tbuckley/cabot-search huggingface dataset:
SGLT2 Inhibitor Dapagliflozin Increases Skeletal Muscle and Brain Fatty Acid Uptake in Individuals With Type 2 Diabetes: A Randomized Double-Blind Placebo-Controlled Positron Emission Tomography Study
Authors: Aino Latva-Rasku, Eleni Rebelos, Jouni Tuisku, Richard Aarnio, Achol Bhowmik, Helmi Keskinen, Sanna Laurila, Minna Lahesmaa-Hatting, Laura Pekkarinen, Henrik Isackson, Anna K. Kirjavainen, Jukka Koffert, Kerstin Heurling, Lauri Nummenmaa, Ele Ferrannini, Jonas Oldgren, Jan Oscarsson, Pirjo Nuutila
Journal: Diabetes Care (2024)

OBJECTIVE The aim of this study was to investigate the impact of the sodium–glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin on tissue fatty acid (FA) uptake in the skeletal muscle, brain, small intestine, and subcutaneous and visceral adipose tissue of individuals with type 2 diabetes by using positron emission tomography (PET). RESEARCH DESIGN AND METHODS In a 6-week randomized double-blind placebo-controlled trial, 53 patients with type 2 diabetes treated with metformin received either 10 mg dapagliflozin or placebo daily. Tissue FA uptake was quantified at baseline and end of treatment with PET and the long-chain FA analog radiotracer 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid. Treatment effects were assessed using ANCOVA, and the results are reported as least square means and 95% CIs for the difference between groups. RESULTS A total of 38 patients (dapagliflozin n = 21; placebo n = 17) completed the study. After 6 weeks, skeletal muscle FA uptake was increased by dapagliflozin compared with placebo (1.0 [0.07, 2.0] μmol ⋅ 100 g−1 ⋅ min−1; P = 0.032), whereas uptake was not significantly changed in the small intestine or visceral or subcutaneous adipose tissue. Dapagliflozin treatment significantly increased whole-brain FA uptake (0.10 [0.02, 0.17] μmol ⋅ 100 g−1 ⋅ min−1; P = 0.01), an effect observed in both gray and white matter regions. CONCLUSIONS Six weeks of treatment with dapagliflozin increases skeletal muscle and brain FA uptake, partly driven by a rise in free FA availability. This finding is in accordance with previous indirect measurements showing enhanced FA metabolism in response to SGLT2 inhibition and extends the notion of a shift toward increased FA use to muscle and brain.
The Renin-Angiotensin-Aldosterone System Regulates Sarcoidosis Granulomatous Inflammation
Authors: Elliott D. Crouser, Mark W Julian, Landon W. Locke, Sabahattin Bicer, Jonah R. Mitchell, Arindam Singha, Patrick J. Kramer, Murugesan Rajaram, Subha V. Raman
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Sarcoidosis is a granulomatous disorder of unclear cause notable for abnormal elevation of blood and tissue ACE1 (angiotensin converting enzyme 1) levels and activity. ACE1 regulates the renin-angiotensin-aldosterone system (RAAS), the terminal product of which is aldosterone, which selectively engages mineralocorticoid receptors to promote inflammation.
Apalutamide and Goserelin for Androgen Receptor-Positive Salivary Gland Carcinoma: A Phase 2 Nonrandomized Clinical Trial, YATAGARASU
Authors: Yoshitaka Honma, Nobuya Monden, Keisuke Yamazaki, Satoshi Kano, Hironaga Satake, Shigenori Kadowaki, Yoshitaka Utsumi, Tomohiko Nakatogawa, Ryo Takano, Koji Fujii, Yosuke Koroki, Junya Aoyama, Shohei Ouchi, Tetsuro Ogawa, Sharon McCarthy, Sabine D. Brookman-May, Suneel Mundle, Jinhui Li, Daksh Thaper, Toshitaka Nagao, Yuichiro Tada
Journal: Clinical Cancer Research (2024)

To assess the efficacy and safety of apalutamide plus goserelin for androgen receptor (AR)-positive unresectable or recurrent/metastatic salivary gland carcinoma.
Suicide-related internet use among mental health patients who died by suicide in the UK: a national clinical survey with case–control analysis
Authors: Lana Bojanić, Pauline Turnbull, Saied Ibrahim, Sandra Flynn, Navneet Kapur, Louis Appleby, Isabelle M Hunt
Journal: The Lancet Regional Health - Europe (2024)

Suicide-related internet use (SRIU) has been shown to be linked to suicide. However, there is limited research on SRIU among mental health patients, who are at 4 to 7 times increased risk of suicide compared to the general population. This study aims to address this gap by exploring the prevalence of SRIU among mental health patients who died by suicide in the UK and describing their characteristics.
Childhood Air Pollution Exposure Associated with Self-Reported Bronchitic Symptoms in Adulthood
Authors: Erika Garcia, Zoe H. Birnhak, Scott West, Steve Howland, Frederick Lurmann, Nathan R. Pavlovic, Rob McConnell, Shohreh F. Farzan, Theresa M Bastain, Rima Habre, Carrie V Breton
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Few studies have examined the effects of long-term childhood air pollution exposure on adult respiratory health, including whether childhood respiratory effects underlie this relation.
A Phase I/II Study of Valemetostat (DS-3201b), an EZH1/2 Inhibitor, in Combination with Irinotecan in Patients with Recurrent Small-Cell Lung Cancer
Authors: Noura J. Choudhury, W. Victoria Lai, Alex Makhnin, Glenn Heller, Juliana Eng, Bob Li, Isabel Preeshagul, Fernando C. Santini, Michael Offin, Kenneth Ng, Paul Paik, Christina Larsen, Michelle S. Ginsberg, Yvonne Lau, Xinyuan Zhang, Marina K. Baine, Natasha Rekhtman, Charles M. Rudin
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Recurrent small-cell lung cancer (SCLC) has few effective treatments. The EZH2-SLFN11 pathway is a driver of acquired chemoresistance that may be targeted. Patients and Methods: This phase I/II trial investigated valemetostat, an EZH1/2 inhibitor, with fixed-dose irinotecan in patients with recurrent SCLC. Phase I primary objectives were to assess safety, tolerability, and a recommended phase II dose (RP2D). The phase II primary objective was overall response rate (ORR), with secondary objectives of determining duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Correlative analyses included immunohistochemistry of pretreatment and on-treatment tumor biopsies and pharmacokinetics analysis. Results: Twenty-two patients were enrolled (phase I, n = 12; phase II, n = 10); one withdrew consent prior to treatment. Three dose-limiting toxicities (DLT) in dose-escalation resulted in valemetostat 100 mg orally daily selected as RP2D. Among 21 evaluable patients, the most frequent (≥20%) treatment-related adverse events were diarrhea, fatigue, nausea, and rash; three patients discontinued treatment for toxicity. Three of the first 10 patients in phase II experienced DLTs triggering a stopping rule. The ORR was 4/19 or 21% [95% confidence interval (CI), 6%–46%]. The median DoR, PFS, and OS were 4.6 months, 2.2 months (95% CI, 1.3–7.6 months), and 6.6 months (95% CI, 4.3 to not reached), respectively. SLFN11/EZH2 expression and SCLC subtyping markers did not correlate with response, but MHC-I expression did increase with treatment. Two responders demonstrated subtype switching on treatment. Conclusions: Combination valemetostat and irinotecan was not tolerated but demonstrated efficacy in recurrent SCLC. Valemetostat, combined with agents without overlapping toxicity, warrants further investigation in SCLC.
Washed microbiota transplantation promotes homing of group 3 innate lymphoid cells to the liver via the CXCL16/CXCR6 axis: a potential treatment for metabolic-associated fatty liver disease
Authors: Hao-Jie Zhong, Yu-Pei Zhuang, Xinqiang Xie, Jia-Yin Song, Si-Qi Wang, Lei Wu, Yong-Qiang Zhan, Qingping Wu, Xing-Xiang He
Journal: Gut Microbes (2024)

Despite the observed decrease in liver fat associated with metabolic-associated fatty liver disease (MAFLD) in mice following fecal microbiota transplantation, the clinical effects and underlying mechanisms of washed microbiota transplantation (WMT), a refined method of fecal microbiota transplantation, for the treatment of MAFLD remain unclear. In this study, both patients and mice with MAFLD exhibit an altered gut microbiota composition. WMT increases the levels of beneficial bacteria, decreases the abundance of pathogenic bacteria, and reduces hepatic steatosis in MAFLD-affected patients and mice. Downregulation of the liver-homing chemokine receptor CXCR6 on ILC3s results in an atypical distribution of ILC3s in patients and mice with MAFLD, characterized by a significant reduction in ILC3s in the liver and an increase in ILC3s outside the liver. Moreover, disease severity is negatively correlated with the proportion of hepatic ILC3s. These hepatic ILC3s demonstrate a mitigating effect on hepatic steatosis through the release of IL-22. Mechanistically, WMT upregulates CXCR6 expression on ILC3s, thereby facilitating their migration to the liver of MAFLD mice via the CXCL16/CXCR6 axis, ultimately contributing to the amelioration of MAFLD. Overall, these findings highlight that WMT and targeting of liver-homing ILC3s could be promising strategies for the treatment of MAFLD.
Lipid droplet accumulation mediates macrophage survival and Treg recruitment via the CCL20/CCR6 axis in human hepatocellular carcinoma
Authors: Yongchun Wang, Weibai Chen, Shuang Qiao, Hao Zou, Xing-juan Yu, Yanyan Yang, Zhixiong Li, Junfeng Wang, Min-shan Chen, Jing Xu, Limin Zheng
Journal: Cellular and Molecular Immunology (2024)
BAG6 restricts pancreatic cancer progression by suppressing the release of IL33-presenting extracellular vesicles and the activation of mast cells
Authors: Bilal Alashkar Alhamwe, Viviane Ponath, Fahd Alhamdan, Bastian Dörsam, Clara Landwehr, Manuel Linder, Kim Pauck, Sarah Miethe, Holger Garn, Florian Finkernagel, Anna Brichkina, Matthias Lauth, Dinesh Kumar Tiwari, Malte Buchholz, Daniel Bachurski, Sabrina Elmshäuser, Andrea Nist, Thorsten Stiewe, Lisa Pogge von Strandmann, Witold Szymański, Vanessa Beutgen, Johannes Graumann, Julia Teply-Szymanski, Corinna Keber, Carsten Denkert, Ralf Jacob, Christian Preußer, Elke Pogge von Strandmann
Journal: Cellular and Molecular Immunology (2024)

Recent studies reveal a critical role of tumor cell-released extracellular vesicles (EVs) in pancreatic cancer (PC) progression. However, driver genes that direct EV function, the EV-recipient cells, and their cellular response to EV uptake remain to be identified. Therefore, we studied the role of Bcl-2-associated-anthanogene 6 (BAG6), a regulator of EV biogenesis for cancer progression. We used a Cre recombinase/LoxP-based reporter system in combination with single-cell RNA sequencing to monitor in vivo EV uptake and tumor microenvironment (TME) changes in mouse models for pancreatic ductal adenocarcinoma (PDAC) in a Bag6 pro- or deficient background. In vivo data were validated using mouse and human organoids and patient samples. Our data demonstrated that Bag6-deficient subcutaneous and orthotopic PDAC tumors accelerated tumor growth dependent on EV release. Mechanistically, this was attributed to mast cell (MC) activation via EV-associated IL33. Activated MCs promoted tumor cell proliferation and altered the composition of the TME affecting fibroblast polarization and immune cell infiltration. Tumor cell proliferation and fibroblast polarization were mediated via the MC secretome containing high levels of PDGF and CD73. Patients with high BAG6 gene expression and high protein plasma level have a longer overall survival indicating clinical relevance. The current study revealed a so far unknown tumor-suppressing activity of BAG6 in PDAC. Bag6-deficiency allowed the release of EV-associated IL33 which modulate the TME via MC activation promoting aggressive tumor growth. MC depletion using imatinib diminished tumor growth providing a scientific rationale to consider imatinib for patients stratified with low BAG6 expression and high MC infiltration. EVs derived from BAG6-deficient pancreatic cancer cells induce MC activation via IL33/Il1rl1. The secretome of activated MCs induces tumor proliferation and changes in the TME, particularly shifting fibroblasts into an inflammatory cancer-associated fibroblast (iCAF) phenotype. Blocking EVs or depleting MCs restricts tumor growth.
P088 Physician-assessed effectiveness, patient-reported outcomes, and safety in adult and adolescent patients with atopic dermatitis treated with dupilumab: real-world insights 1 year into the GLOBOSTAD multinational prospective observational study
Authors: Silvia M Ferrucci, Piergiacomo Calzavara-Pinton, Dédée F Murrell, Anne-Claire Fougerousse, Iva Karlová, Hilde Lapeere, Gregor Holzer, Mona Al-Ahmad, Chia-Yu Chu, Caterina Foti, Bibiana Pérez-García, Anastasia Petrova, Jiangming Wu, Marius Ardeleanu, Kwinten Bosman
Journal: British Journal of Dermatology (2024)

Abstract Real-world studies complement randomized controlled trials (RCTs) by providing data from a more heterogeneous population treated in a normal practice environment. In several RCTs, dupilumab has demonstrated robust efficacy with acceptable safety in patients with moderate-to-severe atopic dermatitis (AD). The main objectives of the ongoing GLOBOSTAD study (NCT03992417) are characterizing the patient population treated with dupilumab, their AD treatment patterns, long-term effectiveness, and safety of dupilumab in the real world. The GLOBOSTAD 5-year, multinational, prospective, observational study enrolled patients aged ≥ 12 years with moderate-to-severe AD. Patients received dupilumab based on country-specific prescribing information, and assessments were performed at baseline, 3 months (± 1 month), 6 months (± 2 months) and 12 months (± 2 months). The data are reported as observed for the enrolment/safety (n = 955; data cutoff March 2023) and follow-up (n = 903) populations. In total, 758, 863 and 705 patients completed at least one follow-up assessment at 3, 6 and 12 months, respectively, with a mean (SD) treatment period of 11.7 (1.2) months. The mean (SD) Eczema Area and Severity Index (EASI; &amp;gt; 21 = severe; ≤ 7 = mild/no disease) at baseline was 25.1 (12.8). During the study, ≥ 75% (EASI 75) and ≥ 90% (EASI 90) reductions in mean EASI scores from baseline were observed in 66.2% and 35.6% of patients at 3 months, 74.6% and 42.4% at 6 months, and 81.0% and 55.8% at the end of the observation period (12 months), respectively. The patient-reported mean (SD) weekly average pruritus numerical rating scale (NRS, range 0–10) at baseline was 6.3 (2.2). A three-point and four-point improvement from baseline or a score of 0 in pruritus NRS was observed in 66.9% and 57.1% of patients at 3 months, 73.6% and 64.1% at 6 months, and 79.0% and 70.3% at 12 months, respectively. Of the follow-up population, 67.4% achieved an absolute pruritus NRS score of ≤ 3 at 3 months, 76.4% at 6 months, and 80.3% at 12 months. Adverse events considered related to dupilumab that led to permanent discontinuation occurred in 2.4% of patients. Patients enrolled in the GLOBOSTAD study achieved rapid improvements in AD signs and symptoms on initiating dupilumab treatment, which were sustained until the end of the 1-year observation period. Safety was consistent with the known dupilumab safety profile. This research was sponsored by Sanofi and Regeneron Pharmaceuticals Inc.
P055 A randomized single-blinded prospective study to compare simulated daylight photodynamic therapy with natural daylight photodynamic therapy for the treatment of multiple actinic keratoses
Authors: Ciara Drumm, Imelda Morgan, Ann Kavanagh, Danielle Gill, Julia Buckley, Matthew Reade, Eamon Loughman, Jackie McCavana, Aisling Ryan, Blaithin Moriarty, Aoife Lally
Journal: British Journal of Dermatology (2024)

Abstract Actinic keratoses (AKs) are considered precursor lesions of cutaneous squamous cell carcinoma, with a reported conversion rate of 3–16%. Photodynamic therapy (PDT) is a widely approved therapy for AKs. Conventional PDT (c-PDT) using red light is limited by pain and a small treatment field. Daylight PDT (d-PDT), an approved alternative, is limited by geographical location and weather conditions. Simulated daylight PDT (sd-PDT) with light-emitting diode (LED) light sources is now commercially available due to robust evidence that these devices are effective, but the devices are limited by cost (∼€30 000). We hypothesized that sd-PDT with a 4000 K white-light LED floodlight, costing €961, is equally as effective and well tolerated as d-PDT in the treatment of AKs across treatment fields of up to 55 cm2 on the scalp. Twenty-two men with a mean age of 74.5 years (SD 7.0) and multiple scalp AKs were enrolled in this prospective, randomized, single-blinded study, which employed a split-scalp design to compare the effectiveness and adverse events of d-PDT and sd-PDT. Block randomization was used to determine which side of the scalp would be treated with d-PDT. Each patient received four treatments in total, two d-PDT and two sd-PDT, each a week apart. The AKs were counted, graded, mapped and photographed at baseline, at blinded 1- and 3-month reviews and at unblinded 6-, 9- and 12-month reviews. The primary endpoint was mean lesion-specific clearance, defined as the mean number and percentage of cleared AKs per treatment field at 3 months. At baseline, the mean (SD) number of AKs per field was 44 (17.4) for the d-PDT group and 45.5 (17.8) for the sd-PDT group (P = 0.4). The mean lesion-specific clearance (percentage reduction) in AKs per field was 35.3 (71.5%) for d-PDT and 35.0 (75.1%) for sd-PDT at 1 month (P &amp;gt; 0.99), 33.6 (66.4%) for d-PDT and 30.3 (61.6%) for sd-PDT at 3 months (P = 0.6). Both d-PDT and sd-PDT were effective, with a significant reduction in AKs from baseline at 1 and 3 months (P &amp;lt; 0.01). Pain was reported by 15 patients with d-PDT and 12 with sd-PDT (median maximum score out of 100, 3.5 vs. 4.5; P = 0.6). Erythema was observed in 17 after d-PDT and 15 after sd-PDT. On a scale of 0 (intolerable) to 10 (very tolerable), patients rated d-PDT as 10 and sd-PDT as 9.8 (P = 0.08). We conclude that sd-PDT with a 4000 K white-light LED floodlight is equally as effective and well tolerated as d-PDT and is an affordable treatment option not limited by pain, small treatment field, geographical location or weather conditions.
PD13 A UK single-centre prospective audit and clinical experience of developing an ultraviolet B phototherapy service using 308-nm excimer pulsed light for inflammatory skin disease
Authors: Haya Mohammed, Victoria Vilenchik, Alexandra Banner, Daniel Keith
Journal: British Journal of Dermatology (2024)

Abstract Phototherapy is commonly recognized as a convenient treatment modality for inflammatory skin diseases (ISDs). It has seen significant technological advancements over the last 2 decades. With variable success, high running costs and demand for trained professionals, treatment outcomes in ISDs using cabinet phototherapy are limited. Due to its high efficacy and safety profile, 308-nm excimer pulsed light (EPL) represents an exciting and practical option in moderate-to-severe ISDs that are treatment resistant and difficult to reach, where only affected areas are targeted and overall fewer patient visits are required for clearance than with conventional phototherapy. A prospective single-centre cohort study was conducted on 36 patients with ISDs treated with EPL, including psoriasis (n = 14), palmoplantar pustular psoriasis (n = 6), vitiligo (n = 2), necrobiosis lipoidica (n = 3), vitiligo (n = 2) and dermatosis (n = 9). The number of sessions required ranged from 4 to 18, with a maximum fluence between 250 and 850 mJ cm−2 among patients. The primary outcome involved assessing lesions post-EPL treatment using Physician’s Global Assessment (PGA) scores including ‘much better’, ‘better’, ‘no difference’ or ‘worsened’. Secondary outcomes included occurrence of complications and comparison of Dermatology Life Quality Index (DLQI) scores before and after EPL. At the end of each completed EPL treatment course, lasting an average of six sessions in total, and requiring an average maximum fluence of 350 mJ cm−2, 72% (n = 26) of patients achieved clearance and were found to have ‘much better’ or ‘better’ lesion outcomes when reviewing PGA scores. A significant reduction in post-EPL DLQI in 28% (n = 10) of patients was also found, with an average score reduction by 4. No complications were reported in 94% of patients (n = 34), with minor post-EPL burn found in 6% of patients (n = 2) but high overall patient satisfaction. In conclusion, our study contributes further supporting evidence to the scarce dermatological literature surrounding the successful use of EPL as a powerful treatment modality in inflammatory skin disease, especially if recalcitrant. Large studies including randomized controlled trials are necessary to help validate these promising results and determine optimal dosing regimens, long-term efficacy and patient satisfaction.
PD11 Simultaneous development of photosensitivity in a father and daughter: <i>de novo</i> or exposure induced?
Authors: Hannah Ross, Donna Parkin, Jean Ayer
Journal: British Journal of Dermatology (2024)

Abstract Chronic actinic dermatitis and photoaggravated eczema are rare photosensitivity disorders that, while considered to be immunologically mediated, usually develop de novo. A 4-year-old White British girl and her 33-year-old White British father presented to a tertiary photobiology clinic with similar photodistributed eruptions that occurred acutely following exposure to an airborne glyphosate organophosphate-containing weedkiller. The eruptions persisted thereafter on exposure to sunlight. Approximately 15 min of sun exposure is sufficient to provoke a red, scaly and blistering eruption around 6–12 h later. The eruption affects only photoexposed sites, including the posterior neck, elbows, dorsal hands and cheeks, and episodes persist for several days. The father underwent monochromated light testing to narrowband widths of ultraviolet (UV)B, UVA and visible radiation and demonstrated exquisite photosensitivity. Provocation testing to broadband UVA and a solar simulator were abandoned after the first exposure due to a significant erythemal and oedematous response. The daughter underwent modified monochromator testing due to her age, but similarly demonstrated significant photosensitivity with reduced thresholds from 300 to 370 nm. Reduced-dose provocation with broadband UVA and a solar simulator resulted in a mild, blotchy, papular erythema. Several months later, both father and daughter reported worsening of their photosensitivity. Repeat photoinvestigation carried out 15 months following the initial exposure to the glyphosate, suspected to be the precipitant, showed an objective deterioration in photosensitivity in both patients, resulting in formal diagnoses of chronic actinic dermatitis. Reports of phototoxicity after contact with glyphosate formulations are exceedingly rare. However, there is a report of the preservative coformulant benzothiazolinone (BIT), found in glyphosate formulations, that was confirmed to be phototoxic through exposure of the skin for 24 h followed by UVA exposure (Hindson C, Diffey B. Phototoxicity of glyphosate in a weedkiller. Contact Dermatitis 1984; 10: 51–2.) The reported papulovesicular eruption that followed BIT and UVA exposure is in keeping with the eruption seen in our patients. However, photopatch testing to BIT was negative in both patients. There are no other reports in the literature of photosensitization following organophosphate exposure with prolonged and worsening effects 15 months after exposure. Therefore could it be possible that two de novo cases have occurred in one family at exactly the same time, or could the initial phototoxic reaction have triggered an immune response that has subsequently caused the development of chronic actinic dermatitis?
Nosocomial outbreak caused by disinfectant-resistant Serratia marcescens in an adult intensive care unit, Hungary, February to March 2022
Authors: Adrienn Hanczvikkel, Ákos Tóth, Irén Anna Kopcsóné Németh, Orsolya Bazsó, Lőrinc Závorszky, Lilla Buzgó, Virág Lesinszki, Dániel Göbhardter, Erika Ungvári, Ivelina Damjanova, Attila Erőss, Ágnes Hajdu
Journal: Eurosurveillance (2024)

In 2022, an outbreak with severe bloodstream infections caused by