in phase‐III clinical trials, daily practice data are needed. Therefore, the aim of this study was to evaluate 28‐week safety and effectiveness, serum proteins and total IgE levels in adult AD patients treated with tralokinumab in daily practice. Materials and Methods Data of all adult AD patients who started treatment with tralokinumab and participated in the BioDay registry were collected at baseline, and after 4,16 and 28 weeks of treatment. Clinical efficacy was evaluated by clinical outcome measures, such as the Eczema Area and Severity Index (EASI) as well as patient‐reported outcome measures, such as the numerical rating scale (NRS) for pruritus. Adverse events were evaluated. In a subgroup of patients, 18 proteins as well as total IgE levels were measured in serum. Results A total of 84 patients were included, of whom 39 were dupilumab‐naïve (D‐naïve) and 45 were dupilumab non‐naïve (D‐non‐naïve) patients. All primary outcomes significantly improved during 28 weeks of tralokinumab treatment and the probability of achieving EASI ≤ 7 and NRS‐pruritis ≤ 4 was 75.8% (56.9–88.2) and 51.4% (28.0–74.2), respectively. The disease severity‐associated proteins TARC/CCL17 and PARC/CCL18 decreased during treatment, and total IgE levels significantly decreased in the D‐naïve patients. The most reported adverse events were eye disorders ( n = 24, 28.6%). A total of 23 patients (27.4%) discontinued treatment due to adverse events and/or ineffectiveness, with hair loss being the most common adverse event leading to treatment discontinuation ( n = 6). Conclusion Tralokinumab is an effective treatment for moderate‐to‐severe AD in adult patients, in both dupilumab‐naïve patients and patients who previously failed on dupilumab treatment. The clinical effect is supported by the biological data.
Extracellular vesicles-based vaccines: Emerging immunotherapies against cancer
Authors: Yuhua Meng, Zhimeng Yao, Xiurong Ke, Mengyuan Hu, Hongzheng Ren, Shegan Gao, Hao Zhang
Journal: Journal of Controlled Release (2024)

Cancer vaccines are promising therapeutic approaches to enhance specific T-cell immunity against most solid tumors. By stimulating anti-tumor immunity, clearing minimal residual disease, and minimizing adverse effects, these vaccines target tumor cells and are effective when combined with immune checkpoint blockade or other immunotherapies. However, the development of tumor cell-based vaccines faces quality issues due to poor immunogenicity, tumor heterogeneity, a suppressive tumor immune microenvironment, and ineffective delivery methods. In contrast, extracellular vesicles (EVs), naturally released by cells, are considered the ideal drug carriers and vaccine platforms. EVs offer highly organ-specific targeting, induce broader and more effective immune responses, and demonstrate superior tissue delivery ability. The development of EV vaccines is crucial for advancing cancer immunotherapy. Compared to cell-based vaccines, EV vaccines produced under Good Manufacturing Practices (GMP) offer advantages such as high safety, ease of preservation and transport, and a wide range of sources. This review summarizes the latest research findings on EV vaccine and potential applications in this field. It also highlights novel neoantigens for the development of EV vaccines against cancer.
Grappling with the complexities of gender transition interruptions: Toward conceptual clarity on “detransitioning” experiences
Authors: N. Eugene Walls, Jarrod Call, Brendon T. Holloway, Tural Mammadli, Darren L. Whitfield
Journal: International Journal of Transgender Health (2024)

The existing literature on gender transition interruptions for transgender/nonbinary (TNB) people (what is frequently termed "detransitioning") lacks conceptual clarity and precision, resulting in conflictual findings, misinterpretations, and the weaponization of the literature to support harmful policies aimed at limiting TNB individuals' access to gender-affirming care. We conducted a review of the existing literature on gender transition interruptions and propose a conceptual framework to address the current weaknesses in the extant scholarship, provide better conceptual clarity, and offer suggestions for improving future research. The paper uses a conceptual review and critique of the extant research including scholarship on transition-related desistence, regret, and gender transition interruptions (i.e. "detransitions"). The lay understanding and, at times, the scholarly understanding of gender transition interruptions from the existing literature is most frequently collapsed under the idea of "detransitioning." This is true even though few studies actually examine the experiences of individuals who transition from TNB to the gender associated with the sex they were assigned at birth. There is significant conflation of findings about different types of transition interruption experiences with transition interruption experiences that encapsulate a true identity shift from transgender to cisgender. This conceptual slippage and misinterpretation is used politically to weaponize the existing scholarship. The paper proposes a conceptual framework of gender transition interruptions that outlines the conceptual nuances including identification of desistance, (6) subcategories of transition-related regret, (2) subcategories of adaptive gender transition interruptions, gender recalibration, embodiment goal attainment, other transition interruption, and gender identity recission. The proposed conceptual framework details the nuances in the various types of gender transition interruptions suggested, and utilizes the extant scholarship to justify the proposed framework.
Hypusination in intestinal epithelial cells protects mice from infectious colitis
Authors: Alain P. Gobert, Caroline V. Hawkins, Kamery J. Williams, Lydia A. Snyder, Daniel P. Barry, Mohammad Asim, Margaret M. Allaman, Kara M. McNamara, Alberto G. Delgado, Yu Wang, Shilin Zhao, Kristie L. Rose, M. Blanca Piazuelo, Keith T. Wilson
Journal: Gut Microbes (2024)

Enteropathogenic Escherichia coli (EPEC) is a bacterium that causes attaching/effacing (A/E) lesions and serious diarrheal disease, a major health issue in developing countries. EPEC pathogenicity results from the effect of virulence factors and dysregulation of host responses. Polyamines, including spermidine, play a major role in intestinal homeostasis. Spermidine is the substrate for deoxyhypusine synthase (DHPS), which catalyzes the conjugation of the amino acid hypusine to eukaryotic translation initiation factor 5A (EIF5A); hypusinated EIF5A (EIF5AHyp) binds specific mRNAs and initiates translation. Our aim was to determine the role of hypusination during infection with A/E pathogens. We found that DHPS and EIF5AHyp levels are induced in i) a colonic epithelial cell line and human-derived colon organoids infected with EPEC, and ii) the colon of mice infected with Citrobacter rodentium, the rodent equivalent of EPEC. Specific deletion of Dhps in intestinal epithelial cells worsened clinical, histological, and pro-inflammatory parameters in C. rodentium-infected mice. These animals also exhibited an exacerbated pathogenic transcriptome in their colon. Furthermore, infected mice with specific Dhps deletion exhibited reduced levels of proteins involved in detoxification of tissue-damaging reactive aldehydes and consequently increased electrophile adducts in the colon. Thus, hypusination in intestinal epithelial cells protects from infectious colitis mediated by A/E pathogens.