tbuckley/cabot-search huggingface dataset:
P98 Blood-based biomarkers of extracellular matrix turnover are elevated in patients with psoriasis compared with healthy controls
Journal: British Journal of Dermatology (2024)

Abstract The extracellular matrix (ECM) is a non-cellular network in all tissues and organs. Collagens are the most abundant proteins in the ECM, and their role is to maintain the tissue architecture of the different layers of the skin. Blood-based biomarkers of ECM fragments have previously been shown to be diagnostic and pharmacodynamic in psoriatic arthritis (PsA) and spondylarthritis. This study aimed to investigate whether ECM biomarkers can differentiate between patients with moderate-to-severe psoriasis (PSO) and healthy controls (HCs) and to determine the potential of ECM biomarkers as pharmacodynamic biomarkers in patients with PSO. This was a case–control study of patients with moderate-to-severe PSO, defined as psoriasis area and severity index (PASI) ≥8, not receiving systemic anti-psoriatic treatment at inclusion, and age-, sex- and body mass index-matched HCs. From each participant, EDTA plasma was collected at inclusion and 3–6 months after successful treatment response (defined as PASI ≤ 2 after treatment) with adalimumab. A panel of 11 ECM biomarkers was measured in EDTA plasma using validated ELISAs and Immunodiagnostic systems automated chemiluminescent assays. A P-value below 0.05 was considered statistically significant. The differences in biomarker levels between patients with PSO and HC were analysed using an unpaired t-test. The pharmacodynamic effect in patients with PSO with successful treatment response (PASI ≤ 2), was analysed using a paired t-test. Pearson correlation was used to detect any potential association between biomarkers and PASI severity. The study comprised 59 patients with PSO and 52 HC. The median PASI among patients with PSO was 10.0 (8.0–36.8), and 15% (9 patients) had physician-diagnosed PsA. We observed significantly elevated levels of PRO-C3, assessing tissue fibrosis (P = 0.028), and PRO-C4, assessing epidermal basement membrane turnover (P = 0.014), in patients with PSO compared with HC. No differences were observed in the remaining biomarker levels between patients with PSO and HC. Furthermore, no correlations were identified between PASI and biomarker levels. A significantly elevated level of ELP-3 (P = 0.024), indicative of neutrophil activity and elastin degradation, was observed in the nine patients with PSO having PsA compared with HC. Notably, the successful treatment of nine patients with PSO using adalimumab did not significantly change PRO-C3 and PRO-C4 levels. The results demonstrated that the levels of PRO-C3 and PRO-C4 were elevated in patients with PSO compared with HC. However, treatment of psoriasis did not modulate these biomarkers. Our findings underline the need for further research to explore the potential of ECM biomarkers in psoriasis.
Natural history of HPV16-E6 serology among cancer-free men in a multicenter longitudinal cohort study
Authors: Jaimie Z Shing, Anna R Giuliano, Nicole L Brenner, Birgitta Michels, Allan Hildesheim, Sudhir Srivastava, Bradley A Sirak, John Schussler, Danping Liu, Wendy Wang, Tim Waterboer, Aimée R Kreimer
Journal: JNCI Journal of the National Cancer Institute (2024)

Human papillomavirus (HPV)16-E6 seropositivity accurately predicts oropharyngeal squamous cell carcinoma (OPSCC) risk decades before diagnosis; but the biomarker's translational potential is unknown. To inform considerations for OPSCC screening, we described HPV16-E6 seroprevalence, predictors, and kinetics among cancer-free men.
HPV genotype-specific prevalence and infection risks: A 10-year population-based study from the United States
Authors: Cosette M Wheeler, Rachael Adcock, William C Hunt, Michael Robertson, Norah E Torrez-Martinez, Ruth McDonald, Emily Merchasin, Steven Jenison, Debbie Saslow, Nancy E Joste, Philip E Castle, Jane J Kim, Jack Cuzick
Journal: JNCI Journal of the National Cancer Institute (2024)

Various studies have reported on the impact of human papillomavirus (HPV) vaccines. Here we present the largest population-based investigation of genotype-specific distributions over the decade following implementation of the 4-valent HPV vaccine (HPV6/11/16/18) in the United States.
Long-term observation to determine durable efficacy and safety of novel paediatric atopic dermatitis treatment, nemolizumab
Authors: Soo Ick Cho, Jung-Im Na
Journal: British Journal of Dermatology (2024)

Journal Article Accepted manuscript Long-term observation to determine durable efficacy and safety of novel paediatric atopic dermatitis treatment, nemolizumab Get access Soo Ick Cho, Soo Ick Cho Lunit, Seoul, Republic of Korea https://orcid.org/0000-0003-3414-9869 Search for other works by this author on: Oxford Academic Google Scholar Jung-Im Na Jung-Im Na Department of Dermatology, Seoul National Univervisy College of Medicine, Seoul, Seoul National University Bundang Hospital, Seongnam, Republic of Korea Correspondence: Jung-Im Na, Email:[email protected] https://orcid.org/0000-0002-5717-2490 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, ljae479, https://doi.org/10.1093/bjd/ljae479 Published: 10 December 2024 Article history Received: 03 December 2024 Accepted: 09 December 2024 Published: 10 December 2024
Cardioprotective effect of 19,20-epoxydocosapentaenoic acid (19,20-EDP) in ischaemic injury involves direct activation of mitochondrial sirtuin 3
Authors: Ahmed M Darwesh, Liye Fang, Tariq R Altamimi, K Lockhart Jamieson, Wesam Bassiouni, Robert Valencia, Andy Huang, Faqi Wang, Hao Zhang, Marawan Ahmed, Keshav Gopal, Yongneng Zhang, Evangelos D Michelakis, John R Ussher, Matthew L Edin, Darryl C Zeldin, Khaled Barakat, Gavin Y Oudit, Zamaneh Kassiri, Gary D Lopaschuk, John M Seubert
Journal: Cardiovascular Research (2024)

Although current clinical therapies following myocardial infarction have improved patient outcomes, morbidity, and mortality rates secondary to ischemic and ischemia reperfusion (IR) injury remains high. Maintaining mitochondrial quality is essential to limit myocardial damage following cardiac ischemia and IR injury. The mitochondrial deacetylase sirtuin 3 (SIRT3) plays a pivotal role in regulating mitochondrial function and cardiac energy metabolism. In the current study, we hypothesize that 19,20-epoxydocosapentaenoic acid (19,20-EDP) attenuates cardiac IR injury via stimulating mitochondrial SIRT3.
Allogeneic hematopoietic stem cell transplantation in adult acute myeloid leukemia with t(16;21)(p11;q22)/FUS::ERG
Authors: Satoshi Mitsuyuki, Yoshimitsu Shimomura, Hiroki Mizumaki, Masamitsu Yanada, Shohei Mizuno, Naoyuki Uchida, Noriko Doki, Ayumu Ito, Masatsugu Tanaka, Tetsuya Nishida, Yuta Katayama, Satoshi Yoshihara, Tetsuya Eto, Satoru Takada, Shuichi Ota, Masako Toyosaki, Yuta Hasegawa, Hirohisa Nakamae, Koji Kawamura, Makoto Onizuka, Takahiro Fukuda, Marie Ohbiki, Yoshiko Atsuta, Takaaki Konuma
Journal: Leukemia (2024)
Differential long-term tamoxifen therapy benefit by menopausal status in breast cancer patients: secondary analysis of a controlled randomized clinical trial
Authors: Annelie Johansson, Huma Dar, Anna Nordenskjöld, Gizeh Perez-Tenorio, Nicholas P Tobin, Christina Yau, Christopher C Benz, Laura J Esserman, Laura J van ‘t Veer, Bo Nordenskjöld, Olle Stål, Tommy Fornander, Linda S Lindström
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract Background Estrogen receptor–positive breast cancer patients have a long-term risk of distant metastatic disease, and premenopausal patients have a higher risk. Randomized studies with long-term follow-up are essential to understand treatment benefit. We elucidated the long-term tamoxifen therapy benefit by menopausal status in the Stockholm tamoxifen trials with 20 years complete follow-up. Methods Secondary analysis of 1242 estrogen receptor–positive and HER2-negative patients that were randomly assigned to 2-5 years of 40 mg adjuvant tamoxifen or no endocrine therapy. Distant recurrence-free interval in tamoxifen-treated vs endocrine untreated patients was assessed by Kaplan–Meier, Cox proportional hazards regression, and time-varying analyses. Results In premenopausal patients, a statistically significant tamoxifen benefit was observed for lymph node–negative (adjusted hazard ratio [HR] = 0.46, 95% confidence interval [CI] = 0.24 to 0.87), progesterone receptor–positive (adjusted HR = 0.61, 95% CI = 0.41 to 0.91), and genomic low-risk tumors (adjusted HR = 0.47, 95% CI = 0.26 to 0.85) but only lasted beyond 10 years for genomic low-risk tumors. Postmenopausal patients showed long-term benefit for all good-prognosis markers including low-grade (adjusted HR = 0.55, 95% CI = 0.41 to 0.73), lymph node–negative (adjusted HR = 0.44, 95% CI = 0.30 to 0.64), progesterone receptor–positive (adjusted HR = 0.60, 95% CI = 0.44 to 0.80), Ki-67 low (adjusted HR = 0.51, 95% CI = 0.38 to 0.68), and genomic low-risk tumors (adjusted HR = 0.53, 95% CI = 0.37 to 0.74), and regardless of tumor size (≤20 mm: adjusted HR = 0.55, 95% CI = 0.39 to 0.77; &amp;gt;20 mm: adjusted HR = 0.64, 95% CI = 0.44 to 0.94). Premenopausal patients with no poor-prognosis tumor characteristics (clinical marker score = 0) showed early benefit and postmenopausal long-term benefit. Conclusions Our study suggests differential tamoxifen benefit by menopausal status. Improved long-term endocrine therapy prediction in premenopausal patients is needed and could involve molecular markers because standard tumor characteristics cannot predict benefit beyond 10 years.
Perturbation of mRNA splicing in liver cancer: insights, opportunities and challenges
Authors: Qi Jia, Xiaoxiao Sun, Haoyu Li, Jianglong Guo, Kongyan Niu, Kui Ming Chan, René Bernards, Wenxin Qin, Haojie Jin
Journal: Gut (2024)

Perturbation of mRNA splicing is commonly observed in human cancers and plays a role in various aspects of cancer hallmarks. Understanding the mechanisms and functions of alternative splicing (AS) not only enables us to explore the complex regulatory network involved in tumour initiation and progression but also reveals potential for RNA-based cancer treatment strategies. This review provides a comprehensive summary of the significance of AS in liver cancer, covering the regulatory mechanisms, cancer-related AS events, abnormal splicing regulators, as well as the interplay between AS and post-transcriptional and post-translational regulations. We present the current bioinformatic approaches and databases to detect and analyse AS in cancer, and discuss the implications and perspectives of AS in the treatment of liver cancer.
Understanding tissue injury and remodelling in eosinophilic oesophagitis: development towards personalised medicine
Authors: Giovanni Santacroce, Carlo Maria Rossi, Marco Vincenzo Lenti, Subrata Ghosh, Marietta Iacucci, Antonio Di Sabatino
Journal: Gut (2024)

Eosinophilic oesophagitis (EoE) is a chronic, immune-mediated condition characterised by eosinophilic infiltration of the oesophagus, leading to significant morbidity due to oesophageal dysfunction. The pathogenic course of EoE begins with tissue injury, marked by the intricate interplay of oesophageal barrier dysfunction and T helper 2-mediated inflammation. In response to tissue damage, a subsequent phase of tissue remodelling features a complex interaction between epithelial cells and stromal cells, aimed at tissue repair. The persistence of inflammation drives these mechanisms towards oesophageal fibrostenosis, mainly through the transforming growth factor-dependent, myofibroblast-driven accumulation of the extracellular matrix. Currently, treatment options for EoE are limited, with dietary intervention, proton pump inhibitors and oral steroids serving as first-line therapies. Dupilumab, an antiinterleukin (IL) 4/IL-13 agent, is the only biologic that has been approved by European and American regulatory authorities. However, emerging OMIC technologies significantly advance our understanding of EoE pathogenesis, revealing novel cellular and molecular mechanisms driving the disease. This progress has accelerated the identification of new therapeutic targets and agents, some already under clinical investigation, potentially expanding our therapeutic arsenal and paving the way for more personalised approaches. In this evolving landscape, artificial intelligence (AI) has shown great potential to further elaborate on the complexities of EoE heterogeneity, offering standardised tools for diagnosis, disease phenotyping, and prediction of treatment response. Though still in their early stages, integrating OMICs and AI marks a pivotal step towards precision medicine in EoE.
Protecting the most vulnerable: The urgent need to include HIV-exposed children in malaria chemoprevention strategies
Authors: Raquel González, Tacilta Nhampossa, Antía Figueroa-Romero, André-Marie Tchouatieu, Christine Manyando, Clara Menendez
Journal: PLoS Medicine (2024)

Raquel González and colleagues discuss the drugs available to HIV-exposed children to prevent malaria infection and the urgent need to evaluate alternative agents.
Immune checkpoint inhibitors and the liver: balancing therapeutic benefit and adverse events
Authors: Eleonora De Martin, Claudia A M Fulgenzi, Ciro Celsa, Astrid Laurent-Bellue, Aria Torkpour, Pasquale Lombardi, Antonio D'Alessio, David J Pinato
Journal: Gut (2024)

Immune checkpoint inhibitors (ICI) have led to breakthrough improvements in the management of malignancy including hepatocellular (HCC) and biliary tract cancer, improving decades-old standards of care and increasing patient survival. In both liver tumour types, which commonly arise in the context of liver inflammation and underlying functional impairment, the lack of validated predictors of response underscores the need to balance predicted gains in survival with risk of treatment-related hepatoxicity and decompensation of underlying chronic liver disease.In addition, the liver is implicated in the toxicity associated with ICI therapy for non-liver cancers, which exhibits a high degree of variability in presentation and severity. An accurate assessment is mandatory for the diagnosis and management of ICI-induced liver injury.In this Recent Advances article, we provide an overview of the mechanisms of efficacy and toxicity of anticancer immunotherapy in liver tumours and liver toxicity in extrahepatic malignancies.We compare and contrast characteristics, management strategies and outcomes from immune-related liver injury in patients with chronic hepatitis/cirrhosis or with an underlying healthy liver and discuss the latest findings on how toxicity and decompensation may impact the outlook of patients with liver tumours and extrahepatic malignancies offering insights into the future directions of clinical research and practice in the field.
Association between Locoregional Failure and <i>NFE2L2/KEAP1/CUL3 </i>Mutations in NRG/RTOG 9512: A Randomized Trial of Radiation Fractionation in T2N0 Glottic Cancer
Authors: Li Guan, Pedro A. Torres-Saavedra, Xiaobei Zhao, Michael B. Major, Brittany J. Holmes, Ngan K. Nguyen, Parasakthy Kumaravelu, Tim Hodge, Maximilian Diehn, Jose P. Zevallos, F. Christopher Holsinger, Bahman Emami, Richard C. Jordan, Michele C. Hayward, Stephen M. Sagar, William Morrison, Christopher Schultz, Jimmy J. Caudell, Christopher U. Jones, Scott V. Bratman, Thomas J. Galloway, Daniel J. Ma, Sue S. Yom, Mahesh Kudrimoti, Harold E. Kim, Jonathan Harris, Quynh-Thu Le, D. Neil. Hayes
Journal: Clinical Cancer Research (2024)

NFE2L2/KEAP1/CUL3 mutations have been validated for radiation resistance in cell-based assays and animal models. However, clinical validation of these biomarkers has been challenging due to multimodality treatment regimens. This study aims to investigate the association between NFE2L2/KEAP1/CUL3 mutations and patient outcomes, including local failure (LF), locoregional failures (LRF), disease-free survival (DFS) and overall survival (OS), using samples from a phase III trial in which patients were treated with radiation monotherapy at 2 controlled doses.
Association of sleep disturbance and itch intensity with quality of life impairment and disease severity in prurigo nodularis
Authors: Weiying Lu, Selina M Yossef, Emily Z Ma, Jaya Manjunath, Yagiz M Akiska, Alexander L Kollhoff, Shawn G Kwatra
Journal: British Journal of Dermatology (2024)

In this study, we explored the relationship between itch intensity, sleep disturbance, and quality of life (QoL) impairment in patients with prurigo nodularis (PN). Using validated assessment tools, we found significant correlations between self-reported itch severity, objective disease measures, and their impact on sleep and QoL. These findings highlight the profound burden of PN on patients' daily lives and the importance of addressing both itch and sleep disturbances in managing this condition.
Debulking Influenza and Herpes Simplex virus strains by a wide-spectrum anti-viral protein formulated in clinical grade chewing gum.
Authors: Henry Daniell, Yuwei Guo, Rahul Singh, Uddhab Karki, Rachel J Kulchar, Geetanjali Wakade, Juha-Matti Pihlava, Hamid Khazaei, Gary H Cohen
Journal: Molecular Therapy (2024)

Lack of Herpes Simplex Virus (HSV) vaccine, low vaccination rates of Influenza viruses, waning immunity and viral transmission after vaccination underscore the need to reduce viral loads at their transmission sites. Oral virus transmission is several orders of magnitude higher than nasal transmission. Therefore, in this study, we evaluated neutralization of viruses using a natural viral trap protein (FRIL) formulated in clinical-grade chewing gum. FRIL is highly stable in the lablab bean powder (683 days) and in chewing gum (790 days), and fully functional (794 days) when stored at ambient temperature. They passed the bioburden test with no aerobic bacteria, yeasts/molds, with minimal moisture content (1.28–5.9%). Bean gum extracts trapped HSV-1/HSV-2 75–94% in a dose-dependent manner through virus self-aggregation. Mastication simulator released >50% release of FRIL within 15 min of chewing the bean gum. In plaque reduction assays, >95% neutralization of H1N1 and H3N2 required ∼40 mg/mL, HSV-1 160 mg/mL, and HSV-2 74 mg/mL of bean gum for 1,000 copies/mL virus particles. Therefore, a 2000 mg bean gum tablet has more than adequate potency for clinical evaluation and is safe with no detectable levels of glycosides. These observations augur well for evaluating bean gum in human clinical studies to minimize virus infection/transmission.Graphical abstract
Tubular FoxP2 and Kidney Fibrosis
Authors: Yixin Zou, Wai Han Yiu, Sarah W.Y. Lok, Jingyuan Ma, Yuchen Feng, Kar Neng Lai, Sydney C.W. Tang
Journal: Journal of the American Society of Nephrology (2024)

Background Kidney fibrosis is the final common pathway of progressive chronic kidney disease (CKD) that leads to kidney failure, for which there are limited therapeutic strategies. The transcription factor, Forkhead box P2 (Foxp2), has been implicated in organ development and tumorigenesis through its association with the epithelial-to-mesenchymal transition (EMT) process. In this study, we uncovered a novel role of Foxp2 in kidney fibrosis. Methods Human kidney biopsies were used to assess Foxp2 expression. Tubule-specific Foxp2 knockout mice were generated through LoxP-Cre transgenic manipulation and applied to murine models progressive CKD, including unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion injury (UIRI). Cultured kidney tubular epithelial cells were used to analyse the underlying cellular mechanisms. Results Foxp2 expression was markedly increased in the tubular nuclei of human kidney biopsies of CKD from patients with IgA nephropathy, membranous nephropathy and diabetic nephropathy. In murine unilateral ureteral obstruction and unilateral ischemic-reperfusion models that recapitulate progressive CKD, tubule-specific deletion of Foxp2 attenuated kidney inflammation and tubulointerstitial fibrosis, accompanied by reduction in cell cycle arrest. In mouse tubular epithelial cells, TGF-β upregulated Foxp2 expression via Smad3 signaling while knockdown of Foxp2 suppressed TGF-β-induced epithelial-to-mesenchymal transition and accumulation of extracellular matrix proteins. Mechanistically, overexpression of Foxp2 inhibited tubular cell proliferation with induction of G2/M cell cycle arrest. Using chromatin-immunoprecipitation sequencing, we identified Foxp2 target genes that are enriched in PI3K/Akt and TGF-β signaling pathways, and further revealed that Foxp2 directly regulated the transcriptional activities of collagen-1, E-cadherin and p21 that are involved in epithelial-to-mesenchymal transition and cell cycle arrest, thereby promoting the profibrotic process. Conclusions Our findings demonstrate a novel role of Foxp2 in promoting kidney fibrosis in murine UUO and UIRI by activating epithelial-to-mesenchymal transition and cell cycle arrest in kidney tubules, contributing to the progression of CKD.
The Win Ratio for Composite Outcomes in Nephrology Clinical Trials
Authors: João Pedro Ferreira, Faiez Zannad
Journal: Journal of the American Society of Nephrology (2024)

1Université de Lorraine, INSERM, Centre d'Investigations Cliniques Plurithématique 1433, Inserm U1116, CHRU de Nancy and F-CRIN INI-CRCT, Nancy, France 2Cardiovascular Research and Development Center (UnIC@RISE), Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal & Heart Failure Clinic, Internal Medicine Department, Centro Hospital de Gaia/Espinho, Vila Nova de Gaia, Portugal. aCorresponding author: Prof. Faiez Zannad, [email protected]
C2230, a preferential use- and state-dependent CaV2.2 channel blocker, mitigates pain behaviors across multiple pain models
Authors: Cheng Tang, Kimberly Gomez, Yan Chen, Heather N. Allen, Sara Hestehave, Erick J. Rodríguez-Palma, Santiago Loya-Lopez, Aida Calderon-Rivera, Paz Duran, Tyler S. Nelson, Siva Rama Raju Kanumuri, Bijal Shah, Nihar R. Panigrahi, Samantha Perez-Miller, Morgan K. Schackmuth, Shivani Ruparel, Amol Patwardhan, Theodore J. Price, Paramjit S. Arora, Ravindra K. Sharma, Abhisheak Sharma, Jie Yu, Olga A. Korczeniewska, Rajesh Khanna
Journal: Journal of Clinical Investigation (2024)

Antagonists (e.g., Ziconotide, Gabapentin) of the CaV2.2 (N-type) calcium channels are used clinically as analgesics for chronic pain. However, their use is limited by narrow therapeutic windows, difficult dosing routes (Ziconotide), misuse and overdoses (Gabapentin), as well as a litany of adverse effects. Expansion of novel pain therapeutics may emerge from mechanism-based interrogation of CaV2.2. Here we report the identification of C2230, an aryloxy-hydroxypropylamine, as a CaV2.2 blocker. C2230 trapped and stabilized inactivated CaV2.2 in a slow-recovering state and accelerated the open-state inactivation of the channel, conferring an advantageous use-dependent inhibition profile. C2230 inhibited CaV2.2 during high-frequency stimulation, while sparing other voltage-gated ion channels. C2230 inhibited CaV2.2 in dorsal root and trigeminal ganglia neurons from rats, marmosets, and humans in a G-protein-coupled receptor-independent manner. Further, C2230 reduced evoked excitatory postsynaptic currents and excitatory neurotransmitter release in the spinal cord, leading to relief of neuropathic, orofacial, and osteoarthritic pain-like behaviors via three different routes of administration. C2230 also decreased fiber photometry-based calcium responses in the parabrachial nucleus, mitigated aversive behavioral responses to mechanical stimuli after neuropathic injury, and preserved protective pain responses, all without affecting motor or cardiovascular function. Finally, site-directed mutation analysis demonstrated that C2230 binds differently than other known CaV2.2 blockers, making it a promising lead compound for analgesic development.